WorldWideScience

Sample records for relevant signaling pathways

  1. M2 macrophages activate WNT signaling pathway in epithelial cells: relevance in ulcerative colitis.

    Directory of Open Access Journals (Sweden)

    Jesús Cosín-Roger

    Full Text Available Macrophages, which exhibit great plasticity, are important components of the inflamed tissue and constitute an essential element of regenerative responses. Epithelial Wnt signalling is involved in mechanisms of proliferation and differentiation and expression of Wnt ligands by macrophages has been reported. We aim to determine whether the macrophage phenotype determines the expression of Wnt ligands, the influence of the macrophage phenotype in epithelial activation of Wnt signalling and the relevance of this pathway in ulcerative colitis. Human monocyte-derived macrophages and U937-derived macrophages were polarized towards M1 or M2 phenotypes and the expression of Wnt1 and Wnt3a was analyzed by qPCR. The effects of macrophages and the role of Wnt1 were analyzed on the expression of β-catenin, Tcf-4, c-Myc and markers of cell differentiation in a co-culture system with Caco-2 cells. Immunohistochemical staining of CD68, CD206, CD86, Wnt1, β-catenin and c-Myc were evaluated in the damaged and non-damaged mucosa of patients with UC. We also determined the mRNA expression of Lgr5 and c-Myc by qPCR and protein levels of β-catenin by western blot. Results show that M2, and no M1, activated the Wnt signaling pathway in co-culture epithelial cells through Wnt1 which impaired enterocyte differentiation. A significant increase in the number of CD206+ macrophages was observed in the damaged mucosa of chronic vs newly diagnosed patients. CD206 immunostaining co-localized with Wnt1 in the mucosa and these cells were associated with activation of canonical Wnt signalling pathway in epithelial cells and diminution of alkaline phosphatase activity. Our results show that M2 macrophages, and not M1, activate Wnt signalling pathways and decrease enterocyte differentiation in co-cultured epithelial cells. In the mucosa of UC patients, M2 macrophages increase with chronicity and are associated with activation of epithelial Wnt signalling and diminution in

  2. Cell volume homeostatic mechanisms: effectors and signalling pathways

    DEFF Research Database (Denmark)

    Hoffmann, E K; Pedersen, Stine Helene Falsig

    2011-01-01

    . Later work addressed the mechanisms through which cellular signalling pathways regulate the volume regulatory effectors or flux pathways. These studies were facilitated by the molecular identification of most of the relevant channels and transporters, and more recently also by the increased...

  3. Interaction Dynamics Determine Signaling and Output Pathway Responses

    Directory of Open Access Journals (Sweden)

    Klement Stojanovski

    2017-04-01

    Full Text Available The understanding of interaction dynamics in signaling pathways can shed light on pathway architecture and provide insights into targets for intervention. Here, we explored the relevance of kinetic rate constants of a key upstream osmosensor in the yeast high-osmolarity glycerol-mitogen-activated protein kinase (HOG-MAPK pathway to signaling output responses. We created mutant pairs of the Sln1-Ypd1 complex interface that caused major compensating changes in the association (kon and dissociation (koff rate constants (kinetic perturbations but only moderate changes in the overall complex affinity (Kd. Yeast cells carrying a Sln1-Ypd1 mutant pair with moderate increases in kon and koff displayed a lower threshold of HOG pathway activation than wild-type cells. Mutants with higher kon and koff rates gave rise to higher basal signaling and gene expression but impaired osmoadaptation. Thus, the kon and koff rates of the components in the Sln1 osmosensor determine proper signaling dynamics and osmoadaptation.

  4. The Fog signaling pathway: Insights into signaling in morphogenesis

    Science.gov (United States)

    Manning, Alyssa J.; Rogers, Stephen L.

    2014-01-01

    Epithelia form the building blocks of many tissue and organ types. Epithelial cells often form a contiguous 2-dimensional sheet that is held together by strong adhesions. The mechanical properties conferred by these adhesions allow the cells to undergo dramatic three-dimensional morphogenetic movements while maintaining cell–cell contacts during embryogenesis and post-embryonic development. The Drosophila Folded gastrulation pathway triggers epithelial cell shape changes that drive gastrulation and tissue folding and is one of the most extensively studied examples of epithelial morphogenesis. This pathway has yielded key insights into the signaling mechanisms and cellular machinery involved in epithelial remodeling. In this review, we discuss principles of morphogenesis and signaling that have been discovered through genetic and cell biological examination of this pathway. We also consider various regulatory mechanisms and the system's relevance to mammalian development. We propose future directions that will continue to broaden our knowledge of morphogenesis across taxa. PMID:25127992

  5. Non-Smad signaling pathways.

    Science.gov (United States)

    Mu, Yabing; Gudey, Shyam Kumar; Landström, Maréne

    2012-01-01

    Transforming growth factor-beta (TGFβ) is a key regulator of cell fate during embryogenesis and has also emerged as a potent driver of the epithelial-mesenchymal transition during tumor progression. TGFβ signals are transduced by transmembrane type I and type II serine/threonine kinase receptors (TβRI and TβRII, respectively). The activated TβR complex phosphorylates Smad2 and Smad3, converting them into transcriptional regulators that complex with Smad4. TGFβ also uses non-Smad signaling pathways such as the p38 and Jun N-terminal kinase (JNK) mitogen-activated protein kinase (MAPK) pathways to convey its signals. Ubiquitin ligase tumor necrosis factor (TNF)-receptor-associated factor 6 (TRAF6) and TGFβ-associated kinase 1 (TAK1) have recently been shown to be crucial for the activation of the p38 and JNK MAPK pathways. Other TGFβ-induced non-Smad signaling pathways include the phosphoinositide 3-kinase-Akt-mTOR pathway, the small GTPases Rho, Rac, and Cdc42, and the Ras-Erk-MAPK pathway. Signals induced by TGFβ are tightly regulated and specified by post-translational modifications of the signaling components, since they dictate the subcellular localization, activity, and duration of the signal. In this review, we discuss recent findings in the field of TGFβ-induced responses by non-Smad signaling pathways.

  6. DMPD: Signal integration between IFNgamma and TLR signalling pathways in macrophages. [Dynamic Macrophage Pathway CSML Database

    Lifescience Database Archive (English)

    Full Text Available 16920490 Signal integration between IFNgamma and TLR signalling pathways in macroph...tml) (.csml) Show Signal integration between IFNgamma and TLR signalling pathways in macrophages. PubmedID 16920490 Title Signal inte...gration between IFNgamma and TLR signalling pathways in

  7. A G Protein-biased Designer G Protein-coupled Receptor Useful for Studying the Physiological Relevance of Gq/11-dependent Signaling Pathways.

    Science.gov (United States)

    Hu, Jianxin; Stern, Matthew; Gimenez, Luis E; Wanka, Lizzy; Zhu, Lu; Rossi, Mario; Meister, Jaroslawna; Inoue, Asuka; Beck-Sickinger, Annette G; Gurevich, Vsevolod V; Wess, Jürgen

    2016-04-08

    Designerreceptorsexclusivelyactivated by adesignerdrug (DREADDs) are clozapine-N-oxide-sensitive designer G protein-coupled receptors (GPCRs) that have emerged as powerful novel chemogenetic tools to study the physiological relevance of GPCR signaling pathways in specific cell types or tissues. Like endogenous GPCRs, clozapine-N-oxide-activated DREADDs do not only activate heterotrimeric G proteins but can also trigger β-arrestin-dependent (G protein-independent) signaling. To dissect the relative physiological relevance of G protein-mediatedversusβ-arrestin-mediated signaling in different cell types or physiological processes, the availability of G protein- and β-arrestin-biased DREADDs would be highly desirable. In this study, we report the development of a mutationally modified version of a non-biased DREADD derived from the M3muscarinic receptor that can activate Gq/11with high efficacy but lacks the ability to interact with β-arrestins. We also demonstrate that this novel DREADD is activein vivoand that cell type-selective expression of this new designer receptor can provide novel insights into the physiological roles of G protein (Gq/11)-dependentversusβ-arrestin-dependent signaling in hepatocytes. Thus, this novel Gq/11-biased DREADD represents a powerful new tool to study the physiological relevance of Gq/11-dependent signaling in distinct tissues and cell types, in the absence of β-arrestin-mediated cellular effects. Such studies should guide the development of novel classes of functionally biased ligands that show high efficacy in various pathophysiological conditions but display a reduced incidence of side effects. © 2016 by The American Society for Biochemistry and Molecular Biology, Inc.

  8. Purinergic signaling pathways in endocrine system.

    Science.gov (United States)

    Bjelobaba, Ivana; Janjic, Marija M; Stojilkovic, Stanko S

    2015-09-01

    Adenosine-5'-triphosphate is released by neuroendocrine, endocrine, and other cell types and acts as an extracellular agonist for ligand-gated P2X cationic channels and G protein-coupled P2Y receptors in numerous organs and tissues, including the endocrine system. The breakdown of ATP by ectonucleotidases not only terminates its extracellular messenger functions, but also provides a pathway for the generation of two additional agonists: adenosine 5'-diphosphate, acting via some P2Y receptors, and adenosine, a native agonist for G protein-coupled adenosine receptors, also expressed in the endocrine system. This article provides a review of purinergic signaling pathways in the hypothalamic magnocellular neurosecretory cells and neurohypophysis, hypothalamic parvocellular neuroendocrine system, adenohypophysis, and effector glands organized in five axes: hypothalamic-pituitary-gonadal, hypothalamic-pituitary-thyroid, hypothalamic-pituitary-adrenal, hypothalamic-pituitary-growth hormone, and hypothalamic-pituitary-prolactin. We attempted to summarize current knowledge of purinergic receptor subtypes expressed in the endocrine system, including their roles in intracellular signaling, hormone secretion, and other cell functions. We also briefly review the release mechanism for adenosine-5'-triphosphate by neuroendocrine, endocrine and surrounding cells, the enzymes involved in adenosine-5'-triphosphate hydrolysis to adenosine-5'-diphosphate and adenosine, and the relevance of this pathway for sequential activation of receptors and termination of signaling. Published by Elsevier B.V.

  9. Purinergic Signaling Pathways in Endocrine System

    Science.gov (United States)

    Bjelobaba, Ivana; Janjic, Marija M.; Stojilkovic, Stanko S.

    2015-01-01

    Adenosine-5′-triphosphate is released by neuroendocrine, endocrine, and other cell types and acts as an extracellular agonist for ligand-gated P2X cationic channels and G protein-coupled P2Y receptors in numerous organs and tissues, including the endocrine system. The breakdown of ATP by ectonucleotidases not only terminates its extracellular messenger functions, but also provides a pathway for the generation of two additional agonists: adenosine 5′-diphosphate, acting via some P2Y receptors, and adenosine, a native agonist for G protein-coupled adenosine receptors, also expressed in the endocrine system. This article provides a review of purinergic signaling pathways in the hypothalamic magnocellular neurosecretory cells and neurohypophysis, hypothalamic parvocellular neuroendocrine system, adenohypophysis, and effector glands organized in five axes: hypothalamic-pituitary-gonadal, hypothalamic-pituitary-thyroid, hypothalamic-pituitary-adrenal, hypothalamic-pituitary-growth hormone, and hypothalamic-pituitary-prolactin. We attempted to summarize current knowledge of purinergic receptor subtypes expressed in the endocrine system, including their roles in intracellular signaling, hormone secretion, and other cell functions. We also briefly review the release mechanism for adenosine-5′-triphosphate by neuroendocrine, endocrine and surrounding cells, the enzymes involved in adenosine-5′-triphosphate hydrolysis to adenosine-5′-diphosphate and adenosine, and the relevance of this pathway for sequential activation of receptors and termination of signaling. PMID:25960051

  10. Hyphae-specific genes HGC1, ALS3, HWP1, and ECE1 and relevant signaling pathways in Candida albicans.

    Science.gov (United States)

    Fan, Yan; He, Hong; Dong, Yan; Pan, Hengbiao

    2013-12-01

    Fungal virulence mechanisms include adhesion to epithelia, morphogenesis, production of secretory hydrolytic enzymes, and phenotype switching, all of which contribute to the process of pathogenesis. A striking feature of the biology of Candida albicans is its ability to grow in yeast, pseudohyphal, and hyphal forms. The hyphal form plays an important role in causing disease, by invading epithelial cells and causing tissue damage. In this review, we illustrate some of the main hyphae-specific genes, namely HGC1, UME6, ALS3, HWP1, and ECE1, and their relevant and reversed signal transduction pathways in reactions stimulated by environmental factors, including pH, CO2, and serum.

  11. Retroactive signaling in short signaling pathways.

    Directory of Open Access Journals (Sweden)

    Jacques-Alexandre Sepulchre

    Full Text Available In biochemical signaling pathways without explicit feedback connections, the core signal transduction is usually described as a one-way communication, going from upstream to downstream in a feedforward chain or network of covalent modification cycles. In this paper we explore the possibility of a new type of signaling called retroactive signaling, offered by the recently demonstrated property of retroactivity in signaling cascades. The possibility of retroactive signaling is analysed in the simplest case of the stationary states of a bicyclic cascade of signaling cycles. In this case, we work out the conditions for which variables of the upstream cycle are affected by a change of the total amount of protein in the downstream cycle, or by a variation of the phosphatase deactivating the same protein. Particularly, we predict the characteristic ranges of the downstream protein, or of the downstream phosphatase, for which a retroactive effect can be observed on the upstream cycle variables. Next, we extend the possibility of retroactive signaling in short but nonlinear signaling pathways involving a few covalent modification cycles.

  12. Modularized TGFbeta-Smad Signaling Pathway

    Science.gov (United States)

    Li, Yongfeng; Wang, M.; Carra, C.; Cucinotta, F. A.

    2011-01-01

    The Transforming Growth Factor beta (TGFbeta) signaling pathway is a prominent regulatory signaling pathway controlling various important cellular processes. It can be induced by several factors, including ionizing radiation. It is regulated by Smads in a negative feedback loop through promoting increases in the regulatory Smads in the cell nucleus, and subsequent expression of inhibitory Smad, Smad7 to form a ubiquitin ligase with Smurf targeting active TGF receptors for degradation. In this work, we proposed a mathematical model to study the radiation-induced Smad-regulated TGF signaling pathway. By modularization, we are able to analyze each module (subsystem) and recover the nonlinear dynamics of the entire network system. Meanwhile the excitability, a common feature observed in the biological systems, along the TGF signaling pathway is discussed by mathematical analysis and numerical simulation.

  13. Aberrant Signaling Pathways in Glioma

    International Nuclear Information System (INIS)

    Nakada, Mitsutoshi; Kita, Daisuke; Watanabe, Takuya; Hayashi, Yutaka; Teng, Lei; Pyko, Ilya V.; Hamada, Jun-Ichiro

    2011-01-01

    Glioblastoma multiforme (GBM), a WHO grade IV malignant glioma, is the most common and lethal primary brain tumor in adults; few treatments are available. Median survival rates range from 12–15 months. The biological characteristics of this tumor are exemplified by prominent proliferation, active invasiveness, and rich angiogenesis. This is mainly due to highly deregulated signaling pathways in the tumor. Studies of these signaling pathways have greatly increased our understanding of the biology and clinical behavior of GBM. An integrated view of signal transduction will provide a more useful approach in designing novel therapies for this devastating disease. In this review, we summarize the current understanding of GBM signaling pathways with a focus on potential molecular targets for anti-signaling molecular therapies

  14. Modularized Smad-regulated TGFβ signaling pathway.

    Science.gov (United States)

    Li, Yongfeng; Wang, Minli; Carra, Claudio; Cucinotta, Francis A

    2012-12-01

    The transforming Growth Factor β (TGFβ) signaling pathway is a prominent regulatory signaling pathway controlling various important cellular processes. TGFβ signaling can be induced by several factors including ionizing radiation. The pathway is regulated in a negative feedback loop through promoting the nuclear import of the regulatory Smads and a subsequent expression of inhibitory Smad7, that forms ubiquitin ligase with Smurf2, targeting active TGFβ receptors for degradation. In this work, we proposed a mathematical model to study the Smad-regulated TGFβ signaling pathway. By modularization, we are able to analyze mathematically each component subsystem and recover the nonlinear dynamics of the entire network system. Meanwhile the excitability, a common feature observed in the biological systems, in the TGFβ signaling pathway is discussed and supported as well by numerical simulation, indicating the robustness of the model. Published by Elsevier Inc.

  15. DMPD: Signaling pathways activated by microorganisms. [Dynamic Macrophage Pathway CSML Database

    Lifescience Database Archive (English)

    Full Text Available 17303405 Signaling pathways activated by microorganisms. Takeuchi O, Akira S. Curr ...Opin Cell Biol. 2007 Apr;19(2):185-91. Epub 2007 Feb 15. (.png) (.svg) (.html) (.csml) Show Signaling pathways activated by microorg...anisms. PubmedID 17303405 Title Signaling pathways activated by microorganisms. Auth

  16. DMPD: When signaling pathways collide: positive and negative regulation of toll-likereceptor signal transduction. [Dynamic Macrophage Pathway CSML Database

    Lifescience Database Archive (English)

    Full Text Available 18631453 When signaling pathways collide: positive and negative regulation of toll-...uction. PubmedID 18631453 Title When signaling pathways collide: positive and neg...l) Show When signaling pathways collide: positive and negative regulation of toll-likereceptor signal transd...likereceptor signal transduction. O'Neill LA. Immunity. 2008 Jul 18;29(1):12-20. (.png) (.svg) (.html) (.csm

  17. Pan-cancer analysis of TCGA data reveals notable signaling pathways

    International Nuclear Information System (INIS)

    Neapolitan, Richard; Horvath, Curt M.; Jiang, Xia

    2015-01-01

    A signal transduction pathway (STP) is a network of intercellular information flow initiated when extracellular signaling molecules bind to cell-surface receptors. Many aberrant STPs have been associated with various cancers. To develop optimal treatments for cancer patients, it is important to discover which STPs are implicated in a cancer or cancer-subtype. The Cancer Genome Atlas (TCGA) makes available gene expression level data on cases and controls in ten different types of cancer including breast cancer, colon adenocarcinoma, glioblastoma, kidney renal papillary cell carcinoma, low grade glioma, lung adenocarcinoma, lung squamous cell carcinoma, ovarian carcinoma, rectum adenocarcinoma, and uterine corpus endometriod carcinoma. Signaling Pathway Impact Analysis (SPIA) is a software package that analyzes gene expression data to identify whether a pathway is relevant in a given condition. We present the results of a study that uses SPIA to investigate all 157 signaling pathways in the KEGG PATHWAY database. We analyzed each of the ten cancer types mentioned above separately, and we perform a pan-cancer analysis by grouping the data for all the cancer types. In each analysis several pathways were found to be markedly more significant than all the other pathways. We call them notable. Research has already established a connection between many of these pathways and the corresponding cancer type. However, some of our discovered pathways appear to be new findings. Altogether there were 37 notable findings in the separate analyses, 26 of them occurred in 7 pathways. These 7 pathways included the 4 notable pathways discovered in the pan-cancer analysis. So, our results suggest that these 7 pathways account for much of the mechanisms of cancer. Furthermore, by looking at the overlap among pathways, we identified possible regions on the pathways where the aberrant activity is occurring. We obtained 37 notable findings concerning 18 pathways. Some of them appear to be

  18. TSLP signaling pathway map: a platform for analysis of TSLP-mediated signaling.

    Science.gov (United States)

    Zhong, Jun; Sharma, Jyoti; Raju, Rajesh; Palapetta, Shyam Mohan; Prasad, T S Keshava; Huang, Tai-Chung; Yoda, Akinori; Tyner, Jeffrey W; van Bodegom, Diederik; Weinstock, David M; Ziegler, Steven F; Pandey, Akhilesh

    2014-01-01

    Thymic stromal lymphopoietin (TSLP) is a four-helix bundle cytokine that plays a critical role in the regulation of immune responses and in the differentiation of hematopoietic cells. TSLP signals through a heterodimeric receptor complex consisting of an interleukin-7 receptor α chain and a unique TSLP receptor (TSLPR) [also known as cytokine receptor-like factor 2 (CRLF2)]. Cellular targets of TSLP include dendritic cells, B cells, mast cells, regulatory T (Treg) cells and CD4+ and CD8+ T cells. The TSLP/TSLPR axis can activate multiple signaling transduction pathways including the JAK/STAT pathway and the PI-3 kinase pathway. Aberrant TSLP/TSLPR signaling has been associated with a variety of human diseases including asthma, atopic dermatitis, nasal polyposis, inflammatory bowel disease, eosinophilic eosophagitis and, most recently, acute lymphoblastic leukemia. A centralized resource of the TSLP signaling pathway cataloging signaling events is not yet available. In this study, we present a literature-annotated resource of reactions in the TSLP signaling pathway. This pathway map is publicly available through NetPath (http://www.netpath.org/), an open access signal transduction pathway resource developed previously by our group. This map includes 236 molecules and 252 reactions that are involved in TSLP/TSLPR signaling pathway. We expect that the TSLP signaling pathway map will provide a rich resource to study the biology of this important cytokine as well as to identify novel therapeutic targets for diseases associated with dysregulated TSLP/TSLPR signaling. Database URL: http://www.netpath.org/pathways?path_id=NetPath_24.

  19. Interleukins and their signaling pathways in the Reactome biological pathway database.

    Science.gov (United States)

    Jupe, Steve; Ray, Keith; Roca, Corina Duenas; Varusai, Thawfeek; Shamovsky, Veronica; Stein, Lincoln; D'Eustachio, Peter; Hermjakob, Henning

    2018-04-01

    much molecular detail as possible and are linked to literature citations that contain supporting experimental details. All newly created events undergo a peer-review process before they are added to the database and made available on the associated Web site. New content is added quarterly. The 63rd release of Reactome in December 2017 contains 10,996 human proteins participating in 11,426 events in 2,179 pathways. In addition, analytic tools allow data set submission for the identification and visualization of pathway enrichment and representation of expression profiles as an overlay on Reactome pathways. Protein-protein and compound-protein interactions from several sources, including custom user data sets, can be added to extend pathways. Pathway diagrams and analytic result displays can be downloaded as editable images, human-readable reports, and files in several standard formats that are suitable for computational reuse. Reactome content is available programmatically through a REpresentational State Transfer (REST)-based content service and as a Neo4J graph database. Signaling pathways for IL-1 to IL-38 are hierarchically classified within the pathway "signaling by interleukins." The classification used is largely derived from Akdis et al. The addition to Reactome of a complete set of the known human interleukins, their receptors, and established signaling pathways linked to annotations of relevant aspects of immune function provides a significant computationally accessible resource of information about this important family. This information can be extended easily as new discoveries become accepted as the consensus in the field. A key aim for the future is to increase coverage of gene expression changes induced by interleukin signaling. Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.

  20. Aberrant Signaling Pathways in T-Cell Acute Lymphoblastic Leukemia

    Science.gov (United States)

    Bongiovanni, Deborah; Saccomani, Valentina

    2017-01-01

    T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive disease caused by the malignant transformation of immature progenitors primed towards T-cell development. Clinically, T-ALL patients present with diffuse infiltration of the bone marrow by immature T-cell blasts high blood cell counts, mediastinal involvement, and diffusion to the central nervous system. In the past decade, the genomic landscape of T-ALL has been the target of intense research. The identification of specific genomic alterations has contributed to identify strong oncogenic drivers and signaling pathways regulating leukemia growth. Notwithstanding, T-ALL patients are still treated with high-dose multiagent chemotherapy, potentially exposing these patients to considerable acute and long-term side effects. This review summarizes recent advances in our understanding of the signaling pathways relevant for the pathogenesis of T-ALL and the opportunities offered for targeted therapy. PMID:28872614

  1. DMPD: Regulation of mitochondrial antiviral signaling pathways. [Dynamic Macrophage Pathway CSML Database

    Lifescience Database Archive (English)

    Full Text Available 18549796 Regulation of mitochondrial antiviral signaling pathways. Moore CB, Ting J...P. Immunity. 2008 Jun;28(6):735-9. (.png) (.svg) (.html) (.csml) Show Regulation of mitochondrial antiviral ...signaling pathways. PubmedID 18549796 Title Regulation of mitochondrial antiviral signaling pathways. Author

  2. Probing the canonicity of the Wnt/Wingless signaling pathway.

    Directory of Open Access Journals (Sweden)

    Alexandra Franz

    2017-04-01

    Full Text Available The hallmark of canonical Wnt signaling is the transcriptional induction of Wnt target genes by the beta-catenin/TCF complex. Several studies have proposed alternative interaction partners for beta-catenin or TCF, but the relevance of potential bifurcations in the distal Wnt pathway remains unclear. Here we study on a genome-wide scale the requirement for Armadillo (Arm, Drosophila beta-catenin and Pangolin (Pan, Drosophila TCF in the Wnt/Wingless(Wg-induced transcriptional response of Drosophila Kc cells. Using somatic genetics, we demonstrate that both Arm and Pan are absolutely required for mediating activation and repression of target genes. Furthermore, by means of STARR-sequencing we identified Wnt/Wg-responsive enhancer elements and found that all responsive enhancers depend on Pan. Together, our results confirm the dogma of canonical Wnt/Wg signaling and argue against the existence of distal pathway branches in this system.

  3. ERβ induces the differentiation of cultured osteoblasts by both Wnt/β-catenin signaling pathway and estrogen signaling pathways

    Energy Technology Data Exchange (ETDEWEB)

    Yin, Xinhua [Department of Spine Surgery, Xiangya Hospital of Central South University, Changsha (China); Wang, Xiaoyuan [Department of Nephrology, Xi An Honghui Hospital, Xi an (China); Hu, Xiongke; Chen, Yong; Zeng, Kefeng [Department of Spine Surgery, Xiangya Hospital of Central South University, Changsha (China); Zhang, Hongqi, E-mail: zhq9699@126.com [Department of Spine Surgery, Xiangya Hospital of Central South University, Changsha (China)

    2015-07-01

    Although 17β-estradial (E2) is known to stimulate bone formation, the underlying mechanisms are not fully understood. Recent studies have implicated the Wnt/β-catenin pathway as a major signaling cascade in bone biology. The interactions between Wnt/β-catenin signaling pathway and estrogen signaling pathways have been reported in many tissues. In this study, E2 significantly increased the expression of β-catenin by inducing phosphorylations of GSK3β at serine 9. ERβ siRNAs were transfected into MC3T3-E1 cells and revealed that ERβ involved E2-induced osteoblasts proliferation and differentiation via Wnt/β-catenin signaling. The osteoblast differentiation genes (BGP, ALP and OPN) and proliferation related gene (cyclin D1) expression were significantly induced by E2-mediated ERβ. Furthermore immunofluorescence and immunoprecipitation analysis demonstrated that E2 induced the accumulation of β-catenin protein in the nucleus which leads to interaction with T-cell-specific transcription factor/lymphoid enhancer binding factor (TCF/LEF) transcription factors. Taken together, these findings suggest that E2 promotes osteoblastic proliferation and differentiation by inducing proliferation-related and differentiation-related gene expression via ERβ/GSK-3β-dependent Wnt/β-catenin signaling pathway. Our findings provide novel insights into the mechanisms of action of E2 in osteoblastogenesis. - Highlights: • 17β-estradial (E2) promotes GSK3-β phosphorylation. • E2 activates the Wnt/β-catenin signaling pathway. • The Wnt/β-catenin signaling pathway interacts with estrogen signaling pathways. • E2-mediated ER induced osteoblast differentiation and proliferation related genes expression.

  4. ERβ induces the differentiation of cultured osteoblasts by both Wnt/β-catenin signaling pathway and estrogen signaling pathways

    International Nuclear Information System (INIS)

    Yin, Xinhua; Wang, Xiaoyuan; Hu, Xiongke; Chen, Yong; Zeng, Kefeng; Zhang, Hongqi

    2015-01-01

    Although 17β-estradial (E2) is known to stimulate bone formation, the underlying mechanisms are not fully understood. Recent studies have implicated the Wnt/β-catenin pathway as a major signaling cascade in bone biology. The interactions between Wnt/β-catenin signaling pathway and estrogen signaling pathways have been reported in many tissues. In this study, E2 significantly increased the expression of β-catenin by inducing phosphorylations of GSK3β at serine 9. ERβ siRNAs were transfected into MC3T3-E1 cells and revealed that ERβ involved E2-induced osteoblasts proliferation and differentiation via Wnt/β-catenin signaling. The osteoblast differentiation genes (BGP, ALP and OPN) and proliferation related gene (cyclin D1) expression were significantly induced by E2-mediated ERβ. Furthermore immunofluorescence and immunoprecipitation analysis demonstrated that E2 induced the accumulation of β-catenin protein in the nucleus which leads to interaction with T-cell-specific transcription factor/lymphoid enhancer binding factor (TCF/LEF) transcription factors. Taken together, these findings suggest that E2 promotes osteoblastic proliferation and differentiation by inducing proliferation-related and differentiation-related gene expression via ERβ/GSK-3β-dependent Wnt/β-catenin signaling pathway. Our findings provide novel insights into the mechanisms of action of E2 in osteoblastogenesis. - Highlights: • 17β-estradial (E2) promotes GSK3-β phosphorylation. • E2 activates the Wnt/β-catenin signaling pathway. • The Wnt/β-catenin signaling pathway interacts with estrogen signaling pathways. • E2-mediated ER induced osteoblast differentiation and proliferation related genes expression

  5. Tofacitinib Represses the Janus Kinase-Signal Transducer and Activators of Transcription Signalling Pathway in Keratinocytes.

    Science.gov (United States)

    Srivastava, Ankit; Ståhle, Mona; Pivarcsi, Andor; Sonkoly, Enikö

    2018-05-08

    Tofacitinib is a Janus kinase (JAK) inhibitor, which has shown efficacy in treating psoriasis. The mode of action of tofacitinib is not completely understood but it has been thought to be mediated by the inhibition of CD4+ T-cell activation. Here, we investigated whether the molecular targets of tofacitinib are expressed in keratinocytes, and whether tofacitinib can modulate the activity of the JAK/Signal Transducer and Activators of Transcription (STAT)-pathway in keratinocytes. Transcriptomic profiling of human keratinocytes treated with IL-22 in combination with tofacitinib revealed that tofacitinib could prevent the majority of IL-22-mediated gene expression changes. Pathway analysis of tofacitinib-regulated genes in keratinocytes revealed enrichment of genes involved in the JAK/STAT signalling pathway. Quantitative real-time-PCR confirmed the upregulation of S100A7 and downregulation of EGR1 expression by IL-22, which was prevented by tofacitinib pre-treatment. These results indicate a direct effect of tofacinitib on keratinocytes, which can have relevance for systemic as well as for topical treatment of psoriasis with tofacitinib.

  6. Non-Smad pathways in TGF-β signaling

    OpenAIRE

    Zhang, Ying E

    2009-01-01

    Transforming growth factor-β utilizes a multitude of intracellular signaling pathways in addition to Smads to regulate a wide array of cellular functions. These non-canonical, non-Smad pathways are activated directly by ligand-occupied receptors to reinforce, attenuate, or otherwise modulate downstream cellular responses. These non-Smad pathways include various branches of MAP kinase pathways, Rho-like GTPase signaling pathways, and phosphatidylinositol-3-kinase/AKT pathways. This review focu...

  7. Critical nodes in signalling pathways

    DEFF Research Database (Denmark)

    Taniguchi, Cullen M; Emanuelli, Brice; Kahn, C Ronald

    2006-01-01

    Physiologically important cell-signalling networks are complex, and contain several points of regulation, signal divergence and crosstalk with other signalling cascades. Here, we use the concept of 'critical nodes' to define the important junctions in these pathways and illustrate their unique role...... using insulin signalling as a model system....

  8. Signaling Pathways Involved in Lunar Dust Induced Cytotoxicity

    Science.gov (United States)

    Zhang, Ye; Lam, Chiu-Wing; Scully, Robert R.; Williams, Kyle; Zalesak, Selina; Wu, Honglu; James, John T.

    2014-01-01

    The Moon's surface is covered by a layer of fine, reactive dust. Lunar dust contain about 1-2% of very fine dust (pathways involved in lunar dust-induced toxicity. F344 rats were exposed for 4 weeks (6h/d; 5d/wk) in nose-only inhalation chambers to concentrations of 0 (control air), 2.1, 6.1, 21, and 61 mg/m(exp 3) of lunar dust. Five rats per group were euthanized 1 day, 1 week, 1 month, and 3 months after the last inhalation exposure. The total RNAs were isolated from the blood or lung tissue after being lavaged, using the Qigen RNeasy kit. The Rat Fibrosis RT2 Profile PCR Array was used to profile the expression of 84 genes relevant to fibrosis. The genes with significant expression changes are identified and the gene expression data were further analyzed using IPA pathway analysis tool to determine the signaling pathways with significant changes.

  9. De novo characterization of the spleen transcriptome of the large yellow croaker (Pseudosciaena crocea) and analysis of the immune relevant genes and pathways involved in the antiviral response

    KAUST Repository

    Mu, Yinnan

    2014-05-12

    The large yellow croaker (Pseudosciaena crocea) is an economically important marine fish in China. To understand the molecular basis for antiviral defense in this species, we used Illumia paired-end sequencing to characterize the spleen transcriptome of polyriboinosinic:polyribocytidylic acid [poly(I:C)]-induced large yellow croakers. The library produced 56,355,728 reads and assembled into 108,237 contigs. As a result, 15,192 unigenes were found from this transcriptome. Gene ontology analysis showed that 4,759 genes were involved in three major functional categories: biological process, cellular component, and molecular function. We further ascertained that numerous consensus sequences were homologous to known immune-relevant genes. Kyoto Encyclopedia of Genes and Genomes orthology mapping annotated 5,389 unigenes and identified numerous immune-relevant pathways. These immune-relevant genes and pathways revealed major antiviral immunity effectors, including but not limited to: pattern recognition receptors, adaptors and signal transducers, the interferons and interferon-stimulated genes, inflammatory cytokines and receptors, complement components, and B-cell and T-cell antigen activation molecules. Moreover, the partial genes of Toll-like receptor signaling pathway, RIG-I-like receptors signaling pathway, Janus kinase-Signal Transducer and Activator of Transcription (JAK-STAT) signaling pathway, and T-cell receptor (TCR) signaling pathway were found to be changed after poly(I:C) induction by real-time polymerase chain reaction (PCR) analysis, suggesting that these signaling pathways may be regulated by poly(I:C), a viral mimic. Overall, the antivirus-related genes and signaling pathways that were identified in response to poly(I:C) challenge provide valuable leads for further investigation of the antiviral defense mechanism in the large yellow croaker. © 2014 Mu et al.

  10. De novo characterization of the spleen transcriptome of the large yellow croaker (Pseudosciaena crocea and analysis of the immune relevant genes and pathways involved in the antiviral response.

    Directory of Open Access Journals (Sweden)

    Yinnan Mu

    Full Text Available The large yellow croaker (Pseudosciaena crocea is an economically important marine fish in China. To understand the molecular basis for antiviral defense in this species, we used Illumia paired-end sequencing to characterize the spleen transcriptome of polyriboinosinic:polyribocytidylic acid [poly(I:C]-induced large yellow croakers. The library produced 56,355,728 reads and assembled into 108,237 contigs. As a result, 15,192 unigenes were found from this transcriptome. Gene ontology analysis showed that 4,759 genes were involved in three major functional categories: biological process, cellular component, and molecular function. We further ascertained that numerous consensus sequences were homologous to known immune-relevant genes. Kyoto Encyclopedia of Genes and Genomes orthology mapping annotated 5,389 unigenes and identified numerous immune-relevant pathways. These immune-relevant genes and pathways revealed major antiviral immunity effectors, including but not limited to: pattern recognition receptors, adaptors and signal transducers, the interferons and interferon-stimulated genes, inflammatory cytokines and receptors, complement components, and B-cell and T-cell antigen activation molecules. Moreover, the partial genes of Toll-like receptor signaling pathway, RIG-I-like receptors signaling pathway, Janus kinase-Signal Transducer and Activator of Transcription (JAK-STAT signaling pathway, and T-cell receptor (TCR signaling pathway were found to be changed after poly(I:C induction by real-time polymerase chain reaction (PCR analysis, suggesting that these signaling pathways may be regulated by poly(I:C, a viral mimic. Overall, the antivirus-related genes and signaling pathways that were identified in response to poly(I:C challenge provide valuable leads for further investigation of the antiviral defense mechanism in the large yellow croaker.

  11. De novo characterization of the spleen transcriptome of the large yellow croaker (Pseudosciaena crocea) and analysis of the immune relevant genes and pathways involved in the antiviral response

    KAUST Repository

    Mu, Yinnan; Li, Mingyu; Ding, Feng; Ding, Yang; Ao, Jingqun; Hu, Songnian; Chen, Xinhua

    2014-01-01

    The large yellow croaker (Pseudosciaena crocea) is an economically important marine fish in China. To understand the molecular basis for antiviral defense in this species, we used Illumia paired-end sequencing to characterize the spleen transcriptome of polyriboinosinic:polyribocytidylic acid [poly(I:C)]-induced large yellow croakers. The library produced 56,355,728 reads and assembled into 108,237 contigs. As a result, 15,192 unigenes were found from this transcriptome. Gene ontology analysis showed that 4,759 genes were involved in three major functional categories: biological process, cellular component, and molecular function. We further ascertained that numerous consensus sequences were homologous to known immune-relevant genes. Kyoto Encyclopedia of Genes and Genomes orthology mapping annotated 5,389 unigenes and identified numerous immune-relevant pathways. These immune-relevant genes and pathways revealed major antiviral immunity effectors, including but not limited to: pattern recognition receptors, adaptors and signal transducers, the interferons and interferon-stimulated genes, inflammatory cytokines and receptors, complement components, and B-cell and T-cell antigen activation molecules. Moreover, the partial genes of Toll-like receptor signaling pathway, RIG-I-like receptors signaling pathway, Janus kinase-Signal Transducer and Activator of Transcription (JAK-STAT) signaling pathway, and T-cell receptor (TCR) signaling pathway were found to be changed after poly(I:C) induction by real-time polymerase chain reaction (PCR) analysis, suggesting that these signaling pathways may be regulated by poly(I:C), a viral mimic. Overall, the antivirus-related genes and signaling pathways that were identified in response to poly(I:C) challenge provide valuable leads for further investigation of the antiviral defense mechanism in the large yellow croaker. © 2014 Mu et al.

  12. Curcumin and emodin down-regulate TGF-β signaling pathway in human cervical cancer cells.

    Directory of Open Access Journals (Sweden)

    Pooja Chandrakant Thacker

    Full Text Available Cervical cancer is the major cause of cancer related deaths in women, especially in developing countries and Human Papilloma Virus infection in conjunction with multiple deregulated signaling pathways leads to cervical carcinogenesis. TGF-β signaling in later stages of cancer is known to induce epithelial to mesenchymal transition promoting tumor growth. Phytochemicals, curcumin and emodin, are effective as chemopreventive and chemotherapeutic compounds against several cancers including cervical cancer. The main objective of this work was to study the effect of curcumin and emodin on TGF-β signaling pathway and its functional relevance to growth, migration and invasion in two cervical cancer cell lines, SiHa and HeLa. Since TGF-β and Wnt/β-catenin signaling pathways are known to cross talk having common downstream targets, we analyzed the effect of TGF-β on β-catenin (an important player in Wnt/β-catenin signaling and also studied whether curcumin and emodin modulate them. We observed that curcumin and emodin effectively down regulate TGF-β signaling pathway by decreasing the expression of TGF-β Receptor II, P-Smad3 and Smad4, and also counterbalance the tumorigenic effects of TGF-β by inhibiting the TGF-β-induced migration and invasion. Expression of downstream effectors of TGF-β signaling pathway, cyclinD1, p21 and Pin1, was inhibited along with the down regulation of key mesenchymal markers (Snail and Slug upon curcumin and emodin treatment. Curcumin and emodin were also found to synergistically inhibit cell population and migration in SiHa and HeLa cells. Moreover, we found that TGF-β activates Wnt/β-catenin signaling pathway in HeLa cells, and curcumin and emodin down regulate the pathway by inhibiting β-catenin. Taken together our data provide a mechanistic basis for the use of curcumin and emodin in the treatment of cervical cancer.

  13. Cerebral insulin, insulin signaling pathway, and brain angiogenesis.

    Science.gov (United States)

    Zeng, Yi; Zhang, Le; Hu, Zhiping

    2016-01-01

    Insulin performs unique non-metabolic functions within the brain. Broadly speaking, two major areas of these functions are those related to brain endothelial cells and the blood-brain barrier (BBB) function, and those related to behavioral effects, like cognition in disease states (Alzheimer's disease, AD) and in health. Recent studies showed that both these functions are associated with brain angiogenesis. These findings raise interesting questions such as how they are linked to each other and whether modifying brain angiogenesis by targeting certain insulin signaling pathways could be an effective strategy to treat dementia as in AD, or even to help secure healthy longevity. The two canonical downstream pathways involved in mediating the insulin signaling pathway, the phosphoinositide-3 kinase (PI3K), and mitogen-activated protein kinase (MAPK) cascades, in the brain are supposed to be similar to those in the periphery. PI3K and MAPK pathways play important roles in angiogenesis. Both are involved in stimulating hypoxia inducible factor (HIF) in angiogenesis and could be activated by the insulin signaling pathway. This suggests that PI3K and MAPK pathways might act as cross-talk between the insulin signaling pathway and the angiogenesis pathway in brain. But the cerebral insulin, insulin signaling pathway, and the detailed mechanism in the connection of insulin signaling pathway, brain angiogenesis pathway, and healthy aging or dementias are still mostly not clear and need further studies.

  14. Hedgehog signaling pathway in neuroblastoma differentiation.

    Science.gov (United States)

    Souzaki, Ryota; Tajiri, Tatsuro; Souzaki, Masae; Kinoshita, Yoshiaki; Tanaka, Sakura; Kohashi, Kenichi; Oda, Yoshinao; Katano, Mitsuo; Taguchi, Tomoaki

    2010-12-01

    The hedgehog (Hh) signaling pathway is activated in some adult cancers. On the other hand, the Hh signaling pathway plays an important role in the development of the neural crest in embryos. The aim of this study is to show the activation of Hh signaling pathway in neuroblastoma (NB), a pediatric malignancy arising from neural crest cells, and to reveal the meaning of the Hh signaling pathway in NB development. This study analyzed the expression of Sonic hedgehog (Shh), GLI1, and Patched 1 (Ptch1), transactivators of Hh signaling pathway, by immunohistochemistry in 82 NB and 10 ganglioneuroblastoma cases. All 92 cases were evaluated for the status of MYCN amplification. Of the 92 cases, 67 (73%) were positive for Shh, 62 cases (67%) were positive for GLI1, and 73 cases (79%) were positive for Ptch1. Only 2 (10%) of the 20 cases with MYCN amplification were positive for Shh and GLI1, and 4 cases (20%) were positive for Ptch1 (MYCN amplification vs no MYCN amplification, P ≦ .01). The percentage of GLI1-positive cells in the cases with INSS stage 1 without MYCN amplification was significantly higher than that with INSS stage 4. Of 72 cases without MYCN amplification, 60 were GLI1-positive. Twelve cases were GLI1-negative, and the prognosis of the GLI1-positive cases was significantly better than that of the GLI1-negative cases (P = .015). Most of NBs without MYCN amplification were positive for Shh, GLI1, and Ptch1. In the cases without MYCN amplification, the high expression of GLI1 was significantly associated with early clinical stage and a good prognosis of the patients. In contrast to adult cancers, the activation of the Hh signaling pathway in NB may be associated with the differentiation of the NB. Copyright © 2010 Elsevier Inc. All rights reserved.

  15. Antagonism between Hedgehog and Wnt signaling pathways regulates tumorigenicity.

    Science.gov (United States)

    Ding, Mei; Wang, Xin

    2017-12-01

    The crosstalk of multiple cellular signaling pathways is crucial in animal development and tissue homeostasis, and its dysregulation may result in tumor formation and metastasis. The Hedgehog (Hh) and Wnt signaling pathways are both considered to be essential regulators of cell proliferation, differentiation and oncogenesis. Recent studies have indicated that the Hh and Wnt signaling pathways are closely associated and involved in regulating embryogenesis and cellular differentiation. Hh signaling acts upstream of the Wnt signaling pathway, and negative regulates Wnt activity via secreted frizzled-related protein 1 (SFRP1), and the Wnt/β-catenin pathway downregulates Hh activity through glioma-associated oncogene homolog 3 transcriptional regulation. This evidence suggests that the imbalance of Hh and Wnt regulation serves a crucial role in cancer-associated processes. The activation of SFRP1, which inhibits Wnt, has been demonstrated to be an important cross-point between the two signaling pathways. The present study reviews the complex interaction between the Hh and Wnt signaling pathways in embryogenesis and tumorigenicity, and the role of SFRP1 as an important mediator associated with the dysregulation of the Hh and Wnt signaling pathways.

  16. Evolutionary conservation of plant gibberellin signalling pathway components

    Directory of Open Access Journals (Sweden)

    Reski Ralf

    2007-11-01

    Full Text Available Abstract Background: Gibberellins (GA are plant hormones that can regulate germination, elongation growth, and sex determination. They ubiquitously occur in seed plants. The discovery of gibberellin receptors, together with advances in understanding the function of key components of GA signalling in Arabidopsis and rice, reveal a fairly short GA signal transduction route. The pathway essentially consists of GID1 gibberellin receptors that interact with F-box proteins, which in turn regulate degradation of downstream DELLA proteins, suppressors of GA-controlled responses. Results: Arabidopsis sequences of the gibberellin signalling compounds were used to screen databases from a variety of plants, including protists, for homologues, providing indications for the degree of conservation of the pathway. The pathway as such appears completely absent in protists, the moss Physcomitrella patens shares only a limited homology with the Arabidopsis proteins, thus lacking essential characteristics of the classical GA signalling pathway, while the lycophyte Selaginella moellendorffii contains a possible ortholog for each component. The occurrence of classical GA responses can as yet not be linked with the presence of homologues of the signalling pathway. Alignments and display in neighbour joining trees of the GA signalling components confirm the close relationship of gymnosperms, monocotyledonous and dicotyledonous plants, as suggested from previous studies. Conclusion: Homologues of the GA-signalling pathway were mainly found in vascular plants. The GA signalling system may have its evolutionary molecular onset in Physcomitrella patens, where GAs at higher concentrations affect gravitropism and elongation growth.

  17. Seeking kinetic pathways relevant to the structural evolution of metal nanoparticles

    International Nuclear Information System (INIS)

    Haldar, Paramita; Chatterjee, Abhijit

    2015-01-01

    Understanding the kinetic pathways that cause metal nanoparticles to structurally evolve over time is essential for predicting their shape and size distributions and catalytic properties. Consequently, we need detailed kinetic models that can provide such information. Most kinetic Monte Carlo models used for metal systems contain a fixed catalogue of atomic moves; the catalogue is largely constructed based on our physical understanding of the material. In some situations, it is possible that an incorrect picture of the overall dynamics is obtained when kinetic pathways that are relevant to the dynamics are missing from the catalogue. Hence, a computational framework that can systematically determine the relevant pathways is required. This work intends to fulfil this requirement. Examples involving an Ag nanoparticle are studied to illustrate how molecular dynamics (MD) calculations can be employed to find the relevant pathways in a system. Since pathways that are unlikely to be selected at short timescales can become relevant at longer times, the accuracy of the catalogue is maintained by continually seeking these pathways using MD. We discuss various aspects of our approach, namely, defining the relevance of atomic moves to the dynamics and determining when additional MD is required to ensure the desired accuracy, as well as physical insights into the Ag nanoparticle. (paper)

  18. Radioresistance-related signaling pathways in nasopharyngeal carcinoma cells

    International Nuclear Information System (INIS)

    Guo Ya; Zhu Xiaodong; Qu Song; Su Fang; Wang Qi; Zhang Wei

    2011-01-01

    Objective: To study the difference of gene expression profile between the radioresistant human nasopharyngeal carcinoma cell line CNE-2R and CNE-2, and to screen the signaling pathway associated with radioresistance of nasopharyngeal carcinoma. Methods: The radioresistant nasopharyngeal carcinoma cell line CNE-2R was constructed from the original cell line CNE-2. CNE-2R and CNE-2 cells were cultured and administered with 60 Co γ-ray irradiation at the dose of 400 cGy for 15 times. Human-6v 3.0 whole genome expression profile was used to screen the differentially expressed genes. Bioinformatic analysis was used to identify the pathways related to radioresistance. Results: The number of the differentially expressed genes that were found in these 2 experiments was 374. The Kegg pathway and Biocarta pathway analysis of the differentially expressed genes showed the biological importance of Toll-like receptor signaling pathway and IL-1 R-mediated signal transduction pathway to the radioresistance of the CNE-2R cells and the significant differences of 13 genes in these 2 pathways,including JUN, MYD88, CCL5, CXCL10, STAT1, LY96, FOS, CCL3, IL-6, IL-8, IL-1α, IL-1β, and IRAK2 (t=13.47-66.57, P<0.05). Conclusions: Toll-like receptor signaling pathway and IL-1R-mediated signal transduction pathway might be related to the occurrence of radioresistance. (authors)

  19. Signal Transduction Pathways that Regulate CAB Gene Expression

    Energy Technology Data Exchange (ETDEWEB)

    Chory, Joanne

    2004-12-31

    The process of chloroplast differentiation, involves the coordinate regulation of many nuclear and chloroplast genes. The cues for the initiation of this developmental program are both extrinsic (e.g., light) and intrinsic (cell-type and plastid signals). During this project period, we utilized a molecular genetic approach to select for Arabidopsis mutants that did not respond properly to environmental light conditions, as well as mutants that were unable to perceive plastid damage. These latter mutants, called gun mutants, define two retrograde signaling pathways that regulate nuclear gene expression in response to chloroplasts. A major finding was to identify a signal from chloroplasts that regulates nuclear gene transcription. This signal is the build-up of Mg-Protoporphyrin IX, a key intermediate of the chlorophyll biosynthetic pathway. The signaling pathways downstream of this signal are currently being studied. Completion of this project has provided an increased understanding of the input signals and retrograde signaling pathways that control nuclear gene expression in response to the functional state of chloroplasts. These studies should ultimately influence our abilities to manipulate plant growth and development, and will aid in the understanding of the developmental control of photosynthesis.

  20. Signal Transduction Pathways that Regulate CAB Gene Expression

    Energy Technology Data Exchange (ETDEWEB)

    Chory, Joanne

    2006-01-16

    The process of chloroplast differentiation, involves the coordinate regulation of many nuclear and chloroplast genes. The cues for the initiation of this developmental program are both extrinsic (e.g., light) and intrinsic (cell-type and plastid signals). During this project period, we utilized a molecular genetic approach to select for Arabidopsis mutants that did not respond properly to environmental light conditions, as well as mutants that were unable to perceive plastid damage. These latter mutants, called gun mutants, define two retrograde signaling pathways that regulate nuclear gene expression in response to chloroplasts. A major finding was to identify a signal from chloroplasts that regulates nuclear gene transcription. This signal is the build-up of Mg-Protoporphyrin IX, a key intermediate of the chlorophyll biosynthetic pathway. The signaling pathways downstream of this signal are currently being studied. Completion of this project has provided an increased understanding of the input signals and retrograde signaling pathways that control nuclear gene expression in response to the functional state of chloroplasts. These studies should ultimately influence our abilities to manipulate plant growth and development, and will aid in the understanding of the developmental control of photosynthesis.

  1. Modelling and Analysis of Biochemical Signalling Pathway Cross-talk

    Directory of Open Access Journals (Sweden)

    Robin Donaldson

    2010-02-01

    Full Text Available Signalling pathways are abstractions that help life scientists structure the coordination of cellular activity. Cross-talk between pathways accounts for many of the complex behaviours exhibited by signalling pathways and is often critical in producing the correct signal-response relationship. Formal models of signalling pathways and cross-talk in particular can aid understanding and drive experimentation. We define an approach to modelling based on the concept that a pathway is the (synchronising parallel composition of instances of generic modules (with internal and external labels. Pathways are then composed by (synchronising parallel composition and renaming; different types of cross-talk result from different combinations of synchronisation and renaming. We define a number of generic modules in PRISM and five types of cross-talk: signal flow, substrate availability, receptor function, gene expression and intracellular communication. We show that Continuous Stochastic Logic properties can both detect and distinguish the types of cross-talk. The approach is illustrated with small examples and an analysis of the cross-talk between the TGF-b/BMP, WNT and MAPK pathways.

  2. Signaling pathways regulating murine pancreatic development

    DEFF Research Database (Denmark)

    Serup, Palle

    2012-01-01

    The recent decades have seen a huge expansion in our knowledge about pancreatic development. Numerous lineage-restricted transcription factor genes have been identified and much has been learned about their function. Similarly, numerous signaling pathways important for pancreas development have...... been identified and the specific roles have been investigated by genetic and cell biological methods. The present review presents an overview of the principal signaling pathways involved in regulating murine pancreatic growth, morphogenesis, and cell differentiation....

  3. The Hippo/YAP pathway interacts with EGFR signaling and HPV oncoproteins to regulate cervical cancer progression

    Science.gov (United States)

    He, Chunbo; Mao, Dagan; Hua, Guohua; Lv, Xiangmin; Chen, Xingcheng; Angeletti, Peter C; Dong, Jixin; Remmenga, Steven W; Rodabaugh, Kerry J; Zhou, Jin; Lambert, Paul F; Yang, Peixin; Davis, John S; Wang, Cheng

    2015-01-01

    The Hippo signaling pathway controls organ size and tumorigenesis through a kinase cascade that inactivates Yes-associated protein (YAP). Here, we show that YAP plays a central role in controlling the progression of cervical cancer. Our results suggest that YAP expression is associated with a poor prognosis for cervical cancer. TGF-α and amphiregulin (AREG), via EGFR, inhibit the Hippo signaling pathway and activate YAP to induce cervical cancer cell proliferation and migration. Activated YAP allows for up-regulation of TGF-α, AREG, and EGFR, forming a positive signaling loop to drive cervical cancer cell proliferation. HPV E6 protein, a major etiological molecule of cervical cancer, maintains high YAP protein levels in cervical cancer cells by preventing proteasome-dependent YAP degradation to drive cervical cancer cell proliferation. Results from human cervical cancer genomic databases and an accepted transgenic mouse model strongly support the clinical relevance of the discovered feed-forward signaling loop. Our study indicates that combined targeting of the Hippo and the ERBB signaling pathways represents a novel therapeutic strategy for prevention and treatment of cervical cancer. PMID:26417066

  4. Signaling Pathways in Cardiac Myocyte Apoptosis

    Science.gov (United States)

    Xia, Peng; Liu, Yuening

    2016-01-01

    Cardiovascular diseases, the number 1 cause of death worldwide, are frequently associated with apoptotic death of cardiac myocytes. Since cardiomyocyte apoptosis is a highly regulated process, pharmacological intervention of apoptosis pathways may represent a promising therapeutic strategy for a number of cardiovascular diseases and disorders including myocardial infarction, ischemia/reperfusion injury, chemotherapy cardiotoxicity, and end-stage heart failure. Despite rapid growth of our knowledge in apoptosis signaling pathways, a clinically applicable treatment targeting this cellular process is currently unavailable. To help identify potential innovative directions for future research, it is necessary to have a full understanding of the apoptotic pathways currently known to be functional in cardiac myocytes. Here, we summarize recent progress in the regulation of cardiomyocyte apoptosis by multiple signaling molecules and pathways, with a focus on the involvement of these pathways in the pathogenesis of heart disease. In addition, we provide an update regarding bench to bedside translation of this knowledge and discuss unanswered questions that need further investigation. PMID:28101515

  5. Rare variants in the neurotrophin signaling pathway implicated in schizophrenia risk.

    Science.gov (United States)

    Kranz, Thorsten M; Goetz, Ray R; Walsh-Messinger, Julie; Goetz, Deborah; Antonius, Daniel; Dolgalev, Igor; Heguy, Adriana; Seandel, Marco; Malaspina, Dolores; Chao, Moses V

    2015-10-01

    Multiple lines of evidence corroborate impaired signaling pathways as relevant to the underpinnings of schizophrenia. There has been an interest in neurotrophins, since they are crucial mediators of neurodevelopment and in synaptic connectivity in the adult brain. Neurotrophins and their receptors demonstrate aberrant expression patterns in cortical areas for schizophrenia cases in comparison to control subjects. There is little known about the contribution of neurotrophin genes in psychiatric disorders. To begin to address this issue, we conducted high-coverage targeted exome capture in a subset of neurotrophin genes in 48 comprehensively characterized cases with schizophrenia-related psychosis. We herein report rare missense polymorphisms and novel missense mutations in neurotrophin receptor signaling pathway genes. Furthermore, we observed that several genes have a higher propensity to harbor missense coding variants than others. Based on this initial analysis we suggest that rare variants and missense mutations in neurotrophin genes might represent genetic contributions involved across psychiatric disorders. Copyright © 2015 Elsevier B.V. All rights reserved.

  6. Nuclear Receptor Signaling Atlas: Opening Access to the Biology of Nuclear Receptor Signaling Pathways.

    Science.gov (United States)

    Becnel, Lauren B; Darlington, Yolanda F; Ochsner, Scott A; Easton-Marks, Jeremy R; Watkins, Christopher M; McOwiti, Apollo; Kankanamge, Wasula H; Wise, Michael W; DeHart, Michael; Margolis, Ronald N; McKenna, Neil J

    2015-01-01

    Signaling pathways involving nuclear receptors (NRs), their ligands and coregulators, regulate tissue-specific transcriptomes in diverse processes, including development, metabolism, reproduction, the immune response and neuronal function, as well as in their associated pathologies. The Nuclear Receptor Signaling Atlas (NURSA) is a Consortium focused around a Hub website (www.nursa.org) that annotates and integrates diverse 'omics datasets originating from the published literature and NURSA-funded Data Source Projects (NDSPs). These datasets are then exposed to the scientific community on an Open Access basis through user-friendly data browsing and search interfaces. Here, we describe the redesign of the Hub, version 3.0, to deploy "Web 2.0" technologies and add richer, more diverse content. The Molecule Pages, which aggregate information relevant to NR signaling pathways from myriad external databases, have been enhanced to include resources for basic scientists, such as post-translational modification sites and targeting miRNAs, and for clinicians, such as clinical trials. A portal to NURSA's Open Access, PubMed-indexed journal Nuclear Receptor Signaling has been added to facilitate manuscript submissions. Datasets and information on reagents generated by NDSPs are available, as is information concerning periodic new NDSP funding solicitations. Finally, the new website integrates the Transcriptomine analysis tool, which allows for mining of millions of richly annotated public transcriptomic data points in the field, providing an environment for dataset re-use and citation, bench data validation and hypothesis generation. We anticipate that this new release of the NURSA database will have tangible, long term benefits for both basic and clinical research in this field.

  7. Nuclear Receptor Signaling Atlas: Opening Access to the Biology of Nuclear Receptor Signaling Pathways.

    Directory of Open Access Journals (Sweden)

    Lauren B Becnel

    Full Text Available Signaling pathways involving nuclear receptors (NRs, their ligands and coregulators, regulate tissue-specific transcriptomes in diverse processes, including development, metabolism, reproduction, the immune response and neuronal function, as well as in their associated pathologies. The Nuclear Receptor Signaling Atlas (NURSA is a Consortium focused around a Hub website (www.nursa.org that annotates and integrates diverse 'omics datasets originating from the published literature and NURSA-funded Data Source Projects (NDSPs. These datasets are then exposed to the scientific community on an Open Access basis through user-friendly data browsing and search interfaces. Here, we describe the redesign of the Hub, version 3.0, to deploy "Web 2.0" technologies and add richer, more diverse content. The Molecule Pages, which aggregate information relevant to NR signaling pathways from myriad external databases, have been enhanced to include resources for basic scientists, such as post-translational modification sites and targeting miRNAs, and for clinicians, such as clinical trials. A portal to NURSA's Open Access, PubMed-indexed journal Nuclear Receptor Signaling has been added to facilitate manuscript submissions. Datasets and information on reagents generated by NDSPs are available, as is information concerning periodic new NDSP funding solicitations. Finally, the new website integrates the Transcriptomine analysis tool, which allows for mining of millions of richly annotated public transcriptomic data points in the field, providing an environment for dataset re-use and citation, bench data validation and hypothesis generation. We anticipate that this new release of the NURSA database will have tangible, long term benefits for both basic and clinical research in this field.

  8. Computational identification of signalling pathways in Plasmodium falciparum.

    Science.gov (United States)

    Oyelade, Jelili; Ewejobi, Itunu; Brors, Benedikt; Eils, Roland; Adebiyi, Ezekiel

    2011-06-01

    Malaria is one of the world's most common and serious diseases causing death of about 3 million people each year. Its most severe occurrence is caused by the protozoan Plasmodium falciparum. Reports have shown that the resistance of the parasite to existing drugs is increasing. Therefore, there is a huge and urgent need to discover and validate new drug or vaccine targets to enable the development of new treatments for malaria. The ability to discover these drug or vaccine targets can only be enhanced from our deep understanding of the detailed biology of the parasite, for example how cells function and how proteins organize into modules such as metabolic, regulatory and signal transduction pathways. It has been noted that the knowledge of signalling transduction pathways in Plasmodium is fundamental to aid the design of new strategies against malaria. This work uses a linear-time algorithm for finding paths in a network under modified biologically motivated constraints. We predicted several important signalling transduction pathways in Plasmodium falciparum. We have predicted a viable signalling pathway characterized in terms of the genes responsible that may be the PfPKB pathway recently elucidated in Plasmodium falciparum. We obtained from the FIKK family, a signal transduction pathway that ends up on a chloroquine resistance marker protein, which indicates that interference with FIKK proteins might reverse Plasmodium falciparum from resistant to sensitive phenotype. We also proposed a hypothesis that showed the FIKK proteins in this pathway as enabling the resistance parasite to have a mechanism for releasing chloroquine (via an efflux process). Furthermore, we also predicted a signalling pathway that may have been responsible for signalling the start of the invasion process of Red Blood Cell (RBC) by the merozoites. It has been noted that the understanding of this pathway will give insight into the parasite virulence and will facilitate rational vaccine design

  9. Intricacies of hedgehog signaling pathways: A perspective in tumorigenesis

    International Nuclear Information System (INIS)

    Kar, Swayamsiddha; Deb, Moonmoon; Sengupta, Dipta; Shilpi, Arunima; Bhutia, Sujit Kumar; Patra, Samir Kumar

    2012-01-01

    The hedgehog (HH) signaling pathway is a crucial negotiator of developmental proceedings in the embryo governing a diverse array of processes including cell proliferation, differentiation, and tissue patterning. The overall activity of the pathway is significantly curtailed after embryogenesis as well as in adults, yet it retains many of its functional capacities. However, aberration in HH signaling mediates the initiation, proliferation and continued sustenance of malignancy in different tissues to varying degrees through different mechanisms. In this review, we provide an overview of the role of constitutively active aberrant HH signaling pathway in different types of human cancer and the underlying molecular and genetic mechanisms that drive tumorigenesis in that particular tissue. An insight into the various modes of anomalous HH signaling in different organs will provide a comprehensive knowledge of the pathway in these tissues and open a window for individually tailored, tissue-specific therapeutic interventions. The synergistic cross talking of HH pathway with many other regulatory molecules and developmentally inclined signaling pathways may offer many avenues for pharmacological advances. Understanding the molecular basis of abnormal HH signaling in cancer will provide an opportunity to inhibit the deregulated pathway in many aggressive and therapeutically challenging cancers where promising options are not available.

  10. Intricacies of hedgehog signaling pathways: A perspective in tumorigenesis

    Energy Technology Data Exchange (ETDEWEB)

    Kar, Swayamsiddha; Deb, Moonmoon; Sengupta, Dipta; Shilpi, Arunima; Bhutia, Sujit Kumar [Epigenetics and Cancer Research Laboratory, Biochemistry and Molecular Biology Group, Department of Life Science, National Institute of Technology, Rourkela, Odisha 769008 (India); Patra, Samir Kumar, E-mail: samirp@nitrkl.ac.in [Epigenetics and Cancer Research Laboratory, Biochemistry and Molecular Biology Group, Department of Life Science, National Institute of Technology, Rourkela, Odisha 769008 (India)

    2012-10-01

    The hedgehog (HH) signaling pathway is a crucial negotiator of developmental proceedings in the embryo governing a diverse array of processes including cell proliferation, differentiation, and tissue patterning. The overall activity of the pathway is significantly curtailed after embryogenesis as well as in adults, yet it retains many of its functional capacities. However, aberration in HH signaling mediates the initiation, proliferation and continued sustenance of malignancy in different tissues to varying degrees through different mechanisms. In this review, we provide an overview of the role of constitutively active aberrant HH signaling pathway in different types of human cancer and the underlying molecular and genetic mechanisms that drive tumorigenesis in that particular tissue. An insight into the various modes of anomalous HH signaling in different organs will provide a comprehensive knowledge of the pathway in these tissues and open a window for individually tailored, tissue-specific therapeutic interventions. The synergistic cross talking of HH pathway with many other regulatory molecules and developmentally inclined signaling pathways may offer many avenues for pharmacological advances. Understanding the molecular basis of abnormal HH signaling in cancer will provide an opportunity to inhibit the deregulated pathway in many aggressive and therapeutically challenging cancers where promising options are not available.

  11. DMPD: Signalling pathways mediating type I interferon gene expression. [Dynamic Macrophage Pathway CSML Database

    Lifescience Database Archive (English)

    Full Text Available 17904888 Signalling pathways mediating type I interferon gene expression. Edwards M...hways mediating type I interferon gene expression. PubmedID 17904888 Title Signalling pathways...R, Slater L, Johnston SL. Microbes Infect. 2007 Sep;9(11):1245-51. Epub 2007 Jul 1. (.png) (.svg) (.html) (.csml) Show Signalling pat

  12. SPV: a JavaScript Signaling Pathway Visualizer.

    Science.gov (United States)

    Calderone, Alberto; Cesareni, Gianni

    2018-03-24

    The visualization of molecular interactions annotated in web resources is useful to offer to users such information in a clear intuitive layout. These interactions are frequently represented as binary interactions that are laid out in free space where, different entities, cellular compartments and interaction types are hardly distinguishable. SPV (Signaling Pathway Visualizer) is a free open source JavaScript library which offers a series of pre-defined elements, compartments and interaction types meant to facilitate the representation of signaling pathways consisting of causal interactions without neglecting simple protein-protein interaction networks. freely available under Apache version 2 license; Source code: https://github.com/Sinnefa/SPV_Signaling_Pathway_Visualizer_v1.0. Language: JavaScript; Web technology: Scalable Vector Graphics; Libraries: D3.js. sinnefa@gmail.com.

  13. Trichoderma Biocontrol: Signal Transduction Pathways Involved in Host Sensing and Mycoparasitism

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    Susanne Zeilinger

    2007-01-01

    Full Text Available Fungi of the genus Trichoderma are used as biocontrol agents against several plant pathogenic fungi like Rhizoctonia spp., Pythium spp., Botrytis cinerea and Fusarium spp. which cause both soil-borne and leaf- or flower-borne diseases of agricultural plants. Plant disease control by Trichoderma is based on complex interactions between Trichoderma, the plant pathogen and the plant. Until now, two main components of biocontrol have been identified: direct activity of Trichoderma against the plant pathogen by mycoparasitism and induced systemic resistance in plants. As the mycoparasitic interaction is host-specific and not merely a contact response, it is likely that signals from the host fungus are recognised by Trichoderma and provoke transcription of mycoparasitism-related genes.In the last few years examination of signalling pathways underlying Trichoderma biocontrol started and it was shown that heterotrimeric G-proteins and mitogen-activated protein (MAP kinases affected biocontrol-relevant processes such as the production of hydrolytic enzymes and antifungal metabolites and the formation of infection structures. MAPK signalling was also found to be involved in induction of plant systemic resistance in Trichoderma virens and in the hyperosmotic stress response in Trichoderma harzianum. Analyses of the function of components of the cAMP pathway during Trichoderma biocontrol revealed that mycoparasitism-associated coiling and chitinase production as well as secondary metabolism are affected by the internal cAMP level; in addition, a cross talk between regulation of light responses and the cAMP signalling pathway was found in Trichoderma atroviride.

  14. Research advances in Hedgehog signaling pathway in hepatocellular carcinoma

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    LIU Jia

    2015-02-01

    Full Text Available Hedgehog (Hh signaling pathway is present in many animals and plays an important role in regulating embryonic development and differentiation. Aberrant activation of Hh signaling contributes to the pathogenesis of many malignancies. Recent studies have shown that dysregulated Hh signaling pathway participates in the tumorigenesis, tumor invasion, and metastasis of hepatocellular carcinoma (HCC. Investigation of the relationship between Hh signaling pathway and HCC will help elucidate the molecular mechanism of pathogenesis of HCC and provide a new insight into the development of novel anticancer therapy and therapeutic target.

  15. Wnt and the Wnt signaling pathway in bone development and disease

    Science.gov (United States)

    Wang, Yiping; Li, Yi-Ping; Paulson, Christie; Shao, Jian-Zhong; Zhang, Xiaoling; Wu, Mengrui; Chen, Wei

    2014-01-01

    Wnt signaling affects both bone modeling, which occurs during development, and bone remodeling, which is a lifelong process involving tissue renewal. Wnt signals are especially known to affect the differentiation of osteoblasts. In this review, we summarize recent advances in understanding the mechanisms of Wnt signaling, which is divided into two major branches: the canonical pathway and the noncanonical pathway. The canonical pathway is also called the Wnt/β-catenin pathway. There are two major noncanonical pathways: the Wnt-planar cell polarity pathway (Wnt-PCP pathway) and the Wnt-calcium pathway (Wnt-Ca2+ pathway). This review also discusses how Wnt ligands, receptors, intracellular effectors, transcription factors, and antagonists affect both the bone modeling and bone remodeling processes. We also review the role of Wnt ligands, receptors, intracellular effectors, transcription factors, and antagonists in bone as demonstrated in mouse models. Disrupted Wnt signaling is linked to several bone diseases, including osteoporosis, van Buchem disease, and sclerosteosis. Studying the mechanism of Wnt signaling and its interactions with other signaling pathways in bone will provide potential therapeutic targets to treat these bone diseases. PMID:24389191

  16. DMPD: Multiple signaling pathways leading to the activation of interferon regulatoryfactor 3. [Dynamic Macrophage Pathway CSML Database

    Lifescience Database Archive (English)

    Full Text Available 12213596 Multiple signaling pathways leading to the activation of interferon regula...(.html) (.csml) Show Multiple signaling pathways leading to the activation of interferon regulatoryfactor 3.... PubmedID 12213596 Title Multiple signaling pathways leading to the activation of

  17. ALK1 signaling inhibits angiogenesis by cooperating with the Notch pathway.

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    Larrivée, Bruno; Prahst, Claudia; Gordon, Emma; del Toro, Raquel; Mathivet, Thomas; Duarte, Antonio; Simons, Michael; Eichmann, Anne

    2012-03-13

    Activin receptor-like kinase 1 (ALK1) is an endothelial-specific member of the TGF-β/BMP receptor family that is inactivated in patients with hereditary hemorrhagic telangiectasia (HHT). How ALK1 signaling regulates angiogenesis remains incompletely understood. Here we show that ALK1 inhibits angiogenesis by cooperating with the Notch pathway. Blocking Alk1 signaling during postnatal development in mice leads to retinal hypervascularization and the appearance of arteriovenous malformations (AVMs). Combined blockade of Alk1 and Notch signaling further exacerbates hypervascularization, whereas activation of Alk1 by its high-affinity ligand BMP9 rescues hypersprouting induced by Notch inhibition. Mechanistically, ALK1-dependent SMAD signaling synergizes with activated Notch in stalk cells to induce expression of the Notch targets HEY1 and HEY2, thereby repressing VEGF signaling, tip cell formation, and endothelial sprouting. Taken together, these results uncover a direct link between ALK1 and Notch signaling during vascular morphogenesis that may be relevant to the pathogenesis of HHT vascular lesions. Copyright © 2012 Elsevier Inc. All rights reserved.

  18. Signaling Pathways Regulating Redox Balance in Cancer Metabolism.

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    De Santis, Maria Chiara; Porporato, Paolo Ettore; Martini, Miriam; Morandi, Andrea

    2018-01-01

    The interplay between rewiring tumor metabolism and oncogenic driver mutations is only beginning to be appreciated. Metabolic deregulation has been described for decades as a bystander effect of genomic aberrations. However, for the biology of malignant cells, metabolic reprogramming is essential to tackle a harsh environment, including nutrient deprivation, reactive oxygen species production, and oxygen withdrawal. Besides the well-investigated glycolytic metabolism, it is emerging that several other metabolic fluxes are relevant for tumorigenesis in supporting redox balance, most notably pentose phosphate pathway, folate, and mitochondrial metabolism. The relationship between metabolic rewiring and mutant genes is still unclear and, therefore, we will discuss how metabolic needs and oncogene mutations influence each other to satisfy cancer cells' demands. Mutations in oncogenes, i.e., PI3K/AKT/mTOR, RAS pathway, and MYC, and tumor suppressors, i.e., p53 and liver kinase B1, result in metabolic flexibility and may influence response to therapy. Since metabolic rewiring is shaped by oncogenic driver mutations, understanding how specific alterations in signaling pathways affect different metabolic fluxes will be instrumental for the development of novel targeted therapies. In the era of personalized medicine, the combination of driver mutations, metabolite levels, and tissue of origins will pave the way to innovative therapeutic interventions.

  19. Interaction of TGFβ and BMP signaling pathways during chondrogenesis.

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    Bettina Keller

    2011-01-01

    Full Text Available TGFβ and BMP signaling pathways exhibit antagonistic activities during the development of many tissues. Although the crosstalk between BMP and TGFβ signaling pathways is well established in bone development, the relationship between these two pathways is less well defined during cartilage development and postnatal homeostasis. We generated hypomorphic mouse models of cartilage-specific loss of BMP and TGFβ signaling to assess the interaction of these pathways in postnatal growth plate homeostasis. We further used the chondrogenic ATDC5 cell line to test effects of BMP and TGFβ signaling on each other's downstream targets. We found that conditional deletion of Smad1 in chondrocytes resulted in a shortening of the growth plate. The addition of Smad5 haploinsufficiency led to a more severe phenotype with shorter prehypertrophic and hypertrophic zones and decreased chondrocyte proliferation. The opposite growth plate phenotype was observed in a transgenic mouse model of decreased chondrocytic TGFβ signaling that was generated by expressing a dominant negative form of the TGFβ receptor I (ΔTβRI in cartilage. Histological analysis demonstrated elongated growth plates with enhanced Ihh expression, as well as an increased proliferation rate with altered production of extracellular matrix components. In contrast, in chondrogenic ATDC5 cells, TGFβ was able to enhance BMP signaling, while BMP2 significantly reduces levels of TGF signaling. In summary, our data demonstrate that during endochondral ossification, BMP and TGFβ signaling can have antagonistic effects on chondrocyte proliferation and differentiation in vivo. We also found evidence of direct interaction between the two signaling pathways in a cell model of chondrogenesis in vitro.

  20. Notch Signaling Pathway Is Activated in Motoneurons of Spinal Muscular Atrophy

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    Gabriel Olmos

    2013-05-01

    Full Text Available Spinal muscular atrophy (SMA is a neurodegenerative disease produced by low levels of Survival Motor Neuron (SMN protein that affects alpha motoneurons in the spinal cord. Notch signaling is a cell-cell communication system well known as a master regulator of neural development, but also with important roles in the adult central nervous system. Aberrant Notch function is associated with several developmental neurological disorders; however, the potential implication of the Notch pathway in SMA pathogenesis has not been studied yet. We report here that SMN deficiency, induced in the astroglioma cell line U87MG after lentiviral transduction with a shSMN construct, was associated with an increase in the expression of the main components of Notch signaling pathway, namely its ligands, Jagged1 and Delta1, the Notch receptor and its active intracellular form (NICD. In the SMNΔ7 mouse model of SMA we also found increased astrocyte processes positive for Jagged1 and Delta1 in intimate contact with lumbar spinal cord motoneurons. In these motoneurons an increased Notch signaling was found, as denoted by increased NICD levels and reduced expression of the proneural gene neurogenin 3, whose transcription is negatively regulated by Notch. Together, these findings may be relevant to understand some pathologic attributes of SMA motoneurons.

  1. Signaling flux redistribution at toll-like receptor pathway junctions.

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    Kumar Selvarajoo

    Full Text Available Various receptors on cell surface recognize specific extracellular molecules and trigger signal transduction altering gene expression in the nucleus. Gain or loss-of-function mutations of one molecule have shown to affect alternative signaling pathways with a poorly understood mechanism. In Toll-like receptor (TLR 4 signaling, which branches into MyD88- and TRAM-dependent pathways upon lipopolysaccharide (LPS stimulation, we investigated the gain or loss-of-function mutations of MyD88. We predict, using a computational model built on the perturbation-response approach and the law of mass conservation, that removal and addition of MyD88 in TLR4 activation, enhances and impairs, respectively, the alternative TRAM-dependent pathway through signaling flux redistribution (SFR at pathway branches. To verify SFR, we treated MyD88-deficient macrophages with LPS and observed enhancement of TRAM-dependent pathway based on increased IRF3 phosphorylation and induction of Cxcl10 and Ifit2. Furthermore, increasing the amount of MyD88 in cultured cells showed decreased TRAM binding to TLR4. Investigating another TLR4 pathway junction, from TRIF to TRAF6, RIP1 and TBK1, the removal of MyD88-dependent TRAF6 increased expression of TRAM-dependent Cxcl10 and Ifit2. Thus, we demonstrate that SFR is a novel mechanism for enhanced activation of alternative pathways when molecules at pathway junctions are removed. Our data suggest that SFR may enlighten hitherto unexplainable intracellular signaling alterations in genetic diseases where gain or loss-of-function mutations are observed.

  2. Linking proteins to signaling pathways for experiment design and evaluation.

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    Illés J Farkas

    Full Text Available Biomedical experimental work often focuses on altering the functions of selected proteins. These changes can hit signaling pathways, and can therefore unexpectedly and non-specifically affect cellular processes. We propose PathwayLinker, an online tool that can provide a first estimate of the possible signaling effects of such changes, e.g., drug or microRNA treatments. PathwayLinker minimizes the users' efforts by integrating protein-protein interaction and signaling pathway data from several sources with statistical significance tests and clear visualization. We demonstrate through three case studies that the developed tool can point out unexpected signaling bias in normal laboratory experiments and identify likely novel signaling proteins among the interactors of known drug targets. In our first case study we show that knockdown of the Caenorhabditis elegans gene cdc-25.1 (meant to avoid progeny may globally affect the signaling system and unexpectedly bias experiments. In the second case study we evaluate the loss-of-function phenotypes of a less known C. elegans gene to predict its function. In the third case study we analyze GJA1, an anti-cancer drug target protein in human, and predict for this protein novel signaling pathway memberships, which may be sources of side effects. Compared to similar services, a major advantage of PathwayLinker is that it drastically reduces the necessary amount of manual literature searches and can be used without a computational background. PathwayLinker is available at http://PathwayLinker.org. Detailed documentation and source code are available at the website.

  3. Identification of potential pathway mediation targets in Toll-like receptor signaling.

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    Fan Li

    2009-02-01

    Full Text Available Recent advances in reconstruction and analytical methods for signaling networks have spurred the development of large-scale models that incorporate fully functional and biologically relevant features. An extended reconstruction of the human Toll-like receptor signaling network is presented herein. This reconstruction contains an extensive complement of kinases, phosphatases, and other associated proteins that mediate the signaling cascade along with a delineation of their associated chemical reactions. A computational framework based on the methods of large-scale convex analysis was developed and applied to this network to characterize input-output relationships. The input-output relationships enabled significant modularization of the network into ten pathways. The analysis identified potential candidates for inhibitory mediation of TLR signaling with respect to their specificity and potency. Subsequently, we were able to identify eight novel inhibition targets through constraint-based modeling methods. The results of this study are expected to yield meaningful avenues for further research in the task of mediating the Toll-like receptor signaling network and its effects.

  4. The Hedgehog Signalling Pathway in Cell Migration and Guidance: What We Have Learned from Drosophila melanogaster

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    Sofia J. Araújo

    2015-10-01

    Full Text Available Cell migration and guidance are complex processes required for morphogenesis, the formation of tumor metastases, and the progression of human cancer. During migration, guidance molecules induce cell directionality and movement through complex intracellular mechanisms. Expression of these molecules has to be tightly regulated and their signals properly interpreted by the receiving cells so as to ensure correct navigation. This molecular control is fundamental for both normal morphogenesis and human disease. The Hedgehog (Hh signaling pathway is evolutionarily conserved and known to be crucial for normal cellular growth and differentiation throughout the animal kingdom. The relevance of Hh signaling for human disease is emphasized by its activation in many cancers. Here, I review the current knowledge regarding the involvement of the Hh pathway in cell migration and guidance during Drosophila development and discuss its implications for human cancer origin and progression.

  5. Oscillatory Dynamics of the Extracellular Signal-regulated Kinase Pathway

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    Shankaran, Harish; Wiley, H. S.

    2010-12-01

    The extracellular signal-regulated kinase (ERK) pathway is a central signaling pathway in development and disease and is regulated by multiple negative and positive feedback loops. Recent studies have shown negative feedback from ERK to upstream regulators can give rise to biochemical oscillations with a periodicity of between 15-30 minutes. Feedback due to the stimulated transcription of negative regulators of the ERK pathway can also give rise to transcriptional oscillations with a periodicity of 1-2h. The biological significance of these oscillations is not clear, but recent evidence suggests that transcriptional oscillations participate in developmental processes, such as somite formation. Biochemical oscillations are more enigmatic, but could provide a mechanism for encoding different types of inputs into a common signaling pathway.

  6. Wnt pathway in Dupuytren disease: connecting profibrotic signals.

    Science.gov (United States)

    van Beuge, Marike M; Ten Dam, Evert-Jan P M; Werker, Paul M N; Bank, Ruud A

    2015-12-01

    A role of Wnt signaling in Dupuytren disease, a fibroproliferative disease of the hand and fingers, has not been fully elucidated. We examined a large set of Wnt pathway components and signaling targets and found significant dysregulation of 41 Wnt-related genes in tissue from the Dupuytren nodules compared with patient-matched control tissue. A large proportion of genes coding for Wnt proteins themselves was downregulated. However, both canonical Wnt targets and components of the noncanonical signaling pathway were upregulated. Immunohistochemical analysis revealed that protein expression of Wnt1-inducible secreted protein 1 (WISP1), a known Wnt target, was increased in nodules compared with control tissue, but knockdown of WISP1 using small interfering RNA (siRNA) in the Dupuytren myofibroblasts did not confirm a functional role. The protein expression of noncanonical pathway components Wnt5A and VANGL2 as well as noncanonical coreceptors Ror2 and Ryk was increased in nodules. On the contrary, the strongest downregulated genes in this study were 4 antagonists of Wnt signaling (DKK1, FRZB, SFRP1, and WIF1). Downregulation of these genes in the Dupuytren tissue was mimicked in vitro by treating normal fibroblasts with transforming growth factor β1 (TGF-β1), suggesting cross talk between different profibrotic pathways. Furthermore, siRNA-mediated knockdown of these antagonists in normal fibroblasts led to increased nuclear translocation of Wnt target β-catenin in response to TGF-β1 treatment. In conclusion, we have shown extensive dysregulation of Wnt signaling in affected tissue from Dupuytren disease patients. Components of both the canonical and the noncanonical pathways are upregulated, whereas endogenous antagonists are downregulated, possibly via interaction with other profibrotic pathways. Copyright © 2015 Elsevier Inc. All rights reserved.

  7. Signaling pathway networks mined from human pituitary adenoma proteomics data

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    Zhan Xianquan

    2010-04-01

    Full Text Available Abstract Background We obtained a series of pituitary adenoma proteomic expression data, including protein-mapping data (111 proteins, comparative proteomic data (56 differentially expressed proteins, and nitroproteomic data (17 nitroproteins. There is a pressing need to clarify the significant signaling pathway networks that derive from those proteins in order to clarify and to better understand the molecular basis of pituitary adenoma pathogenesis and to discover biomarkers. Here, we describe the significant signaling pathway networks that were mined from human pituitary adenoma proteomic data with the Ingenuity pathway analysis system. Methods The Ingenuity pathway analysis system was used to analyze signal pathway networks and canonical pathways from protein-mapping data, comparative proteomic data, adenoma nitroproteomic data, and control nitroproteomic data. A Fisher's exact test was used to test the statistical significance with a significance level of 0.05. Statistical significant results were rationalized within the pituitary adenoma biological system with literature-based bioinformatics analyses. Results For the protein-mapping data, the top pathway networks were related to cancer, cell death, and lipid metabolism; the top canonical toxicity pathways included acute-phase response, oxidative-stress response, oxidative stress, and cell-cycle G2/M transition regulation. For the comparative proteomic data, top pathway networks were related to cancer, endocrine system development and function, and lipid metabolism; the top canonical toxicity pathways included mitochondrial dysfunction, oxidative phosphorylation, oxidative-stress response, and ERK/MAPK signaling. The nitroproteomic data from a pituitary adenoma were related to cancer, cell death, lipid metabolism, and reproductive system disease, and the top canonical toxicity pathways mainly related to p38 MAPK signaling and cell-cycle G2/M transition regulation. Nitroproteins from a

  8. Wnt and Notch signaling pathway involved in wound healing by targeting c-Myc and Hes1 separately.

    Science.gov (United States)

    Shi, Yan; Shu, Bin; Yang, Ronghua; Xu, Yingbin; Xing, Bangrong; Liu, Jian; Chen, Lei; Qi, Shaohai; Liu, Xusheng; Wang, Peng; Tang, Jinming; Xie, Julin

    2015-06-16

    Wnt and Notch signaling pathways are critically involved in relative cell fate decisions within the development of cutaneous tissues. Moreover, several studies identified the above two pathways as having a significant role during wound healing. However, their biological effects during cutaneous tissues repair are unclear. We employed a self-controlled model (Sprague-Dawley rats with full-thickness skin wounds) to observe the action and effect of Wnt/β-catenin and Notch signalings in vivo. The quality of wound repair relevant to the gain/loss-of-function Wnt/β-catenin and Notch activation was estimated by hematoxylin-and-eosin and Masson staining. Immunofluorescence analysis and Western blot analysis were used to elucidate the underlying mechanism of the regulation of Wnt and Notch signaling pathways in wound healing. Meanwhile, epidermal stem cells (ESCs) were cultured in keratinocyte serum-free medium with Jaggedl or in DAPT (N-[(3,5-difluorophenyl)acetyl]-L-alanyl-2-phenyl]glycine-1,1-dimethylethyl) to investigate whether the interruption of Notch signaling contributes to the expression of Wnt/β-catenin signaling. The results showed that in vivo the gain-of-function Wnt/β-catenin and Notch activation extended the ability to promote wound closure. We further determined that activation or inhibition of Wnt signaling and Notch signaling can affect the proliferation of ESCs, the differentiation and migration of keratinocytes, and follicle regeneration by targeting c-Myc and Hes1, which ultimately lead to enhanced or delayed wound healing. Furthermore, Western blot analysis suggested that the two pathways might interact in vivo and in vitro. These results suggest that Wnt and Notch signalings play important roles in cutaneous repair by targeting c-Myc and Hes1 separately. What's more, interaction between the above two pathways might act as a vital role in regulation of wound healing.

  9. Inferring the functional effect of gene expression changes in signaling pathways

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    Sebastián-León, Patricia; Carbonell, José; Salavert, Francisco; Sanchez, Rubén; Medina, Ignacio; Dopazo, Joaquín

    2013-01-01

    Signaling pathways constitute a valuable source of information that allows interpreting the way in which alterations in gene activities affect to particular cell functionalities. There are web tools available that allow viewing and editing pathways, as well as representing experimental data on them. However, few methods aimed to identify the signaling circuits, within a pathway, associated to the biological problem studied exist and none of them provide a convenient graphical web interface. We present PATHiWAYS, a web-based signaling pathway visualization system that infers changes in signaling that affect cell functionality from the measurements of gene expression values in typical expression microarray case–control experiments. A simple probabilistic model of the pathway is used to estimate the probabilities for signal transmission from any receptor to any final effector molecule (taking into account the pathway topology) using for this the individual probabilities of gene product presence/absence inferred from gene expression values. Significant changes in these probabilities allow linking different cell functionalities triggered by the pathway to the biological problem studied. PATHiWAYS is available at: http://pathiways.babelomics.org/. PMID:23748960

  10. Phylogenetic diversity of stress signalling pathways in fungi

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    Stansfield Ian

    2009-02-01

    Full Text Available Abstract Background Microbes must sense environmental stresses, transduce these signals and mount protective responses to survive in hostile environments. In this study we have tested the hypothesis that fungal stress signalling pathways have evolved rapidly in a niche-specific fashion that is independent of phylogeny. To test this hypothesis we have compared the conservation of stress signalling molecules in diverse fungal species with their stress resistance. These fungi, which include ascomycetes, basidiomycetes and microsporidia, occupy highly divergent niches from saline environments to plant or mammalian hosts. Results The fungi displayed significant variation in their resistance to osmotic (NaCl and sorbitol, oxidative (H2O2 and menadione and cell wall stresses (Calcofluor White and Congo Red. There was no strict correlation between fungal phylogeny and stress resistance. Rather, the human pathogens tended to be more resistant to all three types of stress, an exception being the sensitivity of Candida albicans to the cell wall stress, Calcofluor White. In contrast, the plant pathogens were relatively sensitive to oxidative stress. The degree of conservation of osmotic, oxidative and cell wall stress signalling pathways amongst the eighteen fungal species was examined. Putative orthologues of functionally defined signalling components in Saccharomyces cerevisiae were identified by performing reciprocal BLASTP searches, and the percent amino acid identities of these orthologues recorded. This revealed that in general, central components of the osmotic, oxidative and cell wall stress signalling pathways are relatively well conserved, whereas the sensors lying upstream and transcriptional regulators lying downstream of these modules have diverged significantly. There was no obvious correlation between the degree of conservation of stress signalling pathways and the resistance of a particular fungus to the corresponding stress. Conclusion Our

  11. Signaling Pathways in Pathogenesis of Diamond Blackfan Anemia

    Science.gov (United States)

    2015-12-01

    AWARD NUMBER: W81XWH-12-1-0590 TITLE: SIGNALING PATHWAYS IN PATHOGENESIS OF DIAMOND BLACKFAN ANEMIA PRINCIPAL INVESTIGATOR: KATHLEEN M...SUBTITLE 5a. CONTRACT NUMBER W81XWH-12-1-0590 SIGNALING PATHWAYS IN PATHOGENESIS OF DIAMOND BLACKFAN ANEMIA 5b. GRANT NUMBER 5c. PROGRAM ELEMENT NUMBER...Unlimited 13. SUPPLEMENTARY NOTES None 14. ABSTRACT: Diamond Blackfan Anemia (DBA) is a disorder that results in pure red cell aplasia, congenital

  12. Differences in gene expression profiles and signaling pathways in rhabdomyolysis-induced acute kidney injury.

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    Geng, Xiaodong; Wang, Yuanda; Hong, Quan; Yang, Jurong; Zheng, Wei; Zhang, Gang; Cai, Guangyan; Chen, Xiangmei; Wu, Di

    2015-01-01

    Rhabdomyolysis is a threatening syndrome because it causes the breakdown of skeletal muscle. Muscle destruction leads to the release of myoglobin, intracellular proteins, and electrolytes into the circulation. The aim of this study was to investigate the differences in gene expression profiles and signaling pathways upon rhabdomyolysis-induced acute kidney injury (AKI). In this study, we used glycerol-induced renal injury as a model of rhabdomyolysis-induced AKI. We analyzed data and relevant information from the Gene Expression Omnibus database (No: GSE44925). The gene expression data for three untreated mice were compared to data for five mice with rhabdomyolysis-induced AKI. The expression profiling of the three untreated mice and the five rhabdomyolysis-induced AKI mice was performed using microarray analysis. We examined the levels of Cyp3a13, Rela, Aldh7a1, Jun, CD14. And Cdkn1a using RT-PCR to determine the accuracy of the microarray results. The microarray analysis showed that there were 1050 downregulated and 659 upregulated genes in the rhabdomyolysis-induced AKI mice compared to the control group. The interactions of all differentially expressed genes in the Signal-Net were analyzed. Cyp3a13 and Rela had the most interactions with other genes. The data showed that Rela and Aldh7a1 were the key nodes and had important positions in the Signal-Net. The genes Jun, CD14, and Cdkn1a were also significantly upregulated. The pathway analysis classified the differentially expressed genes into 71 downregulated and 48 upregulated pathways including the PI3K/Akt, MAPK, and NF-κB signaling pathways. The results of this study indicate that the NF-κB, MAPK, PI3K/Akt, and apoptotic pathways are regulated in rhabdomyolysis-induced AKI.

  13. Use of Human Induced Pluripotent Stem Cell-Derived Cardiomyocytes (hiPSC-CMs) to Monitor Compound Effects on Cardiac Myocyte Signaling Pathways.

    Science.gov (United States)

    Guo, Liang; Eldridge, Sandy; Furniss, Mike; Mussio, Jodie; Davis, Myrtle

    2015-09-01

    There is a need to develop mechanism-based assays to better inform risk of cardiotoxicity. Human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) are rapidly gaining acceptance as a biologically relevant in vitro model for use in drug discovery and cardiotoxicity screens. Utilization of hiPSC-CMs for mechanistic investigations would benefit from confirmation of the expression and activity of cellular pathways that are known to regulate cardiac myocyte viability and function. This unit describes an approach to demonstrate the presence and function of signaling pathways in hiPSC-CMs and the effects of treatments on these pathways. We present a workflow that employs protocols to demonstrate protein expression and functional integrity of signaling pathway(s) of interest and to characterize biological consequences of signaling modulation. These protocols utilize a unique combination of structural, functional, and biochemical endpoints to interrogate compound effects on cardiomyocytes. Copyright © 2015 John Wiley & Sons, Inc.

  14. The role of the Hedgehog signaling pathway in cancer: A comprehensive review

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    Ana Marija Skoda

    2018-02-01

    Full Text Available The Hedgehog (Hh signaling pathway was first identified in the common fruit fly. It is a highly conserved evolutionary pathway of signal transmission from the cell membrane to the nucleus. The Hh signaling pathway plays an important role in the embryonic development. It exerts its biological effects through a signaling cascade that culminates in a change of balance between activator and repressor forms of glioma-associated oncogene (Gli transcription factors. The components of the Hh signaling pathway involved in the signaling transfer to the Gli transcription factors include Hedgehog ligands (Sonic Hh [SHh], Indian Hh [IHh], and Desert Hh [DHh], Patched receptor (Ptch1, Ptch2, Smoothened receptor (Smo, Suppressor of fused homolog (Sufu, kinesin protein Kif7, protein kinase A (PKA, and cyclic adenosine monophosphate (cAMP. The activator form of Gli travels to the nucleus and stimulates the transcription of the target genes by binding to their promoters. The main target genes of the Hh signaling pathway are PTCH1, PTCH2, and GLI1. Deregulation of the Hh signaling pathway is associated with developmental anomalies and cancer, including Gorlin syndrome, and sporadic cancers, such as basal cell carcinoma, medulloblastoma, pancreatic, breast, colon, ovarian, and small-cell lung carcinomas. The aberrant activation of the Hh signaling pathway is caused by mutations in the related genes (ligand-independent signaling or by the excessive expression of the Hh signaling molecules (ligand-dependent signaling – autocrine or paracrine. Several Hh signaling pathway inhibitors, such as vismodegib and sonidegib, have been developed for cancer treatment. These drugs are regarded as promising cancer therapies, especially for patients with refractory/advanced cancers.

  15. Optimal structural inference of signaling pathways from unordered and overlapping gene sets.

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    Acharya, Lipi R; Judeh, Thair; Wang, Guangdi; Zhu, Dongxiao

    2012-02-15

    A plethora of bioinformatics analysis has led to the discovery of numerous gene sets, which can be interpreted as discrete measurements emitted from latent signaling pathways. Their potential to infer signaling pathway structures, however, has not been sufficiently exploited. Existing methods accommodating discrete data do not explicitly consider signal cascading mechanisms that characterize a signaling pathway. Novel computational methods are thus needed to fully utilize gene sets and broaden the scope from focusing only on pairwise interactions to the more general cascading events in the inference of signaling pathway structures. We propose a gene set based simulated annealing (SA) algorithm for the reconstruction of signaling pathway structures. A signaling pathway structure is a directed graph containing up to a few hundred nodes and many overlapping signal cascades, where each cascade represents a chain of molecular interactions from the cell surface to the nucleus. Gene sets in our context refer to discrete sets of genes participating in signal cascades, the basic building blocks of a signaling pathway, with no prior information about gene orderings in the cascades. From a compendium of gene sets related to a pathway, SA aims to search for signal cascades that characterize the optimal signaling pathway structure. In the search process, the extent of overlap among signal cascades is used to measure the optimality of a structure. Throughout, we treat gene sets as random samples from a first-order Markov chain model. We evaluated the performance of SA in three case studies. In the first study conducted on 83 KEGG pathways, SA demonstrated a significantly better performance than Bayesian network methods. Since both SA and Bayesian network methods accommodate discrete data, use a 'search and score' network learning strategy and output a directed network, they can be compared in terms of performance and computational time. In the second study, we compared SA and

  16. Review of Signaling Pathways Governing MSC Osteogenic and Adipogenic Differentiation

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    Aaron W. James

    2013-01-01

    Full Text Available Mesenchymal stem cells (MSC are multipotent cells, functioning as precursors to a variety of cell types including adipocytes, osteoblasts, and chondrocytes. Between osteogenic and adipogenic lineage commitment and differentiation, a theoretical inverse relationship exists, such that differentiation towards an osteoblast phenotype occurs at the expense of an adipocytic phenotype. This balance is regulated by numerous, intersecting signaling pathways that converge on the regulation of two main transcription factors: peroxisome proliferator-activated receptor-γ (PPARγ and Runt-related transcription factor 2 (Runx2. These two transcription factors, PPARγ and Runx2, are generally regarded as the master regulators of adipogenesis and osteogenesis. This review will summarize signaling pathways that govern MSC fate towards osteogenic or adipocytic differentiation. A number of signaling pathways follow the inverse balance between osteogenic and adipogenic differentiation and are generally proosteogenic/antiadipogenic stimuli. These include β-catenin dependent Wnt signaling, Hedgehog signaling, and NELL-1 signaling. However, other signaling pathways exhibit more context-dependent effects on adipogenic and osteogenic differentiation. These include bone morphogenic protein (BMP signaling and insulin growth factor (IGF signaling, which display both proosteogenic and proadipogenic effects. In summary, understanding those factors that govern osteogenic versus adipogenic MSC differentiation has significant implications in diverse areas of human health, from obesity to osteoporosis to regenerative medicine.

  17. Altered Expression of Wnt Signaling Pathway Components in Osteogenesis of Mesenchymal Stem Cells in Osteoarthritis Patients.

    Science.gov (United States)

    Tornero-Esteban, Pilar; Peralta-Sastre, Ascensión; Herranz, Eva; Rodríguez-Rodríguez, Luis; Mucientes, Arkaitz; Abásolo, Lydia; Marco, Fernando; Fernández-Gutiérrez, Benjamín; Lamas, José Ramón

    2015-01-01

    Osteoarthritis (OA) is characterized by altered homeostasis of joint cartilage and bone, whose functional properties rely on chondrocytes and osteoblasts, belonging to mesenchymal stem cells (MSCs). WNT signaling acts as a hub integrating and crosstalking with other signaling pathways leading to the regulation of MSC functions. The aim of this study was to evaluate the existence of a differential signaling between Healthy and OA-MSCs during osteogenesis. MSCs of seven OA patients and six healthy controls were isolated, characterised and expanded. During in vitro osteogenesis, cells were recovered at days 1, 10 and 21. RNA and protein content was obtained. Expression of WNT pathway genes was evaluated using RT-qPCR. Functional studies were also performed to study the MSC osteogenic commitment and functional and post-traslational status of β-catenin and several receptor tyrosine kinases. Several genes were downregulated in OA-MSCs during osteogenesis in vitro. These included soluble Wnts, inhibitors, receptors, co-receptors, several kinases and transcription factors. Basal levels of β-catenin were higher in OA-MSCs, but calcium deposition and expression of osteogenic genes was similar between Healthy and OA-MSCs. Interestingly an increased phosphorylation of p44/42 MAPK (ERK1/2) signaling node was present in OA-MSCs. Our results point to the existence in OA-MSCs of alterations in expression of Wnt pathway components during in vitro osteogenesis that are partially compensated by post-translational mechanisms modulating the function of other pathways. We also point the relevance of other signaling pathways in OA pathophysiology suggesting their role in the maintenance of joint homeostasis through modulation of MSC osteogenic potential.

  18. Non-genomic actions of retinoic acid induce pi3k signaling pathway and phosphorylation of nuclear proteins

    OpenAIRE

    Laserna Mendieta, Emilio J.; Masiá, Susana; Barettino, Domingo

    2007-01-01

    Retinoic acid (RA), the active form of vitamin A, induces neuroblastoma cells SH-SY5Y to differentiate. In addition to its classical transcriptional actions regulating the expression of specific genes, RA acts in an extra-genomic way, modulating the activity of relevant signalling cascades. In particular, RA treatment of SH-SY5Y neuroblastoma cells results in activation of phosphatidyl-inositol-3-kinase (PI3K) signaling pathway, and this activation is required for RA-induced differentiation (...

  19. Microenvironment Dependent Photobiomodulation on Function-Specific Signal Transduction Pathways

    Directory of Open Access Journals (Sweden)

    Timon Cheng-Yi Liu

    2014-01-01

    Full Text Available Cellular photobiomodulation on a cellular function has been shown to be homeostatic. Its function-specific pathway mechanism would be further discussed in this paper. The signal transduction pathways maintaining a normal function in its function-specific homeostasis (FSH, resisting the activation of many other irrelative signal transduction pathways, are so sparse that it can be supposed that there may be normal function-specific signal transduction pathways (NSPs. A low level laser irradiation or monochromatic light may promote the activation of partially activated NSP and/or its redundant NSP so that it may induce the second-order phase transition of a function from its dysfunctional one far from its FSH to its normal one in a function-specific microenvironment and may also induce the first-order functional phase transition of the normal function from low level to high level.

  20. Role of Notch signalling pathway in cancer and its association with ...

    Indian Academy of Sciences (India)

    The Notch signalling pathway is an evolutionarily conserved cell signalling pathway involved in the development of organ- ... Abnormal Notch signalling is seen in many cancers like T-cell acute ...... Morgan T. H. 1917 The theory of the gene.

  1. Intercellular signaling pathways active during intervertebral disc growth, differentiation, and aging.

    Science.gov (United States)

    Dahia, Chitra Lekha; Mahoney, Eric J; Durrani, Atiq A; Wylie, Christopher

    2009-03-01

    Intervertebral discs at different postnatal ages were assessed for active intercellular signaling pathways. To generate a spatial and temporal map of the signaling pathways active in the postnatal intervertebral disc (IVD). The postnatal IVD is a complex structure, consisting of 3 histologically distinct components, the nucleus pulposus, fibrous anulus fibrosus, and endplate. These differentiate and grow during the first 9 weeks of age in the mouse. Identification of the major signaling pathways active during and after the growth and differentiation period will allow functional analysis using mouse genetics and identify targets for therapy for individual components of the disc. Antibodies specific for individual cell signaling pathways were used on cryostat sections of IVD at different postnatal ages to identify which components of the IVD were responding to major classes of intercellular signal, including sonic hedgehog, Wnt, TGFbeta, FGF, and BMPs. We present a spatial/temporal map of these signaling pathways during growth, differentiation, and aging of the disc. During growth and differentiation of the disc, its different components respond at different times to different intercellular signaling ligands. Most of these are dramatically downregulated at the end of disc growth.

  2. Signal Enhancement as Minimization of Relevant Information Loss

    OpenAIRE

    Geiger, Bernhard C.; Kubin, Gernot

    2012-01-01

    We introduce the notion of relevant information loss for the purpose of casting the signal enhancement problem in information-theoretic terms. We show that many algorithms from machine learning can be reformulated using relevant information loss, which allows their application to the aforementioned problem. As a particular example we analyze principle component analysis for dimensionality reduction, discuss its optimality, and show that the relevant information loss can indeed vanish if the r...

  3. The Wnt signaling pathway in familial exudative vitreoretinopathy and Norrie disease.

    Science.gov (United States)

    Warden, Scott M; Andreoli, Christopher M; Mukai, Shizuo

    2007-01-01

    The Wnt signaling pathway is highly conserved among species and has an important role in many cell biological processes throughout the body. This signaling cascade is involved in regulating ocular growth and development, and recent findings indicate that this is particularly true in the retina. Mutations involving different aspects of the Wnt signaling pathway are being linked to several diseases of retinal development. The aim of this article is to first review the Wnt signaling pathway. We will then describe two conditions, familial exudative vitreoretinopathy (FEVR) and Norrie disease (ND), which have been shown to be caused in part by defects in the Wnt signaling cascade.

  4. Insulin signaling pathways in lepidopteran steroidogenesis

    Directory of Open Access Journals (Sweden)

    Wendy eSmith

    2014-02-01

    Full Text Available Molting and metamorphosis are stimulated by the secretion of ecdysteroid hormones from the prothoracic glands. Insulin-like hormones have been found to enhance prothoracic gland activity, providing a mechanism to link molting to nutritional state. In silk moths (Bombyx mori, the prothoracic glands are directly stimulated by insulin and the insulin-like hormone bombyxin. Further, in Bombyx , the neuropeptide prothoracicotropic hormone (PTTH appears to act at least in part through the insulin-signaling pathway. In the prothoracic glands of Manduca sexta, while insulin stimulates the phosphorylation of the insulin receptor and Akt, neither insulin nor bombyxin II stimulate ecdysone secretion. Involvement of the insulin-signaling pathway in Manduca prothoracic glands was explored using two inhibitors of phosphatidylinositol-3-kinase (PI3K, LY294002 and wortmannin. PI3K inhibitors block the phosphorylation of Akt and 4EBP but have no effect on ecdysone secretion, or on the phosphorylation of the MAPkinase, ERK. Inhibitors that block phosphorylation of ERK, including the MEK inhibitor U0126, and high doses of the RSK inhibitor SL0101, effectively inhibit ecdysone secretion. The results highlight differences between the two lepidopteran insects most commonly used to directly study ecdysteroid secretion. In Bombyx, the PTTH and insulin-signaling pathways intersect; both insulin and PTTH enhance the phosphorylation of Akt and stimulate ecdysteroid secretion, and inhibition of PI3K reduces ecdysteroid secretion. By contrast, in Manduca, the action of PTTH is distinct from insulin. The results highlight species differences in the roles of translational regulators such as 4EBP, and members of the MAPkinase pathway such as ERK and RSK, in the effects of nutritionally-sensitive hormones such as insulin on ecdysone secretion and molting.

  5. Oncogenic Signaling Pathways in The Cancer Genome Atlas

    NARCIS (Netherlands)

    Sanchez-Vega, Francisco; Mina, Marco; Armenia, Joshua; Chatila, Walid K.; Luna, Augustin; La, Konnor C.; Dimitriadoy, Sofia; Liu, David L.; Kantheti, Havish S.; Saghafinia, Sadegh; Chakravarty, Debyani; Daian, Foysal; Gao, Qingsong; Bailey, Matthew H.; Liang, Wen Wei; Foltz, Steven M.; Shmulevich, Ilya; Ding, Li; Heins, Zachary J.; Ochoa, Angelica; Gross, Benjamin E.; Gao, Jianjiong; Zhang, Hongxin; Kundra, Ritika; Kandoth, Cyriac; Bahceci, Istemi; Dervishi, Leonard; Dogrusoz, Ugur; Zhou, Wanding; Shen, Hui; Laird, Peter W.; Way, Gregory P.; Greene, Casey S.; Liang, Han; Xiao, Yonghong; Wang, Chen; Iavarone, Antonio; Berger, Alice H.; Bivona, Trever G.; Lazar, Alexander J.; Hammer, Gary D.; Giordano, Thomas; Kwong, Lawrence N.; McArthur, Grant; Huang, Chenfei; Tward, Aaron D.; Frederick, Mitchell J.; McCormick, Frank; Meyerson, Matthew; Caesar-Johnson, Samantha J.; Demchok, John A.; Felau, Ina; Kasapi, Melpomeni; Ferguson, Martin L.; Hutter, Carolyn M.; Sofia, Heidi J.; Tarnuzzer, Roy; Wang, Zhining; Yang, Liming; Zenklusen, Jean C.; Zhang, Jiashan (Julia); Chudamani, Sudha; Liu, Jia; Lolla, Laxmi; Naresh, Rashi; Pihl, Todd; Sun, Qiang; Wan, Yunhu; Wu, Ye; Cho, Juok; DeFreitas, Timothy; Frazer, Scott; Gehlenborg, Nils; Getz, Gad; Heiman, David I.; Kim, Jaegil; Lawrence, Michael S.; Lin, Pei; Meier, Sam; Noble, Michael S.; Saksena, Gordon; Voet, Doug; Zhang, Hailei; Bernard, Brady; Chambwe, Nyasha; Dhankani, Varsha; Knijnenburg, Theo; Kramer, Roger; Leinonen, Kalle; Liu, Yuexin; Miller, Michael; Reynolds, Sheila; Shmulevich, Ilya; Thorsson, Vesteinn; Zhang, Wei; Akbani, Rehan; Broom, Bradley M.; Hegde, Apurva M.; Ju, Zhenlin; Kanchi, Rupa S.; Korkut, Anil; Li, Jun; Liang, Han; Ling, Shiyun; Liu, Wenbin; Lu, Yiling; Mills, Gordon B.; Ng, Kwok Shing; Rao, Arvind; Ryan, Michael; Wang, Jing; Weinstein, John N.; Zhang, Jiexin; Abeshouse, Adam; Armenia, Joshua; Chakravarty, Debyani; Chatila, Walid K.; de Bruijn, Ino; Gao, Jianjiong; Gross, Benjamin E.; Heins, Zachary J.; Kundra, Ritika; La, Konnor; Ladanyi, Marc; Luna, Augustin; Nissan, Moriah G.; Ochoa, Angelica; Phillips, Sarah M.; Reznik, Ed; Sanchez-Vega, Francisco; Sander, Chris; Schultz, Nikolaus; Sheridan, Robert; Sumer, S. Onur; Sun, Yichao; Taylor, Barry S.; Wang, Jioajiao; Zhang, Hongxin; Anur, Pavana; Peto, Myron; Spellman, Paul; Benz, Christopher; Stuart, Joshua M.; Wong, Christopher K.; Yau, Christina; Hayes, D. Neil; Parker, Joel S.; Wilkerson, Matthew D.; Ally, Adrian; Balasundaram, Miruna; Bowlby, Reanne; Brooks, Denise; Carlsen, Rebecca; Chuah, Eric; Dhalla, Noreen; Holt, Robert; Jones, Steven J.M.; Kasaian, Katayoon; Lee, Darlene; Ma, Yussanne; Marra, Marco A.; Mayo, Michael; Moore, Richard A.; Mungall, Andrew J.; Mungall, Karen; Robertson, A. Gordon; Sadeghi, Sara; Schein, Jacqueline E.; Sipahimalani, Payal; Tam, Angela; Thiessen, Nina; Tse, Kane; Wong, Tina; Berger, Ashton C.; Beroukhim, Rameen; Cherniack, Andrew D.; Cibulskis, Carrie; Gabriel, Stacey B.; Gao, Galen F.; Ha, Gavin; Meyerson, Matthew; Schumacher, Steven E.; Shih, Juliann; Kucherlapati, Melanie H.; Kucherlapati, Raju S.; Baylin, Stephen; Cope, Leslie; Danilova, Ludmila; Bootwalla, Moiz S.; Lai, Phillip H.; Maglinte, Dennis T.; Van Den Berg, David J.; Weisenberger, Daniel J.; Auman, J. Todd; Balu, Saianand; Bodenheimer, Tom; Fan, Cheng; Hoadley, Katherine A.; Hoyle, Alan P.; Jefferys, Stuart R.; Jones, Corbin D.; Meng, Shaowu; Mieczkowski, Piotr A.; Mose, Lisle E.; Perou, Amy H.; Perou, Charles M.; Roach, Jeffrey; Shi, Yan; Simons, Janae V.; Skelly, Tara; Soloway, Matthew G.; Tan, Donghui; Veluvolu, Umadevi; Fan, Huihui; Hinoue, Toshinori; Laird, Peter W.; Shen, Hui; Zhou, Wanding; Bellair, Michelle; Chang, Kyle; Covington, Kyle; Creighton, Chad J.; Dinh, Huyen; Doddapaneni, Harsha Vardhan; Donehower, Lawrence A.; Drummond, Jennifer; Gibbs, Richard A.; Glenn, Robert; Hale, Walker; Han, Yi; Hu, Jianhong; Korchina, Viktoriya; Lee, Sandra; Lewis, Lora; Li, Wei; Liu, Xiuping; Morgan, Margaret; Morton, Donna; Muzny, Donna; Santibanez, Jireh; Sheth, Margi; Shinbrot, Eve; Wang, Linghua; Wang, Min; Wheeler, David A.; Xi, Liu; Zhao, Fengmei; Hess, Julian; Appelbaum, Elizabeth L.; Bailey, Matthew; Cordes, Matthew G.; Ding, Li; Fronick, Catrina C.; Fulton, Lucinda A.; Fulton, Robert S.; Kandoth, Cyriac; Mardis, Elaine R.; McLellan, Michael D.; Miller, Christopher A.; Schmidt, Heather K.; Wilson, Richard K.; Crain, Daniel; Curley, Erin; Gardner, Johanna; Lau, Kevin; Mallery, David; Morris, Scott; Paulauskis, Joseph; Penny, Robert; Shelton, Candace; Shelton, Troy; Sherman, Mark; Thompson, Eric; Yena, Peggy; Bowen, Jay; Gastier-Foster, Julie M.; Gerken, Mark; Leraas, Kristen M.; Lichtenberg, Tara M.; Ramirez, Nilsa C.; Wise, Lisa; Zmuda, Erik; Corcoran, Niall; Costello, Tony; Hovens, Christopher; Carvalho, Andre L.; de Carvalho, Ana C.; Fregnani, José H.; Longatto-Filho, Adhemar; Reis, Rui M.; Scapulatempo-Neto, Cristovam; Silveira, Henrique C.S.; Vidal, Daniel O.; Burnette, Andrew; Eschbacher, Jennifer; Hermes, Beth; Noss, Ardene; Singh, Rosy; Anderson, Matthew L.; Castro, Patricia D.; Ittmann, Michael; Huntsman, David; Kohl, Bernard; Le, Xuan; Thorp, Richard; Andry, Chris; Duffy, Elizabeth R.; Lyadov, Vladimir; Paklina, Oxana; Setdikova, Galiya; Shabunin, Alexey; Tavobilov, Mikhail; McPherson, Christopher; Warnick, Ronald; Berkowitz, Ross; Cramer, Daniel; Feltmate, Colleen; Horowitz, Neil; Kibel, Adam; Muto, Michael; Raut, Chandrajit P.; Malykh, Andrei; Barnholtz-Sloan, Jill S.; Barrett, Wendi; Devine, Karen; Fulop, Jordonna; Ostrom, Quinn T.; Shimmel, Kristen; Wolinsky, Yingli; Sloan, Andrew E.; De Rose, Agostino; Giuliante, Felice; Goodman, Marc; Karlan, Beth Y.; Hagedorn, Curt H.; Eckman, John; Harr, Jodi; Myers, Jerome; Tucker, Kelinda; Zach, Leigh Anne; Deyarmin, Brenda; Hu, Hai; Kvecher, Leonid; Larson, Caroline; Mural, Richard J.; Somiari, Stella; Vicha, Ales; Zelinka, Tomas; Bennett, Joseph; Iacocca, Mary; Rabeno, Brenda; Swanson, Patricia; Latour, Mathieu; Lacombe, Louis; Têtu, Bernard; Bergeron, Alain; McGraw, Mary; Staugaitis, Susan M.; Chabot, John; Hibshoosh, Hanina; Sepulveda, Antonia; Su, Tao; Wang, Timothy; Potapova, Olga; Voronina, Olga; Desjardins, Laurence; Mariani, Odette; Roman-Roman, Sergio; Sastre, Xavier; Stern, Marc Henri; Cheng, Feixiong; Signoretti, Sabina; Berchuck, Andrew; Bigner, Darell; Lipp, Eric; Marks, Jeffrey; McCall, Shannon; McLendon, Roger; Secord, Angeles; Sharp, Alexis; Behera, Madhusmita; Brat, Daniel J.; Chen, Amy; Delman, Keith; Force, Seth; Khuri, Fadlo; Magliocca, Kelly; Maithel, Shishir; Olson, Jeffrey J.; Owonikoko, Taofeek; Pickens, Alan; Ramalingam, Suresh; Shin, Dong M.; Sica, Gabriel; Van Meir, Erwin G.; Zhang, Hongzheng; Eijckenboom, Wil; Gillis, Ad; Korpershoek, Esther; Looijenga, Leendert; Oosterhuis, Wolter; Stoop, Hans; van Kessel, Kim E.; Zwarthoff, Ellen C.; Calatozzolo, Chiara; Cuppini, Lucia; Cuzzubbo, Stefania; DiMeco, Francesco; Finocchiaro, Gaetano; Mattei, Luca; Perin, Alessandro; Pollo, Bianca; Chen, Chu; Houck, John; Lohavanichbutr, Pawadee; Hartmann, Arndt; Stoehr, Christine; Stoehr, Robert; Taubert, Helge; Wach, Sven; Wullich, Bernd; Kycler, Witold; Murawa, Dawid; Wiznerowicz, Maciej; Chung, Ki; Edenfield, W. Jeffrey; Martin, Julie; Baudin, Eric; Bubley, Glenn; Bueno, Raphael; De Rienzo, Assunta; Richards, William G.; Kalkanis, Steven; Mikkelsen, Tom; Noushmehr, Houtan; Scarpace, Lisa; Girard, Nicolas; Aymerich, Marta; Campo, Elias; Giné, Eva; Guillermo, Armando López; Van Bang, Nguyen; Hanh, Phan Thi; Phu, Bui Duc; Tang, Yufang; Colman, Howard; Evason, Kimberley; Dottino, Peter R.; Martignetti, John A.; Gabra, Hani; Juhl, Hartmut; Akeredolu, Teniola; Stepa, Serghei; Hoon, Dave; Ahn, Keunsoo; Kang, Koo Jeong; Beuschlein, Felix; Breggia, Anne; Birrer, Michael; Bell, Debra; Borad, Mitesh; Bryce, Alan H.; Castle, Erik; Chandan, Vishal; Cheville, John; Copland, John A.; Farnell, Michael; Flotte, Thomas; Giama, Nasra; Ho, Thai; Kendrick, Michael; Kocher, Jean Pierre; Kopp, Karla; Moser, Catherine; Nagorney, David; O'Brien, Daniel; O'Neill, Brian Patrick; Patel, Tushar; Petersen, Gloria; Que, Florencia; Rivera, Michael; Roberts, Lewis; Smallridge, Robert; Smyrk, Thomas; Stanton, Melissa; Thompson, R. Houston; Torbenson, Michael; Yang, Ju Dong; Zhang, Lizhi; Brimo, Fadi; Ajani, Jaffer A.; Gonzalez, Ana Maria Angulo; Behrens, Carmen; Bondaruk, Jolanta; Broaddus, Russell; Czerniak, Bogdan; Esmaeli, Bita; Fujimoto, Junya; Gershenwald, Jeffrey; Guo, Charles; Lazar, Alexander J.; Logothetis, Christopher; Meric-Bernstam, Funda; Moran, Cesar; Ramondetta, Lois; Rice, David; Sood, Anil; Tamboli, Pheroze; Thompson, Timothy; Troncoso, Patricia; Tsao, Anne; Wistuba, Ignacio; Carter, Candace; Haydu, Lauren; Hersey, Peter; Jakrot, Valerie; Kakavand, Hojabr; Kefford, Richard; Lee, Kenneth; Long, Georgina; Mann, Graham; Quinn, Michael; Saw, Robyn; Scolyer, Richard; Shannon, Kerwin; Spillane, Andrew; Stretch, Jonathan; Synott, Maria; Thompson, John; Wilmott, James; Al-Ahmadie, Hikmat; Chan, Timothy A.; Ghossein, Ronald; Gopalan, Anuradha; Levine, Douglas A.; Reuter, Victor; Singer, Samuel; Singh, Bhuvanesh; Tien, Nguyen Viet; Broudy, Thomas; Mirsaidi, Cyrus; Nair, Praveen; Drwiega, Paul; Miller, Judy; Smith, Jennifer; Zaren, Howard; Park, Joong Won; Hung, Nguyen Phi; Kebebew, Electron; Linehan, W. Marston; Metwalli, Adam R.; Pacak, Karel; Pinto, Peter A.; Schiffman, Mark; Schmidt, Laura S.; Vocke, Cathy D.; Wentzensen, Nicolas; Worrell, Robert; Yang, Hannah; Moncrieff, Marc; Goparaju, Chandra; Melamed, Jonathan; Pass, Harvey; Botnariuc, Natalia; Caraman, Irina; Cernat, Mircea; Chemencedji, Inga; Clipca, Adrian; Doruc, Serghei; Gorincioi, Ghenadie; Mura, Sergiu; Pirtac, Maria; Stancul, Irina; Tcaciuc, Diana; Albert, Monique; Alexopoulou, Iakovina; Arnaout, Angel; Bartlett, John; Engel, Jay; Gilbert, Sebastien; Parfitt, Jeremy; Sekhon, Harman; Thomas, George; Rassl, Doris M.; Rintoul, Robert C.; Bifulco, Carlo; Tamakawa, Raina; Urba, Walter; Hayward, Nicholas; Timmers, Henri; Antenucci, Anna; Facciolo, Francesco; Grazi, Gianluca; Marino, Mirella; Merola, Roberta; de Krijger, Ronald; Gimenez-Roqueplo, Anne Paule; Piché, Alain; Chevalier, Simone; McKercher, Ginette; Birsoy, Kivanc; Barnett, Gene; Brewer, Cathy; Farver, Carol; Naska, Theresa; Pennell, Nathan A.; Raymond, Daniel; Schilero, Cathy; Smolenski, Kathy; Williams, Felicia; Morrison, Carl; Borgia, Jeffrey A.; Liptay, Michael J.; Pool, Mark; Seder, Christopher W.; Junker, Kerstin; Omberg, Larsson; Dinkin, Mikhail; Manikhas, George; Alvaro, Domenico; Bragazzi, Maria Consiglia; Cardinale, Vincenzo; Carpino, Guido; Gaudio, Eugenio; Chesla, David; Cottingham, Sandra; Dubina, Michael; Moiseenko, Fedor; Dhanasekaran, Renumathy; Becker, Karl Friedrich; Janssen, Klaus Peter; Slotta-Huspenina, Julia; Abdel-Rahman, Mohamed H.; Aziz, Dina; Bell, Sue; Cebulla, Colleen M.; Davis, Amy; Duell, Rebecca; Elder, J. Bradley; Hilty, Joe; Kumar, Bahavna; Lang, James; Lehman, Norman L.; Mandt, Randy; Nguyen, Phuong; Pilarski, Robert; Rai, Karan; Schoenfield, Lynn; Senecal, Kelly; Wakely, Paul; Hansen, Paul; Lechan, Ronald; Powers, James; Tischler, Arthur; Grizzle, William E.; Sexton, Katherine C.; Kastl, Alison; Henderson, Joel; Porten, Sima; Waldmann, Jens; Fassnacht, Martin; Asa, Sylvia L.; Schadendorf, Dirk; Couce, Marta; Graefen, Markus; Huland, Hartwig; Sauter, Guido; Schlomm, Thorsten; Simon, Ronald; Tennstedt, Pierre; Olabode, Oluwole; Nelson, Mark; Bathe, Oliver; Carroll, Peter R.; Chan, June M.; Disaia, Philip; Glenn, Pat; Kelley, Robin K.; Landen, Charles N.; Phillips, Joanna; Prados, Michael; Simko, Jeffry; Smith-McCune, Karen; VandenBerg, Scott; Roggin, Kevin; Fehrenbach, Ashley; Kendler, Ady; Sifri, Suzanne; Steele, Ruth; Jimeno, Antonio; Carey, Francis; Forgie, Ian; Mannelli, Massimo; Carney, Michael; Hernandez, Brenda; Campos, Benito; Herold-Mende, Christel; Jungk, Christin; Unterberg, Andreas; von Deimling, Andreas; Bossler, Aaron; Galbraith, Joseph; Jacobus, Laura; Knudson, Michael; Knutson, Tina; Ma, Deqin; Milhem, Mohammed; Sigmund, Rita; Godwin, Andrew K.; Madan, Rashna; Rosenthal, Howard G.; Adebamowo, Clement; Adebamowo, Sally N.; Boussioutas, Alex; Beer, David; Giordano, Thomas; Mes-Masson, Anne Marie; Saad, Fred; Bocklage, Therese; Landrum, Lisa; Mannel, Robert; Moore, Kathleen; Moxley, Katherine; Postier, Russel; Walker, Joan; Zuna, Rosemary; Feldman, Michael; Valdivieso, Federico; Dhir, Rajiv; Luketich, James; Pinero, Edna M.Mora; Quintero-Aguilo, Mario; Carlotti, Carlos Gilberto; Dos Santos, Jose Sebastião; Kemp, Rafael; Sankarankuty, Ajith; Tirapelli, Daniela; Catto, James; Agnew, Kathy; Swisher, Elizabeth; Creaney, Jenette; Robinson, Bruce; Shelley, Carl Simon; Godwin, Eryn M.; Kendall, Sara; Shipman, Cassaundra; Bradford, Carol; Carey, Thomas; Haddad, Andrea; Moyer, Jeffey; Peterson, Lisa; Prince, Mark; Rozek, Laura; Wolf, Gregory; Bowman, Rayleen; Fong, Kwun M.; Yang, Ian; Korst, Robert; Rathmell, W. Kimryn; Fantacone-Campbell, J. Leigh; Hooke, Jeffrey A.; Kovatich, Albert J.; Shriver, Craig D.; DiPersio, John; Drake, Bettina; Govindan, Ramaswamy; Heath, Sharon; Ley, Timothy; Van Tine, Brian; Westervelt, Peter; Rubin, Mark A.; Lee, Jung Il; Aredes, Natália D.; Mariamidze, Armaz; Van Allen, Eliezer M.; Cherniack, Andrew D.; Ciriello, Giovanni; Sander, Chris; Schultz, Nikolaus

    2018-01-01

    Genetic alterations in signaling pathways that control cell-cycle progression, apoptosis, and cell growth are common hallmarks of cancer, but the extent, mechanisms, and co-occurrence of alterations in these pathways differ between individual tumors and tumor types. Using mutations, copy-number

  6. YAP regulates neuronal differentiation through Sonic hedgehog signaling pathway

    International Nuclear Information System (INIS)

    Lin, Yi-Ting; Ding, Jing-Ya; Li, Ming-Yang; Yeh, Tien-Shun; Wang, Tsu-Wei; Yu, Jenn-Yah

    2012-01-01

    Tight regulation of cell numbers by controlling cell proliferation and apoptosis is important during development. Recently, the Hippo pathway has been shown to regulate tissue growth and organ size in Drosophila. In mammalian cells, it also affects cell proliferation and differentiation in various tissues, including the nervous system. Interplay of several signaling cascades, such as Notch, Wnt, and Sonic Hedgehog (Shh) pathways, control cell proliferation during neuronal differentiation. However, it remains unclear whether the Hippo pathway coordinates with other signaling cascades in regulating neuronal differentiation. Here, we used P19 cells, a mouse embryonic carcinoma cell line, as a model to study roles of YAP, a core component of the Hippo pathway, in neuronal differentiation. P19 cells can be induced to differentiate into neurons by expressing a neural bHLH transcription factor gene Ascl1. Our results showed that YAP promoted cell proliferation and inhibited neuronal differentiation. Expression of Yap activated Shh but not Wnt or Notch signaling activity during neuronal differentiation. Furthermore, expression of Yap increased the expression of Patched homolog 1 (Ptch1), a downstream target of the Shh signaling. Knockdown of Gli2, a transcription factor of the Shh pathway, promoted neuronal differentiation even when Yap was over-expressed. We further demonstrated that over-expression of Yap inhibited neuronal differentiation in primary mouse cortical progenitors and Gli2 knockdown rescued the differentiation defect in Yap over-expressing cells. In conclusion, our study reveals that Shh signaling acts downstream of YAP in regulating neuronal differentiation. -- Highlights: ► YAP promotes cell proliferation and inhibits neuronal differentiation in P19 cells. ► YAP promotes Sonic hedgehog signaling activity during neuronal differentiation. ► Knockdown of Gli2 rescues the Yap-overexpression phenotype in P19 cells. ► Knockdown of Gli2 rescues the Yap

  7. YAP regulates neuronal differentiation through Sonic hedgehog signaling pathway

    Energy Technology Data Exchange (ETDEWEB)

    Lin, Yi-Ting; Ding, Jing-Ya [Department of Life Sciences and Institute of Genome Sciences, National Yang-Ming University, Taipei 112, Taiwan (China); Li, Ming-Yang [Department of Life Science, National Taiwan Normal University, Taipei 116, Taiwan (China); Yeh, Tien-Shun [Department of Anatomy and Cell Biology, National Yang-Ming University, Taipei 112, Taiwan (China); Wang, Tsu-Wei [Department of Life Science, National Taiwan Normal University, Taipei 116, Taiwan (China); Yu, Jenn-Yah [Department of Life Sciences and Institute of Genome Sciences, National Yang-Ming University, Taipei 112, Taiwan (China); Brain Research Center, National Yang-Ming University, Taipei 112, Taiwan (China)

    2012-09-10

    Tight regulation of cell numbers by controlling cell proliferation and apoptosis is important during development. Recently, the Hippo pathway has been shown to regulate tissue growth and organ size in Drosophila. In mammalian cells, it also affects cell proliferation and differentiation in various tissues, including the nervous system. Interplay of several signaling cascades, such as Notch, Wnt, and Sonic Hedgehog (Shh) pathways, control cell proliferation during neuronal differentiation. However, it remains unclear whether the Hippo pathway coordinates with other signaling cascades in regulating neuronal differentiation. Here, we used P19 cells, a mouse embryonic carcinoma cell line, as a model to study roles of YAP, a core component of the Hippo pathway, in neuronal differentiation. P19 cells can be induced to differentiate into neurons by expressing a neural bHLH transcription factor gene Ascl1. Our results showed that YAP promoted cell proliferation and inhibited neuronal differentiation. Expression of Yap activated Shh but not Wnt or Notch signaling activity during neuronal differentiation. Furthermore, expression of Yap increased the expression of Patched homolog 1 (Ptch1), a downstream target of the Shh signaling. Knockdown of Gli2, a transcription factor of the Shh pathway, promoted neuronal differentiation even when Yap was over-expressed. We further demonstrated that over-expression of Yap inhibited neuronal differentiation in primary mouse cortical progenitors and Gli2 knockdown rescued the differentiation defect in Yap over-expressing cells. In conclusion, our study reveals that Shh signaling acts downstream of YAP in regulating neuronal differentiation. -- Highlights: Black-Right-Pointing-Pointer YAP promotes cell proliferation and inhibits neuronal differentiation in P19 cells. Black-Right-Pointing-Pointer YAP promotes Sonic hedgehog signaling activity during neuronal differentiation. Black-Right-Pointing-Pointer Knockdown of Gli2 rescues the Yap

  8. Fluid shear promotes chondrosarcoma cell invasion by activating matrix metalloproteinase 12 via IGF-2 and VEGF signaling pathways

    Science.gov (United States)

    Wang, P; Chen, S-H; Hung, W-C; Paul, C; Zhu, F; Guan, P-P; Huso, DL; Kontrogianni-Konstantopoulos, A; Konstantopoulos, K

    2015-01-01

    Interstitial fluid flow in and around the tumor tissue is a physiologically relevant mechanical signal that regulates intracellular signaling pathways throughout the tumor. Yet, the effects of interstitial flow and associated fluid shear stress on the tumor cell function have been largely overlooked. Using in vitro bioengineering models in conjunction with molecular cell biology tools, we found that fluid shear (2 dyn/cm2) markedly upregulates matrix metalloproteinase 12 (MMP-12) expression and its activity in human chondrosarcoma cells. MMP-12 expression is induced in human chondrocytes during malignant transformation. However, the signaling pathway regulating MMP-12 expression and its potential role in human chondrosarcoma cell invasion and metastasis have yet to be delineated. We discovered that fluid shear stress induces the synthesis of insulin growth factor-2 (IGF-2) and vascular endothelial growth factor (VEGF) B and D, which in turn transactivate MMP-12 via PI3-K, p38 and JNK signaling pathways. IGF-2-, VEGF-B- or VEGF-D-stimulated chondrosarcoma cells display markedly higher migratory and invasive potentials in vitro, which are blocked by inhibiting MMP-12, PI3-K, p38 or JNK activity. Moreover, recombinant human MMP-12 or MMP-12 overexpression can potentiate chondrosarcoma cell invasion in vitro and the lung colonization in vivo. By reconstructing and delineating the signaling pathway regulating MMP-12 activation, potential therapeutic strategies that interfere with chondrosarcoma cell invasion may be identified. PMID:25435370

  9. Targeting Apoptosis Signaling Pathways for Anticancer Therapy

    Energy Technology Data Exchange (ETDEWEB)

    Fulda, Simone, E-mail: simone.fulda@kgu.de [Institute for Experimental Cancer Research in Pediatrics, Goethe-University, Frankfurt (Germany)

    2011-08-29

    Treatment approaches for cancer, for example chemotherapy, radiotherapy, or immunotherapy, primarily act by inducing cell death in cancer cells. Consequently, the inability to trigger cell death pathways or alternatively, evasion of cancer cells to the induction of cell death pathways can result in resistance of cancers to current treatment protocols. Therefore, in order to overcome treatment resistance a better understanding of the underlying mechanisms that regulate cell death and survival pathways in cancers and in response to cancer therapy is necessary to develop molecular-targeted therapies. This strategy should lead to more effective and individualized treatment strategies that selectively target deregulated signaling pathways in a tumor type- and patient-specific manner.

  10. Targeting Apoptosis Signaling Pathways for Anticancer Therapy

    International Nuclear Information System (INIS)

    Fulda, Simone

    2011-01-01

    Treatment approaches for cancer, for example chemotherapy, radiotherapy, or immunotherapy, primarily act by inducing cell death in cancer cells. Consequently, the inability to trigger cell death pathways or alternatively, evasion of cancer cells to the induction of cell death pathways can result in resistance of cancers to current treatment protocols. Therefore, in order to overcome treatment resistance a better understanding of the underlying mechanisms that regulate cell death and survival pathways in cancers and in response to cancer therapy is necessary to develop molecular-targeted therapies. This strategy should lead to more effective and individualized treatment strategies that selectively target deregulated signaling pathways in a tumor type- and patient-specific manner.

  11. Signal transduction in mitogenesis: Further evidence for multiple pathways

    International Nuclear Information System (INIS)

    Rozengurt, E.; Erusalimsky, J.; Mehmet, H.; Morris, C.; Nanberg, E.; Sinnett-Smith, J.

    1988-01-01

    Growth factors are implicated in a wide variety of physiological and pathological processes, including embryogenesis, hematopoiesis, would healing, immune responses, atherosclerosis, and neoplasia. An important link between growth factors and their receptors and oncogene products has also been established. Thus, the elucidation of the mechanism of action of growth factors has emerged as one of the fundamental problems in biology and may prove crucial for understanding the unrestrained proliferation of cancer cells. A new and intriguing development is the discovery that neuropeptides localized in neural and neuroendocrine cells of mammalian tissue can also act as growth factors for cells in culture. Furthermore, indirect evidence is accumulating that the mitogenic effects of neuropeptides may be relevant for a variety of long-term biological processes, including development and oncogenesis. In this context, the peptides of the bombesin family are of particular significance. These peptides are potent mitogens for Swiss 3T3 cells and may act as autocrine growth factors for small cell lung cancer. Here, the authors summarize their recent studies using bombesin-like peptides for elucidating the signal transduction pathways leading to mitogenesis and compare these pathways with those elicited by other growth factors

  12. Clinical Implications of Hedgehog Pathway Signaling in Prostate Cancer

    Directory of Open Access Journals (Sweden)

    Daniel L. Suzman

    2015-09-01

    Full Text Available Activity in the Hedgehog pathway, which regulates GLI-mediated transcription, is important in organogenesis and stem cell regulation in self-renewing organs, but is pathologically elevated in many human malignancies. Mutations leading to constitutive activation of the pathway have been implicated in medulloblastoma and basal cell carcinoma, and inhibition of the pathway has demonstrated clinical responses leading to the approval of the Smoothened inhibitor, vismodegib, for the treatment of advanced basal cell carcinoma. Aberrant Hedgehog pathway signaling has also been noted in prostate cancer with evidence suggesting that it may render prostate epithelial cells tumorigenic, drive the epithelial-to-mesenchymal transition, and contribute towards the development of castration-resistance through autocrine and paracrine signaling within the tumor microenvironment and cross-talk with the androgen pathway. In addition, there are emerging clinical data suggesting that inhibition of the Hedgehog pathway may be effective in the treatment of recurrent and metastatic prostate cancer. Here we will review these data and highlight areas of active clinical research as they relate to Hedgehog pathway inhibition in prostate cancer.

  13. Drug Modulators of B Cell Signaling Pathways and Epstein-Barr Virus Lytic Activation.

    Science.gov (United States)

    Kosowicz, John G; Lee, Jaeyeun; Peiffer, Brandon; Guo, Zufeng; Chen, Jianmeng; Liao, Gangling; Hayward, S Diane; Liu, Jun O; Ambinder, Richard F

    2017-08-15

    Epstein-Barr virus (EBV) is a ubiquitous human gammaherpesvirus that establishes a latency reservoir in B cells. In this work, we show that ibrutinib, idelalisib, and dasatinib, drugs that block B cell receptor (BCR) signaling and are used in the treatment of hematologic malignancies, block BCR-mediated lytic induction at clinically relevant doses. We confirm that the immunosuppressive drugs cyclosporine and tacrolimus also inhibit BCR-mediated lytic induction but find that rapamycin does not inhibit BCR-mediated lytic induction. Further investigation shows that mammalian target of rapamycin complex 2 (mTORC2) contributes to BCR-mediated lytic induction and that FK506-binding protein 12 (FKBP12) binding alone is not adequate to block activation. Finally, we show that BCR signaling can activate EBV lytic induction in freshly isolated B cells from peripheral blood mononuclear cells (PBMCs) and that activation can be inhibited by ibrutinib or idelalisib. IMPORTANCE EBV establishes viral latency in B cells. Activation of the B cell receptor pathway activates lytic viral expression in cell lines. Here we show that drugs that inhibit important kinases in the BCR signaling pathway inhibit activation of lytic viral expression but do not inhibit several other lytic activation pathways. Immunosuppressant drugs such as cyclosporine and tacrolimus but not rapamycin also inhibit BCR-mediated EBV activation. Finally, we show that BCR activation of lytic infection occurs not only in tumor cell lines but also in freshly isolated B cells from patients and that this activation can be blocked by BCR inhibitors. Copyright © 2017 American Society for Microbiology.

  14. Targeting Wnt signaling in colorectal cancer. A Review in the Theme: Cell Signaling: Proteins, Pathways and Mechanisms

    Science.gov (United States)

    Novellasdemunt, Laura; Antas, Pedro

    2015-01-01

    The evolutionarily conserved Wnt signaling pathway plays essential roles during embryonic development and tissue homeostasis. Notably, comprehensive genetic studies in Drosophila and mice in the past decades have demonstrated the crucial role of Wnt signaling in intestinal stem cell maintenance by regulating proliferation, differentiation, and cell-fate decisions. Wnt signaling has also been implicated in a variety of cancers and other diseases. Loss of the Wnt pathway negative regulator adenomatous polyposis coli (APC) is the hallmark of human colorectal cancers (CRC). Recent advances in high-throughput sequencing further reveal many novel recurrent Wnt pathway mutations in addition to the well-characterized APC and β-catenin mutations in CRC. Despite attractive strategies to develop drugs for Wnt signaling, major hurdles in therapeutic intervention of the pathway persist. Here we discuss the Wnt-activating mechanisms in CRC and review the current advances and challenges in drug discovery. PMID:26289750

  15. An enhanced functional interrogation/manipulation of intracellular signaling pathways with the peptide 'stapling' technology.

    Science.gov (United States)

    He, Y; Chen, D; Zheng, W

    2015-11-12

    Specific protein-protein interactions (PPIs) constitute a key underlying mechanism for the presence of a multitude of intracellular signaling pathways, which are essential for the survival of normal and cancer cells. Specific molecular blockers for a crucial PPI would therefore be invaluable tools for an enhanced functional interrogation of the signaling pathway harboring this particular PPI. On the other hand, if a particular PPI is essential for the survival of cancer cells but is absent in or dispensable for the survival of normal cells, its specific molecular blockers could potentially be developed into effective anticancer therapeutics. Due to the flat and extended PPI interface, it would be conceivably difficult for small molecules to achieve an effective blockade, a problem which could be potentially circumvented with peptides or proteins. However, the well-documented proteolytic instability and cellular impermeability of peptides and proteins in general would make their developing into effective intracellular PPI blockers quite a challenge. With the advent of the peptide 'stapling' technology which was demonstrated to be able to stabilize the α-helical conformation of a peptide via bridging two neighboring amino-acid side chains with a 'molecular staple', a linear parent peptide could be transformed into a stronger PPI blocker with enhanced proteolytic stability and cellular permeability. This review will furnish an account on the peptide 'stapling' technology and its exploitation in efforts to achieve an enhanced functional interrogation or manipulation of intracellular signaling pathways especially those that are cancer relevant.

  16. Balancing act: matching growth with environment by the TOR signalling pathway.

    Science.gov (United States)

    Henriques, Rossana; Bögre, László; Horváth, Beátrix; Magyar, Zoltán

    2014-06-01

    One of the most fundamental aspects of growth in plants is its plasticity in relation to fluctuating environmental conditions. Growth of meristematic cells relies predominantly on protein synthesis, one of the most energy-consuming activities in cells, and thus is tightly regulated in accordance with the available nutrient and energy supplies. The Target of Rapamycin (TOR) signalling pathway takes a central position in this regulation. The core of the TOR signalling pathway is conserved throughout evolution, and can be traced back to the last eukaryotic common ancestor. In plants, a single complex constitutes the TOR signalling pathway. Manipulating the components of the TOR complex in Arabidopsis highlighted its common role as a major regulator of protein synthesis and metabolism, that is also involved in other biological functions such as cell-wall integrity, regulation of cell proliferation, and cell size. TOR, as an integral part of the auxin signalling pathway, connects hormonal and nutrient pathways. Downstream of TOR, S6 kinase and the ribosomal S6 protein have been shown to mediate several of these responses, although there is evidence of other complex non-linear TOR signalling pathway structures. © The Author 2014. Published by Oxford University Press on behalf of the Society for Experimental Biology. All rights reserved. For permissions, please email: journals.permissions@oup.com.

  17. POSTRANSLATIONAL MODIFICATIONS OF P53: UPSTREAM SIGNALING PATHWAYS.

    Energy Technology Data Exchange (ETDEWEB)

    ANDERSON,C.W.APPELLA,E.

    2003-10-23

    The p53 tumor suppressor is a tetrameric transcription factor that is posttranslational modified at >20 different sites by phosphorylation, acetylation, or sumoylation in response to various cellular stress conditions. Specific posttranslational modifications, or groups of modifications, that result from the activation of different stress-induced signaling pathways are thought to modulate p53 activity to regulate cell fate by inducing cell cycle arrest, apoptosis, or cellular senescence. Here we review recent progress in characterizing the upstream signaling pathways whose activation in response to various genotoxic and non-genotoxic stresses result in p53 posttranslational modifications.

  18. Inhibition of the adrenomedullin/nitric oxide signaling pathway in early diabetic retinopathy.

    Science.gov (United States)

    Blom, Jan J; Giove, Thomas J; Favazza, Tara L; Akula, James D; Eldred, William D

    2011-06-01

    The nitric oxide (NO) signaling pathway is integrally involved in visual processing and changes in the NO pathway are measurable in eyes of diabetic patients. The small peptide adrenomedullin (ADM) can activate a signaling pathway to increase the enzyme activity of neuronal nitric oxide synthase (nNOS). ADM levels are elevated in eyes of diabetic patients and therefore, ADM may play a role in the pathology of diabetic retinopathy. The goal of this research was to test the effects of inhibiting the ADM/NO signaling pathway in early diabetic retinopathy. Inhibition of this pathway decreased NO production in high-glucose retinal cultures. Treating diabetic mice with the PKC β inhibitor ruboxistaurin for 5 weeks lowered ADM mRNA levels and ADM-like immunoreactivity and preserved retinal function as assessed by electroretinography. The results of this study indicate that inhibiting the ADM/NO signaling pathway prevents neuronal pathology and functional losses in early diabetic retinopathy.

  19. PSFC: a Pathway Signal Flow Calculator App for Cytoscape [version 2; referees: 2 approved

    Directory of Open Access Journals (Sweden)

    Lilit Nersisyan

    2017-04-01

    Full Text Available Cell signaling pathways are sequences of biochemical reactions that propagate an input signal, such as a hormone binding to a cell-surface receptor, into the cell to trigger a reactive process. Assessment of pathway activities is crucial for determining which pathways play roles in disease versus normal conditions. To date various pathway flow/perturbation assessment tools are available, however they are constrained to specific algorithms and specific data types. There are no accepted standards for evaluation of pathway activities or simulation of flow propagation events in pathways, and the results of different software are difficult to compare. Here we present Pathway Signal Flow Calculator (PSFC, a Cytoscape app for calculation of a pathway signal flow based on the pathway topology and node input data. The app provides a rich framework for customization of different signal flow algorithms to allow users to apply various approaches within a single computational framework.

  20. Dissection of the insulin signaling pathway via quantitative phosphoproteomics

    DEFF Research Database (Denmark)

    Krüger, Marcus; Kratchmarova, Irina; Blagoev, Blagoy

    2008-01-01

    spectrum of the tyrosine phosphorylation cascade, we have defined the tyrosine-phosphoproteome of the insulin signaling pathway, using high resolution mass spectrometry in combination with phosphotyrosine immunoprecipitation and stable isotope labeling by amino acids in cell culture (SILAC......The insulin signaling pathway is of pivotal importance in metabolic diseases, such as diabetes, and in cellular processes, such as aging. Insulin activates a tyrosine phosphorylation cascade that branches to create a complex network affecting multiple biological processes. To understand the full...

  1. Identification of a novel Gnao-mediated alternate olfactory signaling pathway in murine OSNs

    Directory of Open Access Journals (Sweden)

    Paul eScholz

    2016-03-01

    Full Text Available It is generally agreed that in olfactory sensory neurons (OSNs, the binding of odorant molecules to their specific olfactory receptor (OR triggers a cAMP-dependent signaling cascade, activating cyclic-nucleotide gated (CNG channels. However, considerable controversy dating back more than 20 years has surrounded the question of whether alternate signaling plays a role in mammalian olfactory transduction. In this study, we demonstrate a specific alternate signaling pathway in Olfr73-expressing OSNs. Methylisoeugenol (MIEG and at least one other known weak Olfr73 agonist (Raspberry Ketone trigger a signaling cascade independent from the canonical pathway, leading to the depolarization of the cell. Interestingly, this pathway is mediated by Gnao activation, leading to Cl- efflux; however, the activation of adenylyl cyclase III (ACIII, the recruitment of Ca2+ from extra-or intracellular stores, and phosphatidylinositol 3-kinase-dependent signaling (PI signaling are not involved. Furthermore, we demonstrated that our newly identified pathway coexists with the canonical olfactory cAMP pathway in the same OSN and can be triggered by the same OR in a ligand-selective manner. We suggest that this pathway might reflect a mechanism for odor recognition predominantly used in early developmental stages before olfactory cAMP signaling is fully developed. Taken together, our findings support the existence of at least one odor-induced alternate signal transduction pathway in native OSNs mediated by Olfr73 in a ligand-selective manner.

  2. JAK/STAT signaling pathway-mediated immune response in silkworm (Bombyx mori) challenged by Beauveria bassiana.

    Science.gov (United States)

    Geng, Tao; Lv, Ding-Ding; Huang, Yu-Xia; Hou, Cheng-Xiang; Qin, Guang-Xing; Guo, Xi-Jie

    2016-12-20

    Innate immunity was critical in insects defensive system and able to be induced by Janus kinase/signal transducer and activator of transcription cascade transduction (JAK/STAT) signaling pathway. Currently, it had been identified many JAK/STAT signaling pathway-related genes in silkworm, but little function was known on insect innate immunity. To explore the roles of JAK/STAT pathway in antifungal immune response in silkworm (Bombyx mori) against Beauveria bassiana infection, the expression patterns of B. mori C-type lectin 5 (BmCTL5) and genes encoding 6 components of JAK/STAT signaling pathway in silkworm challenged by B. bassiana were analyzed using quantitative real time PCR. Meanwhile the activation of JAK/STAT signaling pathway by various pathogenic micro-organisms and the affect of JAK/STAT signaling pathway inhibitors on antifungal activity in silkworm hemolymph was also detected. Moreover, RNAi assay of BmCTL5 and the affect on expression levels of signaling factors were also analyzed. We found that JAK/STAT pathway could be obviously activated in silkworm challenged with B. bassiana and had no response to bacteria and B. mori cytoplasmic polyhedrosis virus (BmCPV). However, the temporal expression patterns of JAK/STAT signaling pathway related genes were significantly different. B. mori downstream receptor kinase (BmDRK) might be a positive regulator of JAK/STAT signaling pathway in silkworm against B. bassiana infection. Moreover, antifungal activity assay showed that the suppression of JAK/STAT signaling pathway by inhibitors could significantly inhibit the antifungal activity in hemolymph and resulted in increased sensitivity of silkworm to B. bassiana infection, indicating that JAK/STAT signaling pathway might be involved in the synthesis and secretion of antifungal substances. The results of RNAi assays suggested that BmCTL5 might be one pattern recognition receptors for JAK/STAT signaling pathway in silkworm. These findings yield insights for better

  3. Autonomous rexinoid death signaling is suppressed by converging signaling pathways in immature leukemia cells.

    Science.gov (United States)

    Benoit, G R; Flexor, M; Besançon, F; Altucci, L; Rossin, A; Hillion, J; Balajthy, Z; Legres, L; Ségal-Bendirdjian, E; Gronemeyer, H; Lanotte, M

    2001-07-01

    On their own, retinoid X receptor (RXR)-selective ligands (rexinoids) are silent in retinoic acid receptor (RAR)-RXR heterodimers, and no selective rexinoid program has been described as yet in cellular systems. We report here on the rexinoid signaling capacity that triggers apoptosis of immature promyelocytic NB4 cells as a default pathway in the absence of survival factors. Rexinoid-induced apoptosis displays all features of bona fide programmed cell death and is inhibited by RXR, but not RAR antagonists. Several types of survival signals block rexinoid-induced apoptosis. RARalpha agonists switch the cellular response toward differentiation and induce the expression of antiapoptosis factors. Activation of the protein kinase A pathway in the presence of rexinoid agonists induces maturation and blocks immature cell apoptosis. Addition of nonretinoid serum factors also blocks cell death but does not induce cell differentiation. Rexinoid-induced apoptosis is linked to neither the presence nor stability of the promyelocytic leukemia-RARalpha fusion protein and operates also in non-acute promyelocytic leukemia cells. Together our results support a model according to which rexinoids activate in certain leukemia cells a default death pathway onto which several other signaling paradigms converge. This pathway is entirely distinct from that triggered by RAR agonists, which control cell maturation and postmaturation apoptosis.

  4. An algorithm for modularization of MAPK and calcium signaling pathways: comparative analysis among different species.

    Science.gov (United States)

    Nayak, Losiana; De, Rajat K

    2007-12-01

    Signaling pathways are large complex biochemical networks. It is difficult to analyze the underlying mechanism of such networks as a whole. In the present article, we have proposed an algorithm for modularization of signal transduction pathways. Unlike studying a signaling pathway as a whole, this enables one to study the individual modules (less complex smaller units) easily and hence to study the entire pathway better. A comparative study of modules belonging to different species (for the same signaling pathway) has been made, which gives an overall idea about development of the signaling pathways over the taken set of species of calcium and MAPK signaling pathways. The superior performance, in terms of biological significance, of the proposed algorithm over an existing community finding algorithm of Newman [Newman MEJ. Modularity and community structure in networks. Proc Natl Acad Sci USA 2006;103(23):8577-82] has been demonstrated using the aforesaid pathways of H. sapiens.

  5. DMPD: Signal transduction pathways mediated by the interaction of CpG DNA withToll-like receptor 9. [Dynamic Macrophage Pathway CSML Database

    Lifescience Database Archive (English)

    Full Text Available 14751759 Signal transduction pathways mediated by the interaction of CpG DNA withTo...;16(1):17-22. (.png) (.svg) (.html) (.csml) Show Signal transduction pathways mediated by the interaction of... CpG DNA withToll-like receptor 9. PubmedID 14751759 Title Signal transduction pathways media

  6. The node-weighted Steiner tree approach to identify elements of cancer-related signaling pathways.

    Science.gov (United States)

    Sun, Yahui; Ma, Chenkai; Halgamuge, Saman

    2017-12-28

    Cancer constitutes a momentous health burden in our society. Critical information on cancer may be hidden in its signaling pathways. However, even though a large amount of money has been spent on cancer research, some critical information on cancer-related signaling pathways still remains elusive. Hence, new works towards a complete understanding of cancer-related signaling pathways will greatly benefit the prevention, diagnosis, and treatment of cancer. We propose the node-weighted Steiner tree approach to identify important elements of cancer-related signaling pathways at the level of proteins. This new approach has advantages over previous approaches since it is fast in processing large protein-protein interaction networks. We apply this new approach to identify important elements of two well-known cancer-related signaling pathways: PI3K/Akt and MAPK. First, we generate a node-weighted protein-protein interaction network using protein and signaling pathway data. Second, we modify and use two preprocessing techniques and a state-of-the-art Steiner tree algorithm to identify a subnetwork in the generated network. Third, we propose two new metrics to select important elements from this subnetwork. On a commonly used personal computer, this new approach takes less than 2 s to identify the important elements of PI3K/Akt and MAPK signaling pathways in a large node-weighted protein-protein interaction network with 16,843 vertices and 1,736,922 edges. We further analyze and demonstrate the significance of these identified elements to cancer signal transduction by exploring previously reported experimental evidences. Our node-weighted Steiner tree approach is shown to be both fast and effective to identify important elements of cancer-related signaling pathways. Furthermore, it may provide new perspectives into the identification of signaling pathways for other human diseases.

  7. DMPD: TLR signaling. [Dynamic Macrophage Pathway CSML Database

    Lifescience Database Archive (English)

    Full Text Available 2007 Feb 1. (.png) (.svg) (.html) (.csml) Show TLR signaling. PubmedID 17275323 Title TLR signaling. Author...s Kawai T, Akira S. Publication Semin Immunol. 2007 Feb;19(1):24-32. Epub 2007 Feb 1. Pathway - PNG File (.png) SVG File (.svg) HTML... File (.html) CSML File (.csml) Open .csml file with CIOP

  8. Rapidly exploring structural and dynamic properties of signaling networks using PathwayOracle

    Directory of Open Access Journals (Sweden)

    Ram Prahlad T

    2008-08-01

    Full Text Available Abstract Background In systems biology the experimentalist is presented with a selection of software for analyzing dynamic properties of signaling networks. These tools either assume that the network is in steady-state or require highly parameterized models of the network of interest. For biologists interested in assessing how signal propagates through a network under specific conditions, the first class of methods does not provide sufficiently detailed results and the second class requires models which may not be easily and accurately constructed. A tool that is able to characterize the dynamics of a signaling network using an unparameterized model of the network would allow biologists to quickly obtain insights into a signaling network's behavior. Results We introduce PathwayOracle, an integrated suite of software tools for computationally inferring and analyzing structural and dynamic properties of a signaling network. The feature which differentiates PathwayOracle from other tools is a method that can predict the response of a signaling network to various experimental conditions and stimuli using only the connectivity of the signaling network. Thus signaling models are relatively easy to build. The method allows for tracking signal flow in a network and comparison of signal flows under different experimental conditions. In addition, PathwayOracle includes tools for the enumeration and visualization of coherent and incoherent signaling paths between proteins, and for experimental analysis – loading and superimposing experimental data, such as microarray intensities, on the network model. Conclusion PathwayOracle provides an integrated environment in which both structural and dynamic analysis of a signaling network can be quickly conducted and visualized along side experimental results. By using the signaling network connectivity, analyses and predictions can be performed quickly using relatively easily constructed signaling network models

  9. Porcine Circovirus-Like Virus P1 Inhibits Wnt Signaling Pathway in Vivo and in Vitro.

    Science.gov (United States)

    Zhu, Xuejiao; Wen, Libin; Sheng, Shaoyang; Wang, Wei; Xiao, Qi; Qu, Meng; Hu, Yiyi; Liu, Chuanmin; He, Kongwang

    2018-01-01

    Porcine circovirus-like virus P1 is an important pathogen of the current pig industry, the infection mechanism is not entirely clear. Wnt signaling pathway plays an important role in the growth of young animals and infection of some viruses. This study was designed to demonstrate the effects of P1 infection on the Wnt signaling pathway. In vivo experiments, we demonstrated the down-regulatory effects of P1 infection in piglets and mice on the downstream components expression levels of Wnt signaling pathway, and the effects of Wnt signaling pathway activation on the pathogenesis of P1. In vitro studies, we found P1 infection down-regulated protein level of β-catenin and mRNA level of mmp2, prevented the β-catenin from entering into nucleus, abolished the TCF/LEF promoter activity, proved that P1 could inhibit the activation of Wnt signaling pathway in vitro . Finally, we found that VP1 of P1 virus also had the inhibitory effects on Wnt signaling pathway in vitro , elucidated the mechanism of P1's inhibitory effects on the Wnt signaling pathway and offered the possibility that the suppression of Wnt signaling pathway was involved in the post-weaning multisystemic wasting syndrome (PMWS), laying a foundation for elucidating the pathogenesis of P1.

  10. Evolution and Design Governing Signal Precision and Amplification in a Bacterial Chemosensory Pathway.

    Directory of Open Access Journals (Sweden)

    Mathilde Guzzo

    2015-08-01

    Full Text Available Understanding the principles underlying the plasticity of signal transduction networks is fundamental to decipher the functioning of living cells. In Myxococcus xanthus, a particular chemosensory system (Frz coordinates the activity of two separate motility systems (the A- and S-motility systems, promoting multicellular development. This unusual structure asks how signal is transduced in a branched signal transduction pathway. Using combined evolution-guided and single cell approaches, we successfully uncoupled the regulations and showed that the A-motility regulation system branched-off an existing signaling system that initially only controlled S-motility. Pathway branching emerged in part following a gene duplication event and changes in the circuit structure increasing the signaling efficiency. In the evolved pathway, the Frz histidine kinase generates a steep biphasic response to increasing external stimulations, which is essential for signal partitioning to the motility systems. We further show that this behavior results from the action of two accessory response regulator proteins that act independently to filter and amplify signals from the upstream kinase. Thus, signal amplification loops may underlie the emergence of new connectivity in signal transduction pathways.

  11. [Cell signaling pathways interaction in cellular proliferation: Potential target for therapeutic interventionism].

    Science.gov (United States)

    Valdespino-Gómez, Víctor Manuel; Valdespino-Castillo, Patricia Margarita; Valdespino-Castillo, Víctor Edmundo

    2015-01-01

    Nowadays, cellular physiology is best understood by analysing their interacting molecular components. Proteins are the major components of the cells. Different proteins are organised in the form of functional clusters, pathways or networks. These molecules are ordered in clusters of receptor molecules of extracellular signals, transducers, sensors and biological response effectors. The identification of these intracellular signaling pathways in different cellular types has required a long journey of experimental work. More than 300 intracellular signaling pathways have been identified in human cells. They participate in cell homeostasis processes for structural and functional maintenance. Some of them participate simultaneously or in a nearly-consecutive progression to generate a cellular phenotypic change. In this review, an analysis is performed on the main intracellular signaling pathways that take part in the cellular proliferation process, and the potential use of some components of these pathways as target for therapeutic interventionism are also underlined. Copyright © 2015 Academia Mexicana de Cirugía A.C. Published by Masson Doyma México S.A. All rights reserved.

  12. Gene Expression Profiling Identifies Downregulation of the Neurotrophin-MAPK Signaling Pathway in Female Diabetic Peripheral Neuropathy Patients.

    Science.gov (United States)

    Luo, Lin; Zhou, Wen-Hua; Cai, Jiang-Jia; Feng, Mei; Zhou, Mi; Hu, Su-Pei; Xu, Jin; Ji, Lin-Dan

    2017-01-01

    Diabetic peripheral neuropathy (DPN) is a common complication of diabetes mellitus (DM). It is not diagnosed or managed properly in the majority of patients because its pathogenesis remains controversial. In this study, human whole genome microarrays identified 2898 and 4493 differentially expressed genes (DEGs) in DM and DPN patients, respectively. A further KEGG pathway analysis indicated that DPN and DM share four pathways, including apoptosis, B cell receptor signaling pathway, endocytosis, and Toll-like receptor signaling pathway. The DEGs identified through comparison of DPN and DM were significantly enriched in MAPK signaling pathway, NOD-like receptor signaling pathway, and neurotrophin signaling pathway, while the "neurotrophin-MAPK signaling pathway" was notably downregulated. Seven DEGs from the neurotrophin-MAPK signaling pathway were validated in additional 78 samples, and the results confirmed the initial microarray findings. These findings demonstrated that downregulation of the neurotrophin-MAPK signaling pathway may be the major mechanism of DPN pathogenesis, thus providing a potential approach for DPN treatment.

  13. Prognostic value of hedgehog signaling pathway in digestive system cancers: A systematic review and meta-analysis.

    Science.gov (United States)

    Wang, Yihan; Peng, Qian; Jia, Hongyuan; Du, Xiao

    2016-01-01

    The Hedgehog (Hh) signaling pathway has recently been reported to be associated with the prognosis of digestive system cancers. However, the results are inconsistent. This study aimed to investigate the association between Hh pathway components and survival outcomes in patients with digestive system cancers. We conducted a comprehensive retrieval in PubMed, EMBASE and Cochrane library for relevant literatures until May 1st, 2015. The pooled hazard ratios (HRs) for overall survival (OS) and disease-free survival (DFS) with 95% confidence intervals (CIs) were calculated to clarify the prognostic value of Hh pathway components, including Shh, Gli1, Gli2, Smo and Ptch1. A total of 16 eligible articles with 3222 patients were included in the meta-analysis. Pooled HR suggested that over-expression of Shh and Gli1 were both associated with poor OS (HR = 1.87, 95% CI: 1.14-3.07 and HR = 1.96, 95% CI: 1.66-2.32, respectively) and DFS (HR = 2.37, 95% CI: 1.19-4.72 and HR = 2.18, 95% CI: 1.61-2.96, respectively). In addition, over-expression of Smo was associated with poor DFS (HR = 1.38, 95% CI: 1.08-1.75). This study reveals that over-expressed Hh pathway components, including Shh, Gli1 and Smo, are associated with poor prognosis in digestive system cancer patients. Hh signaling pathway may become a potential therapeutic target in digestive system cancers.

  14. Signaling Pathways in Leiomyoma: Understanding Pathobiology and Implications for Therapy

    Science.gov (United States)

    Borahay, Mostafa A; Al-Hendy, Ayman; Kilic, Gokhan S; Boehning, Darren

    2015-01-01

    Uterine leiomyomas are the most common tumors of the female genital tract, affecting 50% to 70% of females by the age of 50. Despite their prevalence and enormous medical and economic impact, no effective medical treatment is currently available. This is, in part, due to the poor understanding of their underlying pathobiology. Although they are thought to start as a clonal proliferation of a single myometrial smooth muscle cell, these early cytogenetic alterations are considered insufficient for tumor development and additional complex signaling pathway alterations are crucial. These include steroids, growth factors, transforming growth factor-beta (TGF-β)/Smad; wingless-type (Wnt)/β-catenin, retinoic acid, vitamin D, and peroxisome proliferator-activated receptor γ (PPARγ). An important finding is that several of these pathways converge in a summative way. For example, mitogen-activated protein kinase (MAPK) and Akt pathways seem to act as signal integrators, incorporating input from several signaling pathways, including growth factors, estrogen and vitamin D. This underlines the multifactorial origin and complex nature of these tumors. In this review, we aim to dissect these pathways and discuss their interconnections, aberrations and role in leiomyoma pathobiology. We also aim to identify potential targets for development of novel therapeutics. PMID:25879625

  15. Signaling pathways in a Citrus EST database

    Directory of Open Access Journals (Sweden)

    Angela Mehta

    2007-01-01

    Full Text Available Citrus spp. are economically important crops, which in Brazil are grown mainly in the State of São Paulo. Citrus cultures are attacked by several pathogens, causing severe yield losses. In order to better understand this culture, the Millenium Project (IAC Cordeirópolis was launched in order to sequence Citrus ESTs (expressed sequence tags from different tissues, including leaf, bark, fruit, root and flower. Plants were submitted to biotic and abiotic stresses and investigated under different development stages (adult vs. juvenile. Several cDNA libraries were constructed and the sequences obtained formed the Citrus ESTs database with almost 200,000 sequences. Searches were performed in the Citrus database to investigate the presence of different signaling pathway components. Several of the genes involved in the signaling of sugar, calcium, cytokinin, plant hormones, inositol phosphate, MAPKinase and COP9 were found in the citrus genome and are discussed in this paper. The results obtained may indicate that similar mechanisms described in other plants, such as Arabidopsis, occur in citrus. Further experimental studies must be conducted in order to understand the different signaling pathways present.

  16. Investigation of radiation-induced multilayered signalling response of the inflammatory pathway

    International Nuclear Information System (INIS)

    Babini, G.; Ugolini, M.; Morini, J.; Baiocco, G.; Ottolenghi, A.; Mariotti, L.; Tabarelli de Fatis, P.; Liotta, M.

    2015-01-01

    Ionising radiation exposure of cells might induce the perturbation of cell functions and, in particular, the activation or inhibition of several important pathways. This perturbation can cause the deregulation of both intra- and extra-cellular signalling cascades (such as the inflammatory pathway) and alter not only the behaviour of directly exposed cells but also the neighbouring nonirradiated ones, through the so-called bystander effect. The aim of the present work was to investigate the complex nonlinear interactions between the inflammatory pathway and other strictly interlaced signalling pathways, such as Erk1/2 and Akt/PKB, focusing on the radiation-induced perturbation of such pathways in the dose range of 0 -2 Gy. The results show how radiation affects these interconnected pathways and how confounding factors, such as the change of culture medium, can hide radiation-induced perturbations. (authors)

  17. Porcine Circovirus-Like Virus P1 Inhibits Wnt Signaling Pathway in Vivo and in Vitro

    Directory of Open Access Journals (Sweden)

    Xuejiao Zhu

    2018-03-01

    Full Text Available Porcine circovirus-like virus P1 is an important pathogen of the current pig industry, the infection mechanism is not entirely clear. Wnt signaling pathway plays an important role in the growth of young animals and infection of some viruses. This study was designed to demonstrate the effects of P1 infection on the Wnt signaling pathway. In vivo experiments, we demonstrated the down-regulatory effects of P1 infection in piglets and mice on the downstream components expression levels of Wnt signaling pathway, and the effects of Wnt signaling pathway activation on the pathogenesis of P1. In vitro studies, we found P1 infection down-regulated protein level of β-catenin and mRNA level of mmp2, prevented the β-catenin from entering into nucleus, abolished the TCF/LEF promoter activity, proved that P1 could inhibit the activation of Wnt signaling pathway in vitro. Finally, we found that VP1 of P1 virus also had the inhibitory effects on Wnt signaling pathway in vitro, elucidated the mechanism of P1’s inhibitory effects on the Wnt signaling pathway and offered the possibility that the suppression of Wnt signaling pathway was involved in the post-weaning multisystemic wasting syndrome (PMWS, laying a foundation for elucidating the pathogenesis of P1.

  18. Differential and directional estrogenic signaling pathways induced by enterolignans and their precursors.

    Directory of Open Access Journals (Sweden)

    Yun Zhu

    Full Text Available Mammalian lignans or enterolignans are metabolites of plant lignans, an important category of phytochemicals. Although they are known to be associated with estrogenic activity, cell signaling pathways leading to specific cell functions, and especially the differences among lignans, have not been explored. We examined the estrogenic activity of enterolignans and their precursor plant lignans and cell signaling pathways for some cell functions, cell cycle and chemokine secretion. We used DNA microarray-based gene expression profiling in human breast cancer MCF-7 cells to examine the similarities, as well as the differences, among enterolignans, enterolactone and enterodiol, and their precursors, matairesinol, pinoresinol and sesamin. The profiles showed moderate to high levels of correlation (R values: 0.44 to 0.81 with that of estrogen (17β-estradiol or E2. Significant correlations were observed among lignans (R values: 0.77 to 0.97, and the correlations were higher for cell functions related to enzymes, signaling, proliferation and transport. All the enterolignans/precursors examined showed activation of the Erk1/2 and PI3K/Akt pathways, indicating the involvement of rapid signaling through the non-genomic estrogen signaling pathway. However, when their effects on specific cell functions, cell cycle progression and chemokine (MCP-1 secretion were examined, positive effects were observed only for enterolactone, suggesting that signals are given in certain directions at a position closer to cell functions. We hypothesized that, while estrogen signaling is initiated by the enterolignans/precursors examined, their signals are differentially and directionally modulated later in the pathways, resulting in the differences at the cell function level.

  19. Modeling of non-steroidal anti-inflammatory drug effect within signaling pathways and miRNA-regulation pathways.

    Directory of Open Access Journals (Sweden)

    Jian Li

    Full Text Available To date, it is widely recognized that Non-Steroidal Anti-Inflammatory Drugs (NSAIDs can exert considerable anti-tumor effects regarding many types of cancers. The prolonged use of NSAIDs is highly associated with diverse side effects. Therefore, tailoring down the NSAID application onto individual patients has become a necessary and relevant step towards personalized medicine. This study conducts the systemsbiological approach to construct a molecular model (NSAID model containing a cyclooxygenase (COX-pathway and its related signaling pathways. Four cancer hallmarks are integrated into the model to reflect different developmental aspects of tumorigenesis. In addition, a Flux-Comparative-Analysis (FCA based on Petri net is developed to transfer the dynamic properties (including drug responsiveness of individual cellular system into the model. The gene expression profiles of different tumor-types with available drug-response information are applied to validate the predictive ability of the NSAID model. Moreover, two therapeutic developmental strategies, synthetic lethality and microRNA (miRNA biomarker discovery, are investigated based on the COX-pathway. In conclusion, the result of this study demonstrates that the NSAID model involving gene expression, gene regulation, signal transduction, protein interaction and other cellular processes, is able to predict the individual cellular responses for different therapeutic interventions (such as NS-398 and COX-2 specific siRNA inhibition. This strongly indicates that this type of model is able to reflect the physiological, developmental and pathological processes of an individual. The approach of miRNA biomarker discovery is demonstrated for identifying miRNAs with oncogenic and tumor suppressive functions for individual cell lines of breast-, colon- and lung-tumor. The achieved results are in line with different independent studies that investigated miRNA biomarker related to diagnostics of cancer

  20. Non Linear Programming (NLP) formulation for quantitative modeling of protein signal transduction pathways.

    Science.gov (United States)

    Mitsos, Alexander; Melas, Ioannis N; Morris, Melody K; Saez-Rodriguez, Julio; Lauffenburger, Douglas A; Alexopoulos, Leonidas G

    2012-01-01

    Modeling of signal transduction pathways plays a major role in understanding cells' function and predicting cellular response. Mathematical formalisms based on a logic formalism are relatively simple but can describe how signals propagate from one protein to the next and have led to the construction of models that simulate the cells response to environmental or other perturbations. Constrained fuzzy logic was recently introduced to train models to cell specific data to result in quantitative pathway models of the specific cellular behavior. There are two major issues in this pathway optimization: i) excessive CPU time requirements and ii) loosely constrained optimization problem due to lack of data with respect to large signaling pathways. Herein, we address both issues: the former by reformulating the pathway optimization as a regular nonlinear optimization problem; and the latter by enhanced algorithms to pre/post-process the signaling network to remove parts that cannot be identified given the experimental conditions. As a case study, we tackle the construction of cell type specific pathways in normal and transformed hepatocytes using medium and large-scale functional phosphoproteomic datasets. The proposed Non Linear Programming (NLP) formulation allows for fast optimization of signaling topologies by combining the versatile nature of logic modeling with state of the art optimization algorithms.

  1. Non Linear Programming (NLP formulation for quantitative modeling of protein signal transduction pathways.

    Directory of Open Access Journals (Sweden)

    Alexander Mitsos

    Full Text Available Modeling of signal transduction pathways plays a major role in understanding cells' function and predicting cellular response. Mathematical formalisms based on a logic formalism are relatively simple but can describe how signals propagate from one protein to the next and have led to the construction of models that simulate the cells response to environmental or other perturbations. Constrained fuzzy logic was recently introduced to train models to cell specific data to result in quantitative pathway models of the specific cellular behavior. There are two major issues in this pathway optimization: i excessive CPU time requirements and ii loosely constrained optimization problem due to lack of data with respect to large signaling pathways. Herein, we address both issues: the former by reformulating the pathway optimization as a regular nonlinear optimization problem; and the latter by enhanced algorithms to pre/post-process the signaling network to remove parts that cannot be identified given the experimental conditions. As a case study, we tackle the construction of cell type specific pathways in normal and transformed hepatocytes using medium and large-scale functional phosphoproteomic datasets. The proposed Non Linear Programming (NLP formulation allows for fast optimization of signaling topologies by combining the versatile nature of logic modeling with state of the art optimization algorithms.

  2. Herpes simplex virus triggers activation of calcium-signaling pathways

    Science.gov (United States)

    Cheshenko, Natalia; Del Rosario, Brian; Woda, Craig; Marcellino, Daniel; Satlin, Lisa M.; Herold, Betsy C.

    2003-01-01

    The cellular pathways required for herpes simplex virus (HSV) invasion have not been defined. To test the hypothesis that HSV entry triggers activation of Ca2+-signaling pathways, the effects on intracellular calcium concentration ([Ca2+]i) after exposure of cells to HSV were examined. Exposure to virus results in a rapid and transient increase in [Ca2+]i. Pretreatment of cells with pharmacological agents that block release of inositol 1,4,5-triphosphate (IP3)–sensitive endoplasmic reticulum stores abrogates the response. Moreover, treatment of cells with these pharmacological agents inhibits HSV infection and prevents focal adhesion kinase (FAK) phosphorylation, which occurs within 5 min after viral infection. Viruses deleted in glycoprotein L or glycoprotein D, which bind but do not penetrate, fail to induce a [Ca2+]i response or trigger FAK phosphorylation. Together, these results support a model for HSV infection that requires activation of IP3-responsive Ca2+-signaling pathways and that is associated with FAK phosphorylation. Defining the pathway of viral invasion may lead to new targets for anti-viral therapy. PMID:14568989

  3. Assessing the relevance of light for fungi: Implications and insights into the network of signal transmission.

    Science.gov (United States)

    Schmoll, Monika

    2011-01-01

    Light represents an important environmental cue, which provides information enabling fungi to prepare and react to the different ambient conditions between day and night. This adaptation requires both anticipation of the changing conditions, which is accomplished by daily rhythmicity of gene expression brought about by the circadian clock, and reaction to sudden illumination. Besides perception of the light signal, also integration of this signal with other environmental cues, most importantly nutrient availability, necessitates light-dependent regulation of signal transduction pathways and metabolic pathways. An influence of light and/or the circadian clock is known for the cAMP pathway, heterotrimeric G-protein signaling, mitogen-activated protein kinases, two-component phosphorelays, and Ca(2+) signaling. Moreover, also the target of rapamycin signaling pathway and reactive oxygen species as signal transducing elements are assumed to be connected to the light-response pathway. The interplay of the light-response pathway with signaling cascades results in light-dependent regulation of primary and secondary metabolism, morphology, development, biocontrol activity, and virulence. The frequent use of fungi in biotechnology as well as analysis of fungi in the artificial environment of a laboratory therefore requires careful consideration of still operative evolutionary heritage of these organisms. This review summarizes the diverse effects of light on fungi and the mechanisms they apply to deal both with the information content and with the harmful properties of light. Additionally, the implications of the reaction of fungi to light in a laboratory environment for experimental work and industrial applications are discussed. Copyright © 2011 Elsevier Inc. All rights reserved.

  4. Evaluation of Notch and Hypoxia Signaling Pathways in Chemically ...

    African Journals Online (AJOL)

    Hepatocellular carcinoma (HCC) is a common worldwide malignancy. Notch signaling pathway contributes to the genesis of diverse cancers, however, its role in HCC is unclear. Hypoxia is a common feature of HCC. Signal integration between Notch and hypoxia may be involved in HCC. The aim of this study was to ...

  5. Towards brain-activity-controlled information retrieval: Decoding image relevance from MEG signals.

    Science.gov (United States)

    Kauppi, Jukka-Pekka; Kandemir, Melih; Saarinen, Veli-Matti; Hirvenkari, Lotta; Parkkonen, Lauri; Klami, Arto; Hari, Riitta; Kaski, Samuel

    2015-05-15

    We hypothesize that brain activity can be used to control future information retrieval systems. To this end, we conducted a feasibility study on predicting the relevance of visual objects from brain activity. We analyze both magnetoencephalographic (MEG) and gaze signals from nine subjects who were viewing image collages, a subset of which was relevant to a predetermined task. We report three findings: i) the relevance of an image a subject looks at can be decoded from MEG signals with performance significantly better than chance, ii) fusion of gaze-based and MEG-based classifiers significantly improves the prediction performance compared to using either signal alone, and iii) non-linear classification of the MEG signals using Gaussian process classifiers outperforms linear classification. These findings break new ground for building brain-activity-based interactive image retrieval systems, as well as for systems utilizing feedback both from brain activity and eye movements. Copyright © 2015 Elsevier Inc. All rights reserved.

  6. Construction of large signaling pathways using an adaptive perturbation approach with phosphoproteomic data.

    Science.gov (United States)

    Melas, Ioannis N; Mitsos, Alexander; Messinis, Dimitris E; Weiss, Thomas S; Rodriguez, Julio-Saez; Alexopoulos, Leonidas G

    2012-04-01

    Construction of large and cell-specific signaling pathways is essential to understand information processing under normal and pathological conditions. On this front, gene-based approaches offer the advantage of large pathway exploration whereas phosphoproteomic approaches offer a more reliable view of pathway activities but are applicable to small pathway sizes. In this paper, we demonstrate an experimentally adaptive approach to construct large signaling pathways from phosphoproteomic data within a 3-day time frame. Our approach--taking advantage of the fast turnaround time of the xMAP technology--is carried out in four steps: (i) screen optimal pathway inducers, (ii) select the responsive ones, (iii) combine them in a combinatorial fashion to construct a phosphoproteomic dataset, and (iv) optimize a reduced generic pathway via an Integer Linear Programming formulation. As a case study, we uncover novel players and their corresponding pathways in primary human hepatocytes by interrogating the signal transduction downstream of 81 receptors of interest and constructing a detailed model for the responsive part of the network comprising 177 species (of which 14 are measured) and 365 interactions.

  7. Dietary influence on MAPK-signaling pathways and risk of colon and rectal cancer.

    Science.gov (United States)

    Slattery, Martha L; Lundgreen, Abbie; Wolff, Roger K

    2013-01-01

    Mitogen-activated protein kinase (MAPK) pathways regulate cellular functions including cell proliferation, differentiation, migration, and apoptosis. Associations between genes in the DUSP, ERK1/2, JNK, and p38 MAPK-signaling pathways and dietary factors associated with growth factors, inflammation, and oxidative stress and risk of colon and rectal cancer were evaluated. Data include colon cases (n = 1555) and controls (n = 1956) and rectal cases (n = 754) and controls (n = 959). Statistically significant interactions were observed for the MAPK-signaling pathways after adjustment for multiple comparisons. DUSP genes interacted with carbohydrates, mutagen index, calories, calcium, vitamin D, lycopene, dietary fats, folic acid, and selenium. MAPK1, MAPK3, MAPK1, and RAF1 within the ERK1/2 MAPK-signaling pathway interacted with dietary fats and cruciferous vegetables. Within the JNK MAPK-signaling pathway, interactions between MAP3K7 and protein, vitamin C, iron, folic acid, carbohydrates, and cruciferous vegetables; MAP3K10 and folic acid; MAP3K9 and lutein/zeaxanthin; MAPK8 and calcium; MAP3K3 and calcium and lutein; MAP3K1 and cruciferous vegetables. Interaction within the p38-signaling pathway included MAPK14 with calories, carbohydrates saturated fat, selenium, vitamin C; MAP3K2 and carbohydrates, and folic acid. These data suggest that dietary factors involved in inflammation and oxidative stress interact with MAPK-signaling genes to alter risk of colorectal cancer.

  8. Discovery and characterization of a potent Wnt and hedgehog signaling pathways dual inhibitor.

    Science.gov (United States)

    Ma, Haikuo; Chen, Qin; Zhu, Fang; Zheng, Jiyue; Li, Jiajun; Zhang, Hongjian; Chen, Shuaishuai; Xing, Haimei; Luo, Lusong; Zheng, Long Tai; He, Sudan; Zhang, Xiaohu

    2018-04-10

    Embryonic stem cell pathways such as hedgehog and Wnt pathways are central to the tumorigenic properties of cancer stem cells (CSC). Since CSCs are characterized by their ability to self-renew, form differentiated progeny, and develop resistance to anticancer therapies, targeting the Wnt and hedgehog signaling pathways has been an important strategy for cancer treatment. Although molecules targeting either Wnt or hedgehog are common, to the best of our knowledge, those targeting both pathways have not been documented. Here we report a small molecule (compound 1) that inhibits both Wnt (IC 50  = 0.5 nM) and hedgehog (IC 50  = 71 nM) pathways based on reporter gene assays. We further identified that the molecular target of 1 for Wnt pathway inhibition was porcupine (a member of the membrane-bound O-acyltransferase family of proteins), a post-translational modification node in Wnt signaling; while the target of 1 mitigating hedgehog pathway was Smoothened, a key G protein coupled receptor (GPCR) mediating hedgehog signal transduction. Preliminary analysis of structure-activity-relationship identified key functional elements for hedgehog/Wnt inhibition. In in vivo studies, compound 1 demonstrated good oral exposure and bioavailability while eliciting no overt toxicity in mice. An important consideration in cancer treatment is the potential therapeutic escape through compensatory activation of an interconnected pathway when only one signaling pathway is inhibited. Toward this end, compound 1 may not only lead to the development of new therapeutics for Wnt and hedgehog related cancers, but may also help to develop potential cancer treatment which needs to target Wnt and hedgehog signaling simultaneously. Copyright © 2018 Elsevier Masson SAS. All rights reserved.

  9. Sex and hedgehog: roles of genes in the hedgehog signaling pathway in mammalian sexual differentiation.

    Science.gov (United States)

    Franco, Heather L; Yao, Humphrey H-C

    2012-01-01

    The chromosome status of the mammalian embryo initiates a multistage process of sexual development in which the bipotential reproductive system establishes itself as either male or female. These events are governed by intricate cell-cell and interorgan communication that is regulated by multiple signaling pathways. The hedgehog signaling pathway was originally identified for its key role in the development of Drosophila, but is now recognized as a critical developmental regulator in many species, including humans. In addition to its developmental roles, the hedgehog signaling pathway also modulates adult organ function, and misregulation of this pathway often leads to diseases, such as cancer. The hedgehog signaling pathway acts through its morphogenetic ligands that signal from ligand-producing cells to target cells over a specified distance. The target cells then respond in a graded manner based on the concentration of the ligands that they are exposed to. Through this unique mechanism of action, the hedgehog signaling pathway elicits cell fate determination, epithelial-mesenchymal interactions, and cellular homeostasis. Here, we review current findings on the roles of hedgehog signaling in the sexually dimorphic development of the reproductive organs with an emphasis on mammals and comparative evidence in other species.

  10. International Union of Basic and Clinical Pharmacology Review: WNT/Frizzled signalling: receptor–ligand selectivity with focus on FZD-G protein signalling and its physiological relevance: IUPHAR Review 3

    Science.gov (United States)

    Dijksterhuis, J P; Petersen, J; Schulte, G

    2014-01-01

    The wingless/int1 (WNT)/Frizzled (FZD) signalling pathway controls numerous cellular processes such as proliferation, differentiation, cell-fate decisions, migration and plays a crucial role during embryonic development. Nineteen mammalian WNTs can bind to 10 FZDs thereby activating different downstream pathways such as WNT/β-catenin, WNT/planar cell polarity and WNT/Ca2+. However, the mechanisms of signalling specification and the involvement of heterotrimeric G proteins are still unclear. Disturbances in the pathways can lead to various diseases ranging from cancer, inflammatory diseases to metabolic and neurological disorders. Due to the presence of seven-transmembrane segments, evidence for coupling between FZDs and G proteins and substantial structural differences in class A, B or C GPCRs, FZDs were grouped separately in the IUPHAR GPCR database as the class FZD within the superfamily of GPCRs. Recently, important progress has been made pointing to a direct activation of G proteins after WNT stimulation. WNT/FZD and G protein coupling remain to be fully explored, although the basic observation supporting the nature of FZDs as GPCRs is compelling. Because the involvement of different (i) WNTs; (ii) FZDs; and (iii) intracellular binding partners could selectively affect signalling specification, in this review we present the current understanding of receptor/ligand selectivity of FZDs and WNTs. We pinpoint what is known about signalling specification and the physiological relevance of these interactions with special emphasis on FZD–G protein interactions. LINKED ARTICLESThis article is part of a themed section on Molecular Pharmacology of GPCRs. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2014.171.issue-5 PMID:24032637

  11. Molecular profiling of ALDH1+ colorectal cancer stem cells reveals preferential activation of MAPK, FAK, and oxidative stress prosurvival signalling pathways

    DEFF Research Database (Denmark)

    Vishnubalaji, Radhakrishnan; Manikandan, Muthurangan; Fahad, Mohamed

    2018-01-01

    enrichment related to DNA damage, MAPK, FAK, oxidative stress response, and Wnt signalling. ALDH+ cells showed enhanced ROS stress resistance, whereas MAPK/FAK pathway pharmacologic inhibition limited their survival. Conversely, 5-fluorouracil increased the ALDH+ cell fraction among the SW403, HCT116 and SW.......006) and poor DFS (p = 0.05), thus implicating ALDH1A1 and POU5F1 in CRC prognosis. Our data reveal distinct molecular signature of ALDH+ CSCs in CRC and suggest pathways relevant for successful targeted therapies and management of CRC....

  12. [The function of transcription factor P63 and its signaling pathway during limb development].

    Science.gov (United States)

    Ma, Wei; Tian, Wen

    2014-08-01

    The development of human limb is controlled by several transcription factors and signaling pathways, which are organized in precise time- and space-restricted manners. Recent studies showed that P63 and its signaling pathway play important roles in this process. Transcription factor P63, one member of the P53 family, is characterized by a similar amino acid domain, plays a crucial role in the development of limb and ectoderm differentiation, especially with its DNA binding domain, and sterile alpha motif domains. Mutated P63 gene may produce abnormal transcription factor P63 which can affect the signaling pathway. Furthermore, defective signaling protein in structure and/or quantity is synthesized though the pathway. Eventually, members of the signaling protein family are involved in the regulation of differentiation and development of stem cell, which causes deformity of limbs. In brief, three signaling pathways are related to the digit formation along three axes, including SHH-ZPA, FGFs-AER and Lmx1B-Wnt7a-En1. Each contains numerous signaling molecules which are integrated in self-regulatory modules that assure the acquisition or the correct digit complements. These finding has brought new clues for deciphering the etiology of congenital limb malformation and may provide alternatives for both prevention and treatment.

  13. Role of CSL-dependent and independent Notch signaling pathways in cell apoptosis.

    Science.gov (United States)

    Zeng, Chong; Xing, Rui; Liu, Jing; Xing, Feiyue

    2016-01-01

    Apoptosis is a normally biological phenomenon in various organisms, involving complexly molecular mechanisms with a series of signaling processes. Notch signaling is found evolutionarily conserved in many species, playing a critical role in embryonic development, normal tissue homeostasis, angiogenesis and immunoregulation. The focus of this review is on currently novel advances about roles of CSL-dependent and independent Notch signaling pathways in cell apoptosis. The CSL can bind Notch intracellular domain (NIC) to act as a switch in mediating transcriptional activation or inactivation of the Notch signaling pathway downstream genes in the nucleus. It shows that CSL-dependent signaling regulates the cell apoptosis through Hes-1-PTEN-AKT-mTOR signaling, but rather the CSL-independent signaling mediates the cell apoptosis possibly via NIC-mTORC2-AKT-mTOR signaling, providing a new insight into apoptotic mechanisms.

  14. Network features and pathway analyses of a signal transduction cascade

    Directory of Open Access Journals (Sweden)

    Ryoji Yanashima

    2009-05-01

    Full Text Available The scale-free and small-world network models reflect the functional units of networks. However, when we investigated the network properties of a signaling pathway using these models, no significant differences were found between the original undirected graphs and the graphs in which inactive proteins were eliminated from the gene expression data. We analyzed signaling networks by focusing on those pathways that best reflected cellular function. Therefore, our analysis of pathways started from the ligands and progressed to transcription factors and cytoskeletal proteins. We employed the Python module to assess the target network. This involved comparing the original and restricted signaling cascades as a directed graph using microarray gene expression profiles of late onset Alzheimer's disease. The most commonly used method of shortest-path analysis neglects to consider the influences of alternative pathways that can affect the activation of transcription factors or cytoskeletal proteins. We therefore introduced included k-shortest paths and k-cycles in our network analysis using the Python modules, which allowed us to attain a reasonable computational time and identify k-shortest paths. This technique reflected results found in vivo and identified pathways not found when shortest path or degree analysis was applied. Our module enabled us to comprehensively analyse the characteristics of biomolecular networks and also enabled analysis of the effects of diseases considering the feedback loop and feedforward loop control structures as an alternative path.

  15. Insulin-like growth factor-1 suppresses the Myostatin signaling pathway during myogenic differentiation

    International Nuclear Information System (INIS)

    Retamales, A.; Zuloaga, R.; Valenzuela, C.A.; Gallardo-Escarate, C.; Molina, A.; Valdés, J.A.

    2015-01-01

    Myogenic differentiation is a complex and well-coordinated process for generating mature skeletal muscle fibers. This event is autocrine/paracrine regulated by growth factors, principally Myostatin (MSTN) and Insulin-like Growth Factor-1 (IGF-1). Myostatin, a member of the transforming growth factor-β superfamily, is a negative regulator of skeletal muscle growth in vertebrates that exerts its inhibitory function by activating Smad transcription factors. In contrast, IGF-1 promotes the differentiation of skeletal myoblasts by activating the PI3K/Akt signaling pathway. This study reports on a novel functional crosstalk between the IGF-1 and MSTN signaling pathways, as mediated through interaction between PI3K/Akt and Smad3. Stimulation of skeletal myoblasts with MSTN resulted in a transient increase in the pSmad3:Smad3 ratio and Smad-dependent transcription. Moreover, MSTN inhibited myod gene expression and myoblast fusion in an Activin receptor-like kinase/Smad3-dependent manner. Preincubation of skeletal myoblasts with IGF-1 blocked MSTN-induced Smad3 activation, promoting myod expression and myoblast differentiation. This inhibitory effect of IGF-1 on the MSTN signaling pathway was dependent on IGF-1 receptor, PI3K, and Akt activities. Finally, immunoprecipitation assay analysis determined that IGF-1 pretreatment increased Akt and Smad3 interaction. These results demonstrate that the IGF-1/PI3K/Akt pathway may inhibit MSTN signaling during myoblast differentiation, providing new insight to existing knowledge on the complex crosstalk between both growth factors. - Highlights: • IGF-1 inhibits Myostatin canonical signaling pathway through IGF-1R/PI3K/Akt pathway. • IGF-1 promotes myoblast differentiation through a direct blocking of Myostatin signaling pathway. • IGF-1 induces the interaction of Akt with Smad3 in skeletal myoblast

  16. Insulin-like growth factor-1 suppresses the Myostatin signaling pathway during myogenic differentiation

    Energy Technology Data Exchange (ETDEWEB)

    Retamales, A.; Zuloaga, R.; Valenzuela, C.A. [Laboratorio de Biotecnología Molecular, Facultad de Ciencias Biológicas, Universidad Andrés Bello, Santiago (Chile); Gallardo-Escarate, C. [Laboratory of Biotechnology and Aquatic Genomics, Universidad de Concepción, Concepción (Chile); Interdisciplinary Center for Aquaculture Research (INCAR), P.O. Box 160-C, Concepción (Chile); Molina, A. [Laboratorio de Biotecnología Molecular, Facultad de Ciencias Biológicas, Universidad Andrés Bello, Santiago (Chile); Interdisciplinary Center for Aquaculture Research (INCAR), P.O. Box 160-C, Concepción (Chile); Valdés, J.A., E-mail: jvaldes@unab.cl [Laboratorio de Biotecnología Molecular, Facultad de Ciencias Biológicas, Universidad Andrés Bello, Santiago (Chile); Interdisciplinary Center for Aquaculture Research (INCAR), P.O. Box 160-C, Concepción (Chile)

    2015-08-21

    Myogenic differentiation is a complex and well-coordinated process for generating mature skeletal muscle fibers. This event is autocrine/paracrine regulated by growth factors, principally Myostatin (MSTN) and Insulin-like Growth Factor-1 (IGF-1). Myostatin, a member of the transforming growth factor-β superfamily, is a negative regulator of skeletal muscle growth in vertebrates that exerts its inhibitory function by activating Smad transcription factors. In contrast, IGF-1 promotes the differentiation of skeletal myoblasts by activating the PI3K/Akt signaling pathway. This study reports on a novel functional crosstalk between the IGF-1 and MSTN signaling pathways, as mediated through interaction between PI3K/Akt and Smad3. Stimulation of skeletal myoblasts with MSTN resulted in a transient increase in the pSmad3:Smad3 ratio and Smad-dependent transcription. Moreover, MSTN inhibited myod gene expression and myoblast fusion in an Activin receptor-like kinase/Smad3-dependent manner. Preincubation of skeletal myoblasts with IGF-1 blocked MSTN-induced Smad3 activation, promoting myod expression and myoblast differentiation. This inhibitory effect of IGF-1 on the MSTN signaling pathway was dependent on IGF-1 receptor, PI3K, and Akt activities. Finally, immunoprecipitation assay analysis determined that IGF-1 pretreatment increased Akt and Smad3 interaction. These results demonstrate that the IGF-1/PI3K/Akt pathway may inhibit MSTN signaling during myoblast differentiation, providing new insight to existing knowledge on the complex crosstalk between both growth factors. - Highlights: • IGF-1 inhibits Myostatin canonical signaling pathway through IGF-1R/PI3K/Akt pathway. • IGF-1 promotes myoblast differentiation through a direct blocking of Myostatin signaling pathway. • IGF-1 induces the interaction of Akt with Smad3 in skeletal myoblast.

  17. High-frequency deregulated expression of Wnt signaling pathway members in breast carcinomas.

    Science.gov (United States)

    Khan, Zahid; Arafah, Maha; Shaik, Jilani Purusottapatnam; Mahale, Alka; Alanazi, Mohammad Saud

    2018-01-01

    Breast carcinoma is the most common malignancy and leading cause of cancer-related deaths in women worldwide including Saudi Arabia. Breast cancer in Saudi women develops at a much early age with median age of onset of 49 years compared to 62 years observed in patients from USA. Aberrations in wingless and integration site growth factor (Wnt) signaling pathway have been pathologically implicated in development of breast cancers and hence its role was examined in Saudi patients. We immunohistochemically examined various components of Wnt signaling pathway including β-catenin, tumor suppressor proteins, adenomatous polyposis coli (APC), and Axin, expression of naturally occurring pathway antagonists such as Dickkopf Wnt signaling pathway inhibitor 3 (DKK3), FRP2, and WIF1, as well as Wnt target cyclin D1 and c-Myc to establish if the pathway is constitutively activated in breast cancers arising in Saudi women. Cytoplasmic β-catenin, indicative of activation of the pathway, was observed in 24% of cases. Expression of APC and Axin, which are components of β-catenin destruction complex, was lost in 5% and 10% of tumors, respectively. Additionally, Wnt signaling inhibitors DKK3, FRP2, and Wnt inhibitory factor 1 (WIF1) were not expressed in 8%, 14%, and 5% breast tumors, respectively. Overall, accumulation of cytoplasmic β-catenin and downregulation of other Wnt pathway proteins (APC/Axin/DKK3/FRP2/WIF1) were found in approximately half of the breast cancers (47%) in our cohort. Consistent with this, analysis of Wnt target genes demonstrated moderate-to-strong expression of c-Myc in 58% and cyclin D1 in 50% of breast cancers. Deregulation of Wnt pathway was not associated with age of onset of the disease, tumor grade, and triple-negative status of breast cancers. High level of deregulated expression of Wnt pathway proteins suggests its important role in pathogenesis of breast cancers arising in Saudi women who may benefit from development of therapeutic drugs

  18. [Review for treatment effect and signaling pathway regulation of kidney-tonifying traditional Chinese medicine on osteoporosis].

    Science.gov (United States)

    Xiao, Ya-Ping; Zeng, Jie; Jiao, Lin-Na; Xu, Xiao-Yu

    2018-01-01

    The treatment effect and signaling pathway regulation effects of kidney-tonifying traditional Chinese medicine on osteoporosis have been widely studied, but there is no systematic summary currently. This review comprehensively collected and analyzed the traditional Chinese medicines on the treatment and signaling pathway regulation of osteoporosis in recent ten years, such as Epimedii Folium, Drynariae Rhizoma, Cnidii Fructus, Eucommiae Cortex, Psoraleae Fructus and Dipsaci Radix. Based on the existing findings, the following conclusions were obtained: ①kidney-tonifying traditional Chinese medicine treated osteoporosis mainly through BMP-Smads, Wnt/ β -catenin, MAPK, PI3K/AKT signaling pathway to promote osteoblast bone formation and through OPG/RANKL/ RANK, estrogen, CTSK signaling pathway to inhibit osteoclasts of bone resorption. Epimedii Folium, Drynariae Rhizoma, Cnidii Fructus and Psoraleae Fructus up-regulated the expression of key proteins and genes of BMP-Smads and Wnt/ β -catenin signaling pathways to promote bone formation. Epimedii Folium, Drynariae Rhizoma, Cnidii Fructus, Eucommiae Cortex, Psoraleae Fructus and Dipsaci Radix inhibited the bone resorption by mediating the OPG/RANKL/RANK signaling pathway. ②Kidney-tonifying traditional Chinese medicine prevented and treated osteoporosis through a variety of ways: icariin in Epimedii Folium, naringin in Drynariae Rhizoma, osthole in Cnidii Fructus and psoralen in Psoraleae Fructus can regulate BMP-Smads, Wnt/ β -catenin signaling pathway to promote bone formation, but also activate OPG/RANKL/RANK, CTSK and other signaling pathways to inhibit bone resorption. ③The crosstalk of the signaling pathways and the animal experiments of the traditional Chinese medicine on the prevention and treatment of osteoporosis as well as their multi-target mechanism and comprehensive regulation need further clarification. Copyright© by the Chinese Pharmaceutical Association.

  19. ent-Steroids: novel tools for studies of signaling pathways.

    Science.gov (United States)

    Covey, Douglas F

    2009-07-01

    Membrane receptors are often modulated by steroids and it is necessary to distinguish the effects of steroids at these receptors from effects occurring at nuclear receptors. Additionally, it may also be mechanistically important to distinguish between direct effects caused by binding of steroids to membrane receptors and indirect effects on membrane receptor function caused by steroid perturbation of the membrane containing the receptor. In this regard, ent-steroids, the mirror images of naturally occurring steroids, are novel tools for distinguishing between these various actions of steroids. The review provides a background for understanding the different actions that can be expected of steroids and ent-steroids in biological systems, references for the preparation of ent-steroids, a short discussion about relevant forms of stereoisomerism and the requirements that need to be fulfilled for the interaction between two molecules to be enantioselective. The review then summarizes results of biophysical, biochemical and pharmacological studies published since 1992 in which ent-steroids have been used to investigate the actions of steroids in membranes and/or receptor-mediated signaling pathways.

  20. Calcium-Dependent Protein Kinases in Phytohormone Signaling Pathways

    Directory of Open Access Journals (Sweden)

    Wuwu Xu

    2017-11-01

    Full Text Available Calcium-dependent protein kinases (CPKs/CDPKs are Ca2+-sensors that decode Ca2+ signals into specific physiological responses. Research has reported that CDPKs constitute a large multigene family in various plant species, and play diverse roles in plant growth, development, and stress responses. Although numerous CDPKs have been exhaustively studied, and many of them have been found to be involved in plant hormone biosynthesis and response mechanisms, a comprehensive overview of the manner in which CDPKs participate in phytohormone signaling pathways, regulating nearly all aspects of plant growth, has not yet been undertaken. In this article, we reviewed the structure of CDPKs and the mechanism of their subcellular localization. Some CDPKs were elucidated to influence the intracellular localization of their substrates. Since little work has been done on the interaction between CDPKs and cytokinin signaling pathways, or on newly defined phytohormones such as brassinosteroids, strigolactones and salicylic acid, this paper mainly focused on discussing the integral associations between CDPKs and five plant hormones: auxins, gibberellins, ethylene, jasmonates, and abscisic acid. A perspective on future work is provided at the end.

  1. Dynamics and control of the ERK signaling pathway: Sensitivity, bistability, and oscillations.

    Science.gov (United States)

    Arkun, Yaman; Yasemi, Mohammadreza

    2018-01-01

    Cell signaling is the process by which extracellular information is transmitted into the cell to perform useful biological functions. The ERK (extracellular-signal-regulated kinase) signaling controls several cellular processes such as cell growth, proliferation, differentiation and apoptosis. The ERK signaling pathway considered in this work starts with an extracellular stimulus and ends with activated (double phosphorylated) ERK which gets translocated into the nucleus. We model and analyze this complex pathway by decomposing it into three functional subsystems. The first subsystem spans the initial part of the pathway from the extracellular growth factor to the formation of the SOS complex, ShC-Grb2-SOS. The second subsystem includes the activation of Ras which is mediated by the SOS complex. This is followed by the MAPK subsystem (or the Raf-MEK-ERK pathway) which produces the double phosphorylated ERK upon being activated by Ras. Although separate models exist in the literature at the subsystems level, a comprehensive model for the complete system including the important regulatory feedback loops is missing. Our dynamic model combines the existing subsystem models and studies their steady-state and dynamic interactions under feedback. We establish conditions under which bistability and oscillations exist for this important pathway. In particular, we show how the negative and positive feedback loops affect the dynamic characteristics that determine the cellular outcome.

  2. Regulation of Cell Wall Biogenesis in Saccharomyces cerevisiae: The Cell Wall Integrity Signaling Pathway

    Science.gov (United States)

    Levin, David E.

    2011-01-01

    The yeast cell wall is a strong, but elastic, structure that is essential not only for the maintenance of cell shape and integrity, but also for progression through the cell cycle. During growth and morphogenesis, and in response to environmental challenges, the cell wall is remodeled in a highly regulated and polarized manner, a process that is principally under the control of the cell wall integrity (CWI) signaling pathway. This pathway transmits wall stress signals from the cell surface to the Rho1 GTPase, which mobilizes a physiologic response through a variety of effectors. Activation of CWI signaling regulates the production of various carbohydrate polymers of the cell wall, as well as their polarized delivery to the site of cell wall remodeling. This review article centers on CWI signaling in Saccharomyces cerevisiae through the cell cycle and in response to cell wall stress. The interface of this signaling pathway with other pathways that contribute to the maintenance of cell wall integrity is also discussed. PMID:22174182

  3. Monitoring UV-induced signalling pathways in an ex vivo skin organ culture model using phospho-antibody array.

    Science.gov (United States)

    Lenain, Christelle; Gamboa, Bastien; Perrin, Agnes; Séraïdaris, Alexia; Bertino, Béatrice; Rival, Yves; Bernardi, Mathieu; Piwnica, David; Méhul, Bruno

    2018-05-01

    We investigated UV-induced signalling in an ex vivo skin organ culture model using phospho-antibody array. Phosphorylation modulations were analysed in time-course experiments following exposure to solar-simulated UV and validated by Western blot analyses. We found that UV induced P-p38 and its substrates, P-ERK1/2 and P-AKT, which were previously shown to be upregulated by UV in cultured keratinocytes and in vivo human skin. This indicates that phospho-antibody array applied to ex vivo skin organ culture is a relevant experimental system to investigate signalling events following perturbations. As the identified proteins are components of pathways implicated in skin tumorigenesis, UV-exposed skin organ culture model could be used to investigate the effect on these pathways of NMSC cancer drug candidates. In addition, we found that phospho-HCK is induced upon UV exposure, producing a new candidate for future studies investigating its role in the skin response to UV and UV-induced carcinogenesis. © 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  4. Endothelial Mechanotransduction, Redox Signaling and the Regulation of Vascular Inflammatory Pathways

    Directory of Open Access Journals (Sweden)

    Shampa Chatterjee

    2018-06-01

    Full Text Available The endothelium that lines the interior of blood vessels is directly exposed to blood flow. The shear stress arising from blood flow is “sensed” by the endothelium and is “transduced” into biochemical signals that eventually control vascular tone and homeostasis. Sensing and transduction of physical forces occur via signaling processes whereby the forces associated with blood flow are “sensed” by a mechanotransduction machinery comprising of several endothelial cell elements. Endothelial “sensing” involves converting the physical cues into cellular signaling events such as altered membrane potential and activation of kinases, which are “transmission” signals that cause oxidant production. Oxidants produced are the “transducers” of the mechanical signals? What is the function of these oxidants/redox signals? Extensive data from various studies indicate that redox signals initiate inflammation signaling pathways which in turn can compromise vascular health. Thus, inflammation, a major response to infection or endotoxins, can also be initiated by the endothelium in response to various flow patterns ranging from aberrant flow to alteration of flow such as cessation or sudden increase in blood flow. Indeed, our work has shown that endothelial mechanotransduction signaling pathways participate in generation of redox signals that affect the oxidant and inflammation status of cells. Our goal in this review article is to summarize the endothelial mechanotransduction pathways that are activated with stop of blood flow and with aberrant flow patterns; in doing so we focus on the complex link between mechanical forces and inflammation on the endothelium. Since this “inflammation susceptible” phenotype is emerging as a trigger for pathologies ranging from atherosclerosis to rejection post-organ transplant, an understanding of the endothelial machinery that triggers these processes is very crucial and timely.

  5. Bipolar cell gap junctions serve major signaling pathways in the human retina.

    Science.gov (United States)

    Kántor, Orsolya; Varga, Alexandra; Nitschke, Roland; Naumann, Angela; Énzsöly, Anna; Lukáts, Ákos; Szabó, Arnold; Németh, János; Völgyi, Béla

    2017-08-01

    Connexin36 (Cx36) constituent gap junctions (GJ) throughout the brain connect neurons into functional syncytia. In the retina they underlie the transmission, averaging and correlation of signals prior conveying visual information to the brain. This is the first study that describes retinal bipolar cell (BC) GJs in the human inner retina, whose function is enigmatic even in the examined animal models. Furthermore, a number of unique features (e.g. fovea, trichromacy, midget system) necessitate a reexamination of the animal model results in the human retina. Well-preserved postmortem human samples of this study are allowed to identify Cx36 expressing BCs neurochemically. Results reveal that both rod and cone pathway interneurons display strong Cx36 expression. Rod BC inputs to AII amacrine cells (AC) appear in juxtaposition to AII GJs, thus suggesting a strategic AII cell targeting by rod BCs. Cone BCs serving midget, parasol or koniocellular signaling pathways display a wealth of Cx36 expression to form homologously coupled arrays. In addition, they also establish heterologous GJ contacts to serve an exchange of information between parallel signaling streams. Interestingly, a prominent Cx36 expression was exhibited by midget system BCs that appear to maintain intimate contacts with bistratified BCs serving other pathways. These findings suggest that BC GJs in parallel signaling streams serve both an intra- and inter-pathway exchange of signals in the human retina.

  6. Stem cell maintenance by manipulating signaling pathways: past, current and future

    Science.gov (United States)

    Chen, Xi; Ye, Shoudong; Ying, Qi-Long

    2015-01-01

    Pluripotent stem cells only exist in a narrow window during early embryonic development, whereas multipotent stem cells are abundant throughout embryonic development and are retainedin various adult tissues and organs. While pluripotent stem cell lines have been established from several species, including mouse, rat, and human, it is still challenging to establish stable multipotent stem cell lines from embryonic or adult tissues. Based on current knowledge, we anticipate that by manipulating extrinsic and intrinsic signaling pathways, most if not all types of stem cells can be maintained in a long-term culture. In this article, we summarize current culture conditions established for the long-term maintenance of authentic pluripotent and multipotent stem cells and the signaling pathways involved. We also discuss the general principles of stem cell maintenance and propose several strategies on the establishment of novel stem cell lines through manipulation of signaling pathways. [BMB Reports 2015; 48(12): 668-676] PMID:26497581

  7. Necrotrophic pathogens use the salicylic acid signaling pathway to promote disease development in tomato.

    Science.gov (United States)

    Rahman, Taha Abd El; Oirdi, Mohamed El; Gonzalez-Lamothe, Rocio; Bouarab, Kamal

    2012-12-01

    Plants use different immune pathways to combat pathogens. The activation of the jasmonic acid (JA)-signaling pathway is required for resistance against necrotrophic pathogens; however, to combat biotrophic pathogens, the plants activate mainly the salicylic acid (SA)-signaling pathway. SA can antagonize JA signaling and vice versa. NPR1 (noninducible pathogenesis-related 1) is considered a master regulator of SA signaling. NPR1 interacts with TGA transcription factors, ultimately leading to the activation of SA-dependent responses. SA has been shown to promote disease development caused by the necrotrophic pathogen Botrytis cinerea through NPR1, by suppressing the expression of two JA-dependent defense genes, proteinase inhibitors I and II. We show here that the transcription factor TGA1.a contributes to disease development caused by B. cinerea in tomato by suppressing the expression of proteinase inhibitors I and II. Finally, we present evidence that the SA-signaling pathway contributes to disease development caused by another necrotrophic pathogen, Alternaria solani, in tomato. Disease development promoted by SA through NPR1 requires the TGA1.a transcription factor. These data highlight how necrotrophs manipulate the SAsignaling pathway to promote their disease in tomato.

  8. DMPD: TLR signaling. [Dynamic Macrophage Pathway CSML Database

    Lifescience Database Archive (English)

    Full Text Available kira S. Publication Cell Death Differ. 2006 May;13(5):816-25. Pathway - PNG File (.png) SVG File (.svg) HTML File (.html...16410796 TLR signaling. Kawai T, Akira S. Cell Death Differ. 2006 May;13(5):816-25. (.png) (.svg) (.html

  9. Downstream reporter gene imaging for signal transduction pathway of dopamine type 2 receptor

    International Nuclear Information System (INIS)

    Le, Uyenchi N.; Min, Jung Joon; Moon, Sung Min; Bom, Hee Seung

    2004-01-01

    The Dopamine 2 receptor (D2R) signal pathway regulates gene expression by phosphorylation of proteins including cAMP reponse element-binding protein (CREB), a transcription factor. In this study, we developed a reporter strategy using the GAL4 fusion CREB to assess the phosphorylation of CREB, one of the targets of the D2R signal transduction pathway. We used three plasmids: GAL4 fusion transactivator (pCMV-CREB), firefly luciferase reporter with GAL4 binding sites (pG5-FLUC), and D2R plasmid (pCMV-D2R). Group 1 293T cells were transiently transfected with pCMV-CREB and pG5-FLUC, and group 2 cells were transfected with all three plasmids. Transfected cells were stimulated with different concentrations of dopamine (0-200 M). For animal studies, group 1 and 2 cells (1x10 6 ) were subcutaneously injected on the left and right thigh of six nude mice, respectively. Dopamine stimiulation was performed with intraperitoneal injection of L-DOPA incombination with carbidopa, a peripheral DOPA decarboxylase inhibitor. Bioluminescence optical imaging studies were performed before and after L-DOPA injection. In cell culture studies, group 1 cells showed strong luciferase activity which implies direct activation of the signaling pathway due to growth factors contained in culture medium. Group 2 cells showed strong luciferase activity and a further increase after administration of dopamine. In animal studies, group 1 and 2 cells showed bioluminescence signal before L-DOPA injection, but signal from group 2 cells significantly increased 12 h after L-DOPA injection. The signal from group 1 cells disappeared thereafter, but group 2 cells continued to show signal until 36 h of L-DOPA injection. This study demonstrates imaging of the D2R signal transduction pathway and should be useful for noninvasive imaging of downstream effects of G-coupled protein pathways

  10. Creating and analyzing pathway and protein interaction compendia for modelling signal transduction networks

    Directory of Open Access Journals (Sweden)

    Kirouac Daniel C

    2012-05-01

    Full Text Available Abstract Background Understanding the information-processing capabilities of signal transduction networks, how those networks are disrupted in disease, and rationally designing therapies to manipulate diseased states require systematic and accurate reconstruction of network topology. Data on networks central to human physiology, such as the inflammatory signalling networks analyzed here, are found in a multiplicity of on-line resources of pathway and interactome databases (Cancer CellMap, GeneGo, KEGG, NCI-Pathway Interactome Database (NCI-PID, PANTHER, Reactome, I2D, and STRING. We sought to determine whether these databases contain overlapping information and whether they can be used to construct high reliability prior knowledge networks for subsequent modeling of experimental data. Results We have assembled an ensemble network from multiple on-line sources representing a significant portion of all machine-readable and reconcilable human knowledge on proteins and protein interactions involved in inflammation. This ensemble network has many features expected of complex signalling networks assembled from high-throughput data: a power law distribution of both node degree and edge annotations, and topological features of a “bow tie” architecture in which diverse pathways converge on a highly conserved set of enzymatic cascades focused around PI3K/AKT, MAPK/ERK, JAK/STAT, NFκB, and apoptotic signaling. Individual pathways exhibit “fuzzy” modularity that is statistically significant but still involving a majority of “cross-talk” interactions. However, we find that the most widely used pathway databases are highly inconsistent with respect to the actual constituents and interactions in this network. Using a set of growth factor signalling networks as examples (epidermal growth factor, transforming growth factor-beta, tumor necrosis factor, and wingless, we find a multiplicity of network topologies in which receptors couple to downstream

  11. Halobenzoquinone-Induced Alteration of Gene Expression Associated with Oxidative Stress Signaling Pathways.

    Science.gov (United States)

    Li, Jinhua; Moe, Birget; Liu, Yanming; Li, Xing-Fang

    2018-06-05

    Halobenzoquinones (HBQs) are emerging disinfection byproducts (DBPs) that effectively induce reactive oxygen species and oxidative damage in vitro. However, the impacts of HBQs on oxidative-stress-related gene expression have not been investigated. In this study, we examined alterations in the expression of 44 genes related to oxidative-stress-induced signaling pathways in human uroepithelial cells (SV-HUC-1) upon exposure to six HBQs. The results show the structure-dependent effects of HBQs on the studied gene expression. After 2 h of exposure, the expression levels of 9 to 28 genes were altered, while after 8 h of exposure, the expression levels of 29 to 31 genes were altered. Four genes ( HMOX1, NQO1, PTGS2, and TXNRD1) were significantly upregulated by all six HBQs at both exposure time points. Ingenuity pathway analysis revealed that the Nrf2 pathway was significantly responsive to HBQ exposure. Other canonical pathways responsive to HBQ exposure included GSH redox reductions, superoxide radical degradation, and xenobiotic metabolism signaling. This study has demonstrated that HBQs significantly alter the gene expression of oxidative-stress-related signaling pathways and contributes to the understanding of HBQ-DBP-associated toxicity.

  12. Comparison of growth factor signalling pathway utilisation in cultured normal melanocytes and melanoma cell lines

    International Nuclear Information System (INIS)

    Kim, Ji Eun; Stones, Clare; Joseph, Wayne R; Leung, Euphemia; Finlay, Graeme J; Shelling, Andrew N; Phillips, Wayne A; Shepherd, Peter R; Baguley, Bruce C

    2012-01-01

    The phosphatidylinositol-3-kinase (PI3K-PKB), mitogen activated protein kinase (MEK-ERK) and the mammalian target of rapamycin (mTOR- p70S6K), are thought to regulate many aspects of tumour cell proliferation and survival. We have examined the utilisation of these three signalling pathways in a number of cell lines derived from patients with metastatic malignant melanoma of known PIK3CA, PTEN, NRAS and BRAF mutational status. Western blotting was used to compare the phosphorylation status of components of the PI3K-PKB, MEK-ERK and mTOR-p70S6K signalling pathways, as indices of pathway utilisation. Normal melanocytes could not be distinguished from melanoma cells on the basis of pathway utilisation when grown in the presence of serum, but could be distinguished upon serum starvation, where signalling protein phosphorylation was generally abrogated. Surprisingly, the differential utilisation of individual pathways was not consistently associated with the presence of an oncogenic or tumour suppressor mutation of genes in these pathways. Utilisation of the PI3K-PKB, MEK-ERK and mTOR-p70S6K signalling pathways in melanoma, as determined by phosphorylation of signalling components, varies widely across a series of cell lines, and does not directly reflect mutation of genes coding these components. The main difference between cultured normal melanocytes and melanoma cells is not the pathway utilisation itself, but rather in the serum dependence of pathway utilisation

  13. Natural brain-information interfaces: Recommending information by relevance inferred from human brain signals

    Science.gov (United States)

    Eugster, Manuel J. A.; Ruotsalo, Tuukka; Spapé, Michiel M.; Barral, Oswald; Ravaja, Niklas; Jacucci, Giulio; Kaski, Samuel

    2016-01-01

    Finding relevant information from large document collections such as the World Wide Web is a common task in our daily lives. Estimation of a user’s interest or search intention is necessary to recommend and retrieve relevant information from these collections. We introduce a brain-information interface used for recommending information by relevance inferred directly from brain signals. In experiments, participants were asked to read Wikipedia documents about a selection of topics while their EEG was recorded. Based on the prediction of word relevance, the individual’s search intent was modeled and successfully used for retrieving new relevant documents from the whole English Wikipedia corpus. The results show that the users’ interests toward digital content can be modeled from the brain signals evoked by reading. The introduced brain-relevance paradigm enables the recommendation of information without any explicit user interaction and may be applied across diverse information-intensive applications. PMID:27929077

  14. Modeling the intra- and extracellular cytokine signaling pathway under heat stroke in the liver.

    Directory of Open Access Journals (Sweden)

    Maria Rodriguez-Fernandez

    Full Text Available Heat stroke (HS is a life-threatening illness induced by prolonged exposure to a hot environment that causes central nervous system abnormalities and severe hyperthermia. Current data suggest that the pathophysiological responses to heat stroke may not only be due to the immediate effects of heat exposure per se but also the result of a systemic inflammatory response syndrome (SIRS. The observation that pro- (e.g., IL-1 and anti-inflammatory (e.g., IL-10 cytokines are elevated concomitantly during recovery suggests a complex network of interactions involved in the manifestation of heat-induced SIRS. In this study, we measured a set of circulating cytokine/soluble cytokine receptor proteins and liver cytokine and receptor mRNA accumulation in wild-type and tumor necrosis factor (TNF receptor knockout mice to assess the effect of neutralization of TNF signaling on the SIRS following HS. Using a systems approach, we developed a computational model describing dynamic changes (intra- and extracellular events in the cytokine signaling pathways in response to HS that was fitted to novel genomic (liver mRNA accumulation and proteomic (circulating cytokines and receptors data using global optimization. The model allows integration of relevant biological knowledge and formulation of new hypotheses regarding the molecular mechanisms behind the complex etiology of HS that may serve as future therapeutic targets. Moreover, using our unique modeling framework, we explored cytokine signaling pathways with three in silico experiments (e.g. by simulating different heat insult scenarios and responses in cytokine knockout strains in silico.

  15. Interleukin 4 signals through two related pathways.

    Science.gov (United States)

    Pernis, A; Witthuhn, B; Keegan, A D; Nelms, K; Garfein, E; Ihle, J N; Paul, W E; Pierce, J H; Rothman, P

    1995-08-15

    The interleukin 4 (IL-4) signaling pathway involves activation, by tyrosine phosphorylation, of two distinct substrates, a signal-transducing factor (STF-IL4) and the IL-4-induced phosphotyrosine substrate (4PS). It is not known whether the IL-4-mediated activation of these substrates occurs via related or distinct signaling pathways. We report that 32D cells, an IL-3-dependent myeloid progenitor cell line in which no phosphorylated 4PS is found, activate high levels of STF-IL4 in response to IL-4. Consistent with the known requirement for 4PS or insulin receptor substrate 1 (IRS-1) in IL-4-mediated mitogenesis, activation of STF-IL4 in 32D cells is not sufficient for IL-4-inducible c-myc expression. In addition, we have examined the ability of 32D cells transfected with different truncation mutants of the human IL-4 receptor to activate Jak-3 kinase and STF-IL4 in response to human IL-4. As in the case of 4PS/IRS-1, we have found that activation of both Jak-3 and STF-IL4 requires the presence of the IL-4 receptor region comprising aa 437-557. The finding that the same region of the IL-4 receptor is required for the induction of both 4PS/IRS-1 and STF-IL4 suggests that the IL-4-stimulated activation of these two substrates might involve common factors.

  16. Ties that bind: the integration of plastid signalling pathways in plant cell metabolism.

    Science.gov (United States)

    Brunkard, Jacob O; Burch-Smith, Tessa M

    2018-04-13

    Plastids are critical organelles in plant cells that perform diverse functions and are central to many metabolic pathways. Beyond their major roles in primary metabolism, of which their role in photosynthesis is perhaps best known, plastids contribute to the biosynthesis of phytohormones and other secondary metabolites, store critical biomolecules, and sense a range of environmental stresses. Accordingly, plastid-derived signals coordinate a host of physiological and developmental processes, often by emitting signalling molecules that regulate the expression of nuclear genes. Several excellent recent reviews have provided broad perspectives on plastid signalling pathways. In this review, we will highlight recent advances in our understanding of chloroplast signalling pathways. Our discussion focuses on new discoveries illuminating how chloroplasts determine life and death decisions in cells and on studies elucidating tetrapyrrole biosynthesis signal transduction networks. We will also examine the role of a plastid RNA helicase, ISE2, in chloroplast signalling, and scrutinize intriguing results investigating the potential role of stromules in conducting signals from the chloroplast to other cellular locations. © 2018 The Author(s). Published by Portland Press Limited on behalf of the Biochemical Society.

  17. Proteomic analysis of the signaling pathway mediated by the heterotrimeric Gα protein Pga1 of Penicillium chrysogenum.

    Science.gov (United States)

    Carrasco-Navarro, Ulises; Vera-Estrella, Rosario; Barkla, Bronwyn J; Zúñiga-León, Eduardo; Reyes-Vivas, Horacio; Fernández, Francisco J; Fierro, Francisco

    2016-10-06

    The heterotrimeric Gα protein Pga1-mediated signaling pathway regulates the entire developmental program in Penicillium chrysogenum, from spore germination to the formation of conidia. In addition it participates in the regulation of penicillin biosynthesis. We aimed to advance the understanding of this key signaling pathway using a proteomics approach, a powerful tool to identify effectors participating in signal transduction pathways. Penicillium chrysogenum mutants with different levels of activity of the Pga1-mediated signaling pathway were used to perform comparative proteomic analyses by 2D-DIGE and LC-MS/MS. Thirty proteins were identified which showed differences in abundance dependent on Pga1 activity level. By modifying the intracellular levels of cAMP we could establish cAMP-dependent and cAMP-independent pathways in Pga1-mediated signaling. Pga1 was shown to regulate abundance of enzymes in primary metabolic pathways involved in ATP, NADPH and cysteine biosynthesis, compounds that are needed for high levels of penicillin production. An in vivo phosphorylated protein containing a pleckstrin homology domain was identified; this protein is a candidate for signal transduction activity. Proteins with possible roles in purine metabolism, protein folding, stress response and morphogenesis were also identified whose abundance was regulated by Pga1 signaling. Thirty proteins whose abundance was regulated by the Pga1-mediated signaling pathway were identified. These proteins are involved in primary metabolism, stress response, development and signal transduction. A model describing the pathways through which Pga1 signaling regulates different cellular processes is proposed.

  18. CD147 regulates extrinsic apoptosis in spermatocytes by modulating NFκB signaling pathways.

    Science.gov (United States)

    Wang, Chaoqun; Fok, Kin Lam; Cai, Zhiming; Chen, Hao; Chan, Hsiao Chang

    2017-01-10

    CD147 null mutant male mice are infertile with arrested spermatogenesis and increased apoptotic germ cells. Our previous studies have shown that CD147 prevents apoptosis in mouse spermatocytes but not spermatogonia. However, the underlying mechanism remains elusive. In the present study, we aim to determine the CD147-regulated apoptotic pathway in mouse spermatocytes. Our results showed that immunodepletion of CD147 triggered apoptosis through extrinsic apoptotic pathway in mouse testis and spermatocyte cell line (GC-2 cells), accompanied by activation of non-canonical NFκB signaling and suppression of canonical NFκB signaling. Furthermore, CD147 was found to interact with TRAF2, a factor known to regulate NFκB and extrinsic apoptotic signaling, and interfering CD147 led to the decrease of TRAF2. Consistently, depletion of CD147 by CRISPR/Cas9 technique in GC-2 cells down-regulated TRAF2 and resulted in cell death with suppressed canonical NFκB and activated non-canonical NFκB signaling. On the contrary, interfering of CD147 had no effect on NFκB signaling pathways as well as TRAF2 protein level in mouse spermatogonia cell line (GC-1 cells). Taken together, these results suggested that CD147 plays a key role in reducing extrinsic apoptosis in spermatocytes, but not spermatogonia, through modulating NFκB signaling pathway.

  19. Cross-regulation of signaling pathways: An example of nuclear hormone receptors and the canonical Wnt pathway

    Energy Technology Data Exchange (ETDEWEB)

    Beildeck, Marcy E. [Lombardi Comprehensive Cancer Center, Georgetown University, 3970 Reservoir Road, NW, Washington, DC 20057 (United States); Gelmann, Edward P. [Columbia University, Department of Medicine, New York, NY (United States); Byers, Stephen W., E-mail: byerss@georgetown.edu [Lombardi Comprehensive Cancer Center, Georgetown University, 3970 Reservoir Road, NW, Washington, DC 20057 (United States)

    2010-07-01

    Predicting the potential physiological outcome(s) of any given molecular pathway is complex because of cross-talk with other pathways. This is particularly evident in the case of the nuclear hormone receptor and canonical Wnt pathways, which regulate cell growth and proliferation, differentiation, apoptosis, and metastatic potential in numerous tissues. These pathways are known to intersect at many levels: in the intracellular space, at the membrane, in the cytoplasm, and within the nucleus. The outcomes of these interactions are important in the control of stem cell differentiation and maintenance, feedback loops, and regulating oncogenic potential. The aim of this review is to demonstrate the importance of considering pathway cross-talk when predicting functional outcomes of signaling, using nuclear hormone receptor/canonical Wnt pathway cross-talk as an example.

  20. Cross-regulation of signaling pathways: An example of nuclear hormone receptors and the canonical Wnt pathway

    International Nuclear Information System (INIS)

    Beildeck, Marcy E.; Gelmann, Edward P.; Byers, Stephen W.

    2010-01-01

    Predicting the potential physiological outcome(s) of any given molecular pathway is complex because of cross-talk with other pathways. This is particularly evident in the case of the nuclear hormone receptor and canonical Wnt pathways, which regulate cell growth and proliferation, differentiation, apoptosis, and metastatic potential in numerous tissues. These pathways are known to intersect at many levels: in the intracellular space, at the membrane, in the cytoplasm, and within the nucleus. The outcomes of these interactions are important in the control of stem cell differentiation and maintenance, feedback loops, and regulating oncogenic potential. The aim of this review is to demonstrate the importance of considering pathway cross-talk when predicting functional outcomes of signaling, using nuclear hormone receptor/canonical Wnt pathway cross-talk as an example.

  1. Alternate day fasting impacts the brain insulin-signaling pathway of young adult male C57BL/6 mice.

    Science.gov (United States)

    Lu, Jianghua; E, Lezi; Wang, Wenfang; Frontera, Jennifer; Zhu, Hao; Wang, Wen-Tung; Lee, Phil; Choi, In Young; Brooks, William M; Burns, Jeffrey M; Aires, Daniel; Swerdlow, Russell H

    2011-04-01

    Dietary restriction (DR) has recognized health benefits that may extend to brain. We examined how DR affects bioenergetics-relevant enzymes and signaling pathways in the brains of C57BL/6 mice. Five-month-old male mice were placed in ad libitum or one of two repeated fasting and refeeding (RFR) groups, an alternate day (intermittent fed; IF) or alternate day plus antioxidants (blueberry, pomegranate, and green tea extracts) (IF + AO) fed group. During the 24-h fast blood glucose levels initially fell but stabilized within 6 h of starting the fast, thus avoiding frank hypoglycemia. DR in general appeared to enhance insulin sensitivity. After six weeks brain AKT and glycogen synthase kinase 3 beta phosphorylation were lower in the RFR mice, suggesting RFR reduced brain insulin-signaling pathway activity. Pathways that mediate mitochondrial biogenesis were not activated; AMP kinase phosphorylation, silent information regulator 2 phosphorylation, peroxisomal proliferator-activated receptor-gamma coactivator 1 alpha levels, and cytochrome oxidase subunit 4 levels did not change. ATP levels also did not decline, which suggests the RFR protocols did not directly impact brain bioenergetics. Antioxidant supplementation did not affect the brain parameters we evaluated. Our data indicate in young adult male C57BL/6 mice, RFR primarily affects brain energy metabolism by reducing brain insulin signaling, which potentially results indirectly as a consequence of reduced peripheral insulin production. © 2011 The Authors. Journal of Neurochemistry © 2011 International Society for Neurochemistry.

  2. Multiple intracellular signaling pathways orchestrate adipocytic differentiation of human bone marrow stromal stem cells

    DEFF Research Database (Denmark)

    Ayesh Hafez Ali, Dalia; Abuelreich, Sarah; Alkeraishan, Nora

    2018-01-01

    during adipocyte differentiation of human bone marrow stromal (mesenchymal) stem cells (hMSCs) and identified 2,589 up-regulated and 2,583 down-regulated mRNA transcripts. Pathway analysis on the up-regulated gene list untraveled enrichment in multiple signaling pathways including insulin receptor......Bone marrow adipocyte formation plays a role in bone homeostasis and whole body energy metabolism. However, the transcriptional landscape and signaling pathways associated with adipocyte lineage commitment and maturation are not fully delineated. Thus, we performed global gene expression profiling...... signaling, focal Adhesion, metapathway biotransformation, a number of metabolic pathways e.g. selenium metabolism, Benzo(a)pyrene metabolism, fatty acid, triacylglycerol, ketone body metabolism, tryptophan metabolism, and catalytic cycle of mammalian flavin-containing monooxygenase (FMOs). On the other hand...

  3. Constraint-based modeling and kinetic analysis of the Smad dependent TGF-beta signaling pathway.

    Directory of Open Access Journals (Sweden)

    Zhike Zi

    Full Text Available BACKGROUND: Investigation of dynamics and regulation of the TGF-beta signaling pathway is central to the understanding of complex cellular processes such as growth, apoptosis, and differentiation. In this study, we aim at using systems biology approach to provide dynamic analysis on this pathway. METHODOLOGY/PRINCIPAL FINDINGS: We proposed a constraint-based modeling method to build a comprehensive mathematical model for the Smad dependent TGF-beta signaling pathway by fitting the experimental data and incorporating the qualitative constraints from the experimental analysis. The performance of the model generated by constraint-based modeling method is significantly improved compared to the model obtained by only fitting the quantitative data. The model agrees well with the experimental analysis of TGF-beta pathway, such as the time course of nuclear phosphorylated Smad, the subcellular location of Smad and signal response of Smad phosphorylation to different doses of TGF-beta. CONCLUSIONS/SIGNIFICANCE: The simulation results indicate that the signal response to TGF-beta is regulated by the balance between clathrin dependent endocytosis and non-clathrin mediated endocytosis. This model is useful to be built upon as new precise experimental data are emerging. The constraint-based modeling method can also be applied to quantitative modeling of other signaling pathways.

  4. Signaling pathways activation profiles make better markers of cancer than expression of individual genes

    OpenAIRE

    Borisov, Nikolay M.; Terekhanova, Nadezhda V.; Aliper, Alexander M.; Venkova, Larisa S.; Smirnov, Philip Yu; Roumiantsev, Sergey; Korzinkin, Mikhail B.; Zhavoronkov, Alex A.; Buzdin, Anton A.

    2014-01-01

    Identification of reliable and accurate molecular markers remains one of the major challenges of contemporary biomedicine. We developed a new bioinformatic technique termed OncoFinder that for the first time enables to quantatively measure activation of intracellular signaling pathways basing on transcriptomic data. Signaling pathways regulate all major cellular events in health and disease. Here, we showed that the Pathway Activation Strength (PAS) value itself may serve as the biomarker for...

  5. Sensitivity analysis of intracellular signaling pathway kinetics predicts targets for stem cell fate control.

    Directory of Open Access Journals (Sweden)

    Alborz Mahdavi

    2007-07-01

    Full Text Available Directing stem cell fate requires knowledge of how signaling networks integrate temporally and spatially segregated stimuli. We developed and validated a computational model of signal transducer and activator of transcription-3 (Stat3 pathway kinetics, a signaling network involved in embryonic stem cell (ESC self-renewal. Our analysis identified novel pathway responses; for example, overexpression of the receptor glycoprotein-130 results in reduced pathway activation and increased ESC differentiation. We used a systematic in silico screen to identify novel targets and protein interactions involved in Stat3 activation. Our analysis demonstrates that signaling activation and desensitization (the inability to respond to ligand restimulation is regulated by balancing the activation state of a distributed set of parameters including nuclear export of Stat3, nuclear phosphatase activity, inhibition by suppressor of cytokine signaling, and receptor trafficking. This knowledge was used to devise a temporally modulated ligand delivery strategy that maximizes signaling activation and leads to enhanced ESC self-renewal.

  6. C-Jun N-terminal kinase signalling pathway in response to cisplatin.

    Science.gov (United States)

    Yan, Dong; An, GuangYu; Kuo, Macus Tien

    2016-11-01

    Cisplatin (cis diamminedichloroplatinum II, cDDP) is one of the most effective cancer chemotherapeutic agents and is used in the treatment of many types of human malignancies. However, inherent tumour resistance is a major barrier to effective cisplatin therapy. So far, the mechanism of cDDP resistance has not been well defined. In general, cisplatin is considered to be a cytotoxic drug, for damaging DNA and inhibiting DNA synthesis, resulting in apoptosis via the mitochondrial death pathway or plasma membrane disruption. cDDP-induced DNA damage triggers signalling pathways that will eventually decide between cell life and death. As a member of the mitogen-activated protein kinases family, c-Jun N-terminal kinase (JNK) is a signalling pathway in response to extracellular stimuli, especially drug treatment, to modify the activity of numerous proteins locating in the mitochondria or the nucleus. Recent studies suggest that JNK signalling pathway plays a major role in deciding the fate of the cell and inducing resistance to cDDP-induced apoptosis in human tumours. c-Jun N-terminal kinase regulates several important cellular functions including cell proliferation, differentiation, survival and apoptosis while activating and inhibiting substrates for phosphorylation transcription factors (c-Jun, ATF2: Activating transcription factor 2, p53 and so on), which subsequently induce pro-apoptosis and pro-survival factors expression. Therefore, it is suggested that JNK signal pathway is a double-edged sword in cDDP treatment, simultaneously being a significant pro-apoptosis factor but also being associated with increased resistance to cisplatin-based chemotherapy. This review focuses on current knowledge concerning the role of JNK in cell response to cDDP, as well as their role in cisplatin resistance. © 2016 The Authors. Journal of Cellular and Molecular Medicine published by John Wiley & Sons Ltd and Foundation for Cellular and Molecular Medicine.

  7. Signalling pathways involved in adult heart formation revealed by gene expression profiling in Drosophila.

    Directory of Open Access Journals (Sweden)

    Bruno Zeitouni

    2007-10-01

    Full Text Available Drosophila provides a powerful system for defining the complex genetic programs that drive organogenesis. Under control of the steroid hormone ecdysone, the adult heart in Drosophila forms during metamorphosis by a remodelling of the larval cardiac organ. Here, we evaluated the extent to which transcriptional signatures revealed by genomic approaches can provide new insights into the molecular pathways that underlie heart organogenesis. Whole-genome expression profiling at eight successive time-points covering adult heart formation revealed a highly dynamic temporal map of gene expression through 13 transcript clusters with distinct expression kinetics. A functional atlas of the transcriptome profile strikingly points to the genomic transcriptional response of the ecdysone cascade, and a sharp regulation of key components belonging to a few evolutionarily conserved signalling pathways. A reverse genetic analysis provided evidence that these specific signalling pathways are involved in discrete steps of adult heart formation. In particular, the Wnt signalling pathway is shown to participate in inflow tract and cardiomyocyte differentiation, while activation of the PDGF-VEGF pathway is required for cardiac valve formation. Thus, a detailed temporal map of gene expression can reveal signalling pathways responsible for specific developmental programs and provides here substantial grasp into heart formation.

  8. Human cytomegalovirus infection dysregulates the canonical Wnt/β-catenin signaling pathway.

    Directory of Open Access Journals (Sweden)

    Magdalena Angelova

    Full Text Available Human Cytomegalovirus (HCMV is a ubiquitous herpesvirus that currently infects a large percentage of the world population. Although usually asymptomatic in healthy individuals, HCMV infection during pregnancy may cause spontaneous abortions, premature delivery, or permanent neurological disabilities in infants infected in utero. During infection, the virus exerts control over a multitude of host signaling pathways. Wnt/β-catenin signaling, an essential pathway involved in cell cycle control, differentiation, embryonic development, placentation and metastasis, is frequently dysregulated by viruses. How HCMV infection affects this critical pathway is not currently known. In this study, we demonstrate that HCMV dysregulates Wnt/β-catenin signaling in dermal fibroblasts and human placental extravillous trophoblasts. Infection inhibits Wnt-induced transcriptional activity of β-catenin and expression of β-catenin target genes in these cells. HCMV infection leads to β-catenin protein accumulation in a discrete juxtanuclear region. Levels of β-catenin in membrane-associated and cytosolic pools, as well as nuclear β-catenin, are reduced after infection; while transcription of the β-catenin gene is unchanged, suggesting enhanced degradation. Given the critical role of Wnt/β-catenin signaling in cellular processes, these findings represent a novel and important mechanism whereby HCMV disrupts normal cellular function.

  9. Drosophila Nociceptive Sensitization Requires BMP Signaling via the Canonical SMAD Pathway.

    Science.gov (United States)

    Follansbee, Taylor L; Gjelsvik, Kayla J; Brann, Courtney L; McParland, Aidan L; Longhurst, Colin A; Galko, Michael J; Ganter, Geoffrey K

    2017-08-30

    Nociceptive sensitization is a common feature in chronic pain, but its basic cellular mechanisms are only partially understood. The present study used the Drosophila melanogaster model system and a candidate gene approach to identify novel components required for modulation of an injury-induced nociceptive sensitization pathway presumably downstream of Hedgehog. This study demonstrates that RNAi silencing of a member of the Bone Morphogenetic Protein (BMP) signaling pathway, Decapentaplegic (Dpp), specifically in the Class IV multidendritic nociceptive neuron, significantly attenuated ultraviolet injury-induced sensitization. Furthermore, overexpression of Dpp in Class IV neurons was sufficient to induce thermal hypersensitivity in the absence of injury. The requirement of various BMP receptors and members of the SMAD signal transduction pathway in nociceptive sensitization was also demonstrated. The effects of BMP signaling were shown to be largely specific to the sensitization pathway and not associated with changes in nociception in the absence of injury or with changes in dendritic morphology. Thus, the results demonstrate that Dpp and its pathway play a crucial and novel role in nociceptive sensitization. Because the BMP family is so strongly conserved between vertebrates and invertebrates, it seems likely that the components analyzed in this study represent potential therapeutic targets for the treatment of chronic pain in humans. SIGNIFICANCE STATEMENT This report provides a genetic analysis of primary nociceptive neuron mechanisms that promote sensitization in response to injury. Drosophila melanogaster larvae whose primary nociceptive neurons were reduced in levels of specific components of the BMP signaling pathway, were injured and then tested for nocifensive responses to a normally subnoxious stimulus. Results suggest that nociceptive neurons use the BMP2/4 ligand, along with identified receptors and intracellular transducers to transition to a

  10. Xtalk: a path-based approach for identifying crosstalk between signaling pathways

    Science.gov (United States)

    Tegge, Allison N.; Sharp, Nicholas; Murali, T. M.

    2016-01-01

    Motivation: Cells communicate with their environment via signal transduction pathways. On occasion, the activation of one pathway can produce an effect downstream of another pathway, a phenomenon known as crosstalk. Existing computational methods to discover such pathway pairs rely on simple overlap statistics. Results: We present Xtalk, a path-based approach for identifying pairs of pathways that may crosstalk. Xtalk computes the statistical significance of the average length of multiple short paths that connect receptors in one pathway to the transcription factors in another. By design, Xtalk reports the precise interactions and mechanisms that support the identified crosstalk. We applied Xtalk to signaling pathways in the KEGG and NCI-PID databases. We manually curated a gold standard set of 132 crosstalking pathway pairs and a set of 140 pairs that did not crosstalk, for which Xtalk achieved an area under the receiver operator characteristic curve of 0.65, a 12% improvement over the closest competing approach. The area under the receiver operator characteristic curve varied with the pathway, suggesting that crosstalk should be evaluated on a pathway-by-pathway level. We also analyzed an extended set of 658 pathway pairs in KEGG and to a set of more than 7000 pathway pairs in NCI-PID. For the top-ranking pairs, we found substantial support in the literature (81% for KEGG and 78% for NCI-PID). We provide examples of networks computed by Xtalk that accurately recovered known mechanisms of crosstalk. Availability and implementation: The XTALK software is available at http://bioinformatics.cs.vt.edu/~murali/software. Crosstalk networks are available at http://graphspace.org/graphs?tags=2015-bioinformatics-xtalk. Contact: ategge@vt.edu, murali@cs.vt.edu Supplementary information: Supplementary data are available at Bioinformatics online. PMID:26400040

  11. In vivo relevance of intercellular calcium signaling in Drosophila wing development

    OpenAIRE

    Brodskiy, Pavel; Brito-Robinson, Teresa; Levis, Megan; Narciso, Cody; Jangula, Jamison; Huizar, Francisco; Wu, Qinfeng; Zartman, Jeremiah

    2017-01-01

    Recently, organ-scale intercellular Ca2+ transients (ICTs) were reported in the Drosophila wing disc. However, the functional in vivo significance of ICTs remains largely unknown. Here we demonstrate the in vivo relevance of intercellular Ca2+ signaling and its impact on wing development. We report that Ca2+ signaling in vivo decreases as wing discs mature. Ca2+ signaling ex vivo responds to fly extract in a dose-dependent manner. This suggests ICTs occur in vivo due to chemical stimulus that...

  12. Pattern-recognition receptors: signaling pathways and dysregulation in canine chronic enteropathies-brief review.

    Science.gov (United States)

    Heilmann, Romy M; Allenspach, Karin

    2017-11-01

    Pattern-recognition receptors (PRRs) are expressed by innate immune cells and recognize pathogen-associated molecular patterns (PAMPs) as well as endogenous damage-associated molecular pattern (DAMP) molecules. With a large potential for synergism or convergence between their signaling pathways, PRRs orchestrate a complex interplay of cellular mediators and transcription factors, and thus play a central role in homeostasis and host defense. Aberrant activation of PRR signaling, mutations of the receptors and/or their downstream signaling molecules, and/or DAMP/PAMP complex-mediated receptor signaling can potentially lead to chronic auto-inflammatory diseases or development of cancer. PRR signaling pathways appear to also present an interesting new avenue for the modulation of inflammatory responses and to serve as potential novel therapeutic targets. Evidence for a dysregulation of the PRR toll-like receptor (TLR)2, TLR4, TLR5, and TLR9, nucleotide-binding oligomerization domain-containing protein (NOD)2, and the receptor of advanced glycation end products (RAGE) exists in dogs with chronic enteropathies. We describe the TLR, NOD2, and RAGE signaling pathways and evaluate the current veterinary literature-in comparison to human medicine-to determine the role of TLRs, NOD2, and RAGE in canine chronic enteropathies.

  13. The Notch Signaling Pathway Is Balancing Type 1 Innate Lymphoid Cell Immune Functions

    Directory of Open Access Journals (Sweden)

    Thibaut Perchet

    2018-06-01

    Full Text Available The Notch pathway is one of the canonical signaling pathways implicated in the development of various solid tumors. During carcinogenesis, the Notch pathway dysregulation induces tumor expression of Notch receptor ligands participating to escape the immune surveillance. The Notch pathway conditions both the development and the functional regulation of lymphoid subsets. Its importance on T cell subset polarization has been documented contrary to its action on innate lymphoid cells (ILC. We aim to analyze the effect of the Notch pathway on type 1 ILC polarization and functions after disruption of the RBPJk-dependent Notch signaling cascade. Indeed, type 1 ILC comprises conventional NK (cNK cells and type 1 helper innate lymphoid cells (ILC1 that share Notch-related functional characteristics such as the IFNg secretion downstream of T-bet expression. cNK cells have strong antitumor properties. However, data are controversial concerning ILC1 functions during carcinogenesis with models showing antitumoral capacities and others reporting ILC1 inability to control tumor growth. Using various mouse models of Notch signaling pathway depletion, we analyze the effects of its absence on type 1 ILC differentiation and cytotoxic functions. We also provide clues into its role in the maintenance of immune homeostasis in tissues. We show that modulating the Notch pathway is not only acting on tumor-specific T cell activity but also on ILC immune subset functions. Hence, our study uncovers the intrinsic Notch signaling pathway in ILC1/cNK populations and their response in case of abnormal Notch ligand expression. This study help evaluating the possible side effects mediated by immune cells different from T cells, in case of multivalent forms of the Notch receptor ligand delta 1 treatments. In definitive, it should help determining the best novel combination of therapeutic strategies in case of solid tumors.

  14. The octadecanoid signalling pathway in plants mediates a response to ultraviolet radiation

    International Nuclear Information System (INIS)

    Conconi, A.; Smerdon, M.J.; Howe, G.A.; Ryan, C.A.

    1996-01-01

    Many plant genes that respond to environmental and developmental changes are regulated by jasmonic acid, which is derived from linolenic acid via the octadecanoid pathway. Linolenic acid is an important fatty-acid constituent of membranes in most plant species and its intracellular levels increase in response to certain signals. Here we report that irradiation of tomato leaves with ultraviolet light induces the expression of several plant defensive genes that are normally activated through the octadecanoid pathway after wounding. The response to ultraviolet light is blocked by an inhibitor of the octadecanoid pathway and it does not occur in a tomato mutant defective in this pathway. The ultraviolet irradiation maximally induces the defence genes at levels where cyclobutane pyrimidine dimer formation, an indicator of DNA damage, is less than 0.2 dimers per gene. Our evidence indicates that this plant defence response to certain wavelengths of ultraviolet radiation requires the activation of the octadecanoid defence signalling pathway. (author)

  15. An interplay between 2 signaling pathways: Melatonin-cAMP and IP3–Ca2+ signaling pathways control intraerythrocytic development of the malaria parasite Plasmodium falciparum

    International Nuclear Information System (INIS)

    Furuyama, Wakako; Enomoto, Masahiro; Mossaad, Ehab; Kawai, Satoru; Mikoshiba, Katsuhiko; Kawazu, Shin-ichiro

    2014-01-01

    Highlights: • A melatonin receptor antagonist blocked Ca 2+ oscillation in P. falciparum and inhibited parasite growth. • P. falciparum development is controlled by Ca 2+ - and cAMP-signaling pathways. • The cAMP-signaling pathway at ring form and late trophozoite stages governs parasite growth of P. falciparum. - Abstract: Plasmodium falciparum spends most of its asexual life cycle within human erythrocytes, where proliferation and maturation occur. Development into the mature forms of P. falciparum causes severe symptoms due to its distinctive sequestration capability. However, the physiological roles and the molecular mechanisms of signaling pathways that govern development are poorly understood. Our previous study showed that P. falciparum exhibits stage-specific spontaneous Calcium (Ca 2+ ) oscillations in ring and early trophozoites, and the latter was essential for parasite development. In this study, we show that luzindole (LZ), a selective melatonin receptor antagonist, inhibits parasite growth. Analyses of development and morphology of LZ-treated P. falciparum revealed that LZ severely disrupted intraerythrocytic maturation, resulting in parasite death. When LZ was added at ring stage, the parasite could not undergo further development, whereas LZ added at the trophozoite stage inhibited development from early into late schizonts. Live-cell Ca 2+ imaging showed that LZ treatment completely abolished Ca 2+ oscillation in the ring forms while having little effect on early trophozoites. Further, the melatonin-induced cAMP increase observed at ring and late trophozoite stage was attenuated by LZ treatment. These suggest that a complex interplay between IP 3 –Ca 2+ and cAMP signaling pathways is involved in intraerythrocytic development of P. falciparum

  16. Autoimmunity and autoinflammation: A systems view on signaling pathway dysregulation profiles.

    Directory of Open Access Journals (Sweden)

    Arsen Arakelyan

    Full Text Available Autoinflammatory and autoimmune disorders are characterized by aberrant changes in innate and adaptive immunity that may lead from an initial inflammatory state to an organ specific damage. These disorders possess heterogeneity in terms of affected organs and clinical phenotypes. However, despite the differences in etiology and phenotypic variations, they share genetic associations, treatment responses and clinical manifestations. The mechanisms involved in their initiation and development remain poorly understood, however the existence of some clear similarities between autoimmune and autoinflammatory disorders indicates variable degrees of interaction between immune-related mechanisms.Our study aims at contributing to a holistic, pathway-centered view on the inflammatory condition of autoimmune and autoinflammatory diseases. We have evaluated similarities and specificities of pathway activity changes in twelve autoimmune and autoinflammatory disorders by performing meta-analysis of publicly available gene expression datasets generated from peripheral blood mononuclear cells, using a bioinformatics pipeline that integrates Self Organizing Maps and Pathway Signal Flow algorithms along with KEGG pathway topologies.The results reveal that clinically divergent disease groups share common pathway perturbation profiles. We identified pathways, similarly perturbed in all the studied diseases, such as PI3K-Akt, Toll-like receptor, and NF-kappa B signaling, that serve as integrators of signals guiding immune cell polarization, migration, growth, survival and differentiation. Further, two clusters of diseases were identified based on specifically dysregulated pathways: one gathering mostly autoimmune and the other mainly autoinflammatory diseases. Cluster separation was driven not only by apparent involvement of pathways implicated in adaptive immunity in one case, and inflammation in the other, but also by processes not explicitly related to immune

  17. Mechanisms Underlying the Antidepressant Response of Acupuncture via PKA/CREB Signaling Pathway.

    Science.gov (United States)

    Jiang, Huili; Zhang, Xuhui; Wang, Yu; Zhang, Huimin; Li, Jing; Yang, Xinjing; Zhao, Bingcong; Zhang, Chuntao; Yu, Miao; Xu, Mingmin; Yu, Qiuyun; Liang, Xingchen; Li, Xiang; Shi, Peng; Bao, Tuya

    2017-01-01

    Protein kinase A (PKA)/cAMP response element-binding (CREB) protein signaling pathway, contributing to impaired neurogenesis parallel to depressive-like behaviors, has been identified as the crucial factor involved in the antidepressant response of acupuncture. However, the molecular mechanisms associated with antidepressant response of acupuncture, neurogenesis, and depressive-like behaviors ameliorating remain unexplored. The objective was to identify the mechanisms underlying the antidepressant response of acupuncture through PKA signaling pathway in depression rats by employing the PKA signaling pathway inhibitor H89 in in vivo experiments. Our results indicated that the expression of hippocampal PKA- α and p-CREB was significantly downregulated by chronic unpredicted mild stress (CUMS) procedures. Importantly, acupuncture reversed the downregulation of PKA- α and p-CREB. The expression of PKA- α was upregulated by fluoxetine, but not p-CREB. No significant difference was found between Acu and FLX groups on the expression of PKA- α and p-CREB. Interestingly, H89 inhibited the effects of acupuncture or fluoxetine on upregulating the expression of p-CREB, but not PKA- α . There was no significant difference in expression of CREB among the groups. Conclusively, our findings further support the hypothesis that acupuncture could ameliorate depressive-like behaviors by regulating PKA/CREB signaling pathway, which might be mainly mediated by regulating the phosphorylation level of CREB.

  18. Pathway Relevance Ranking for Tumor Samples through Network-Based Data Integration.

    Directory of Open Access Journals (Sweden)

    Lieven P C Verbeke

    Full Text Available The study of cancer, a highly heterogeneous disease with different causes and clinical outcomes, requires a multi-angle approach and the collection of large multi-omics datasets that, ideally, should be analyzed simultaneously. We present a new pathway relevance ranking method that is able to prioritize pathways according to the information contained in any combination of tumor related omics datasets. Key to the method is the conversion of all available data into a single comprehensive network representation containing not only genes but also individual patient samples. Additionally, all data are linked through a network of previously identified molecular interactions. We demonstrate the performance of the new method by applying it to breast and ovarian cancer datasets from The Cancer Genome Atlas. By integrating gene expression, copy number, mutation and methylation data, the method's potential to identify key pathways involved in breast cancer development shared by different molecular subtypes is illustrated. Interestingly, certain pathways were ranked equally important for different subtypes, even when the underlying (epi-genetic disturbances were diverse. Next to prioritizing universally high-scoring pathways, the pathway ranking method was able to identify subtype-specific pathways. Often the score of a pathway could not be motivated by a single mutation, copy number or methylation alteration, but rather by a combination of genetic and epi-genetic disturbances, stressing the need for a network-based data integration approach. The analysis of ovarian tumors, as a function of survival-based subtypes, demonstrated the method's ability to correctly identify key pathways, irrespective of tumor subtype. A differential analysis of survival-based subtypes revealed several pathways with higher importance for the bad-outcome patient group than for the good-outcome patient group. Many of the pathways exhibiting higher importance for the bad

  19. Wnt/β-catenin signalling pathway mediated aberrant hippocampal neurogenesis in kainic acid-induced epilepsy.

    Science.gov (United States)

    Qu, Zhengyi; Su, Fang; Qi, Xueting; Sun, Jianbo; Wang, Hongcai; Qiao, Zhenkui; Zhao, Hong; Zhu, Yulan

    2017-10-01

    Temporal lobe epilepsy is a chronic disorder of nerve system, mainly characterized by hippocampal sclerosis with massive neuronal loss and severe gliosis. Aberrant neurogenesis has been shown in the epileptogenesis process of temporal lobe epilepsy. However, the molecular mechanisms underlying aberrant neurogenesis remain unclear. The roles of Wnt signalling cascade have been well established in neurogenesis during multiple aspects. Here, we used kainic acid-induced rat epilepsy model to investigate whether Wnt/β-catenin signalling pathway is involved in the aberrant neurogenesis in temporal lobe epilepsy. Immunostaining and western blotting results showed that the expression levels of β-catenin, Wnt3a, and cyclin D1, the key regulators in Wnt signalling pathway, were up-regulated during acute epilepsy induced by the injection of kainic acids, indicating that Wnt signalling pathway was activated in kainic acid-induced temporal lobe epilepsy. Moreover, BrdU labelling results showed that blockade of the Wnt signalling by knocking down β-catenin attenuated aberrant neurogenesis induced by kainic acids injection. Altogether, Wnt/β-catenin signalling pathway mediated hippocampal neurogenesis during epilepsy, which might provide new strategies for clinical treatment of temporal lobe epilepsy. Temporal lobe epilepsy is a chronic disorder of nerve system, mainly characterized by hippocampal sclerosis. Aberrant neurogenesis has been shown to involve in the epileptogenesis process of temporal lobe epilepsy. In the present study, we discovered that Wnt3a/β-catenin signalling pathway serves as a link between aberrant neurogenesis and underlying remodelling in the hippocampus, leading to temporal lobe epilepsy, which might provide new strategies for clinical treatment of temporal lobe epilepsy. Copyright © 2017 John Wiley & Sons, Ltd.

  20. Concise Review: Wnt Signaling Pathways in Skin Development and Epidermal Stem Cells.

    Science.gov (United States)

    Veltri, Anthony; Lang, Christopher; Lien, Wen-Hui

    2018-01-01

    Mammalian skin and its appendages constitute the integumentary system forming a barrier between the organism and its environment. During development, skin epidermal cells divide rapidly and stratify into a multilayered epithelium, as well as invaginate downward in the underlying mesenchyme to form hair follicles (HFs). In postnatal skin, the interfollicular epidermal (IFE) cells continuously proliferate and differentiate while HFs undergo cycles of regeneration. Epidermal regeneration is fueled by epidermal stem cells (SCs) located in the basal layer of the IFE and the outer layer of the bulge in the HF. Epidermal development and SC behavior are mainly regulated by various extrinsic cues, among which Wnt-dependent signaling pathways play crucial roles. This review not only summarizes the current knowledge of Wnt signaling pathways in the regulation of skin development and governance of SCs during tissue homeostasis, but also discusses the potential crosstalk of Wnt signaling with other pathways involved in these processes. Stem Cells 2018;36:22-35. © 2017 AlphaMed Press.

  1. Calcium homeostasis and signaling in fungi and their relevance for pathogenicity of yeasts and filamentous fungi

    Directory of Open Access Journals (Sweden)

    Renata Tisi

    2016-09-01

    Full Text Available Though fungi show peculiarities in the purposes and specific traits of calcium signaling pathways, the general scheme and the most important players are well conserved if compared to higher eukaryotes. This provides a powerful opportunity either to investigate shared features using yeast as a model or to exploit fungal specificities as potential targets for antifungal therapies. The sequenced genomes from yeast Saccharomyces cerevisiae, Schizosaccharomyces pombe and the filamentous fungus Neurospora crassa were already published more than ten years ago. More recently the genome sequences of filamentous fungi of Aspergillus genus, some of which threatening pathogens, and dimorphic fungi Ustilago maydis were published, giving the chance to identify several proteins involved in calcium signaling based on their homology to yeast or mammalian counterparts. Nonetheless, unidentified calcium transporters are still present in these organisms which await to be molecularly characterized. Despite the relative simplicity in yeast calcium machinery and the availability of sophisticated molecular tools, in the last years, a number of new actors have been identified, albeit not yet fully characterized. This review will try to describe the state of the art in calcium channels and calcium signaling knowledge in yeast, with particular attention to the relevance of this knowledge with respect to pathological fungi.

  2. Modulation of neurotrophic signaling pathways by polyphenols

    Directory of Open Access Journals (Sweden)

    Moosavi F

    2015-12-01

    Full Text Available Fatemeh Moosavi,1,2 Razieh Hosseini,1,2 Luciano Saso,3 Omidreza Firuzi1 1Medicinal and Natural Products Chemistry Research Center, Shiraz University of Medical Sciences, Shiraz, Iran; 2Department of Pharmacology, School of Veterinary Medicine, Shiraz University, Shiraz, Iran; 3Department of Physiology and Pharmacology “Vittorio Erspamer”, Sapienza University of Rome, Rome, Italy Abstract: Polyphenols are an important class of phytochemicals, and several lines of evidence have demonstrated their beneficial effects in the context of a number of pathologies including neurodegenerative disorders such as Alzheimer’s and Parkinson’s disease. In this report, we review the studies on the effects of polyphenols on neuronal survival, growth, proliferation and differentiation, and the signaling pathways involved in these neurotrophic actions. Several polyphenols including flavonoids such as baicalein, daidzein, luteolin, and nobiletin as well as nonflavonoid polyphenols such as auraptene, carnosic acid, curcuminoids, and hydroxycinnamic acid derivatives including caffeic acid phentyl ester enhance neuronal survival and promote neurite outgrowth in vitro, a hallmark of neuronal differentiation. Assessment of underlying mechanisms, especially in PC12 neuronal-like cells, reveals that direct agonistic effect on tropomyosin receptor kinase (Trk receptors, the main receptors of neurotrophic factors including nerve growth factor (NGF and brain-derived neurotrophic factor (BDNF explains the action of few polyphenols such as 7,8-dihydroxyflavone. However, several other polyphenolic compounds activate extracellular signal-regulated kinase (ERK and phosphoinositide 3-kinase (PI3K/Akt pathways. Increased expression of neurotrophic factors in vitro and in vivo is the mechanism of neurotrophic action of flavonoids such as scutellarin, daidzein, genistein, and fisetin, while compounds like apigenin and ferulic acid increase cyclic adenosine monophosphate

  3. Regulation of insect behavior via the insulin-signaling pathway

    Directory of Open Access Journals (Sweden)

    Renske eErion

    2013-12-01

    Full Text Available The insulin/insulin-like growth factor signaling (IIS pathway is well established as a critical regulator of growth and metabolic homeostasis across the animal kingdom. Insulin-like peptides (ILPs, the functional analogs of mammalian insulin, were initially discovered in the silkmoth Bombyx mori and subsequently identified in many other insect species. Initial research focused on the role of insulin signaling in metabolism, cell proliferation, development, reproduction and aging. More recently however, increasing attention has been given to the role of insulin in the regulation of neuronal function and behavior. Here we review the role of insulin signaling in two specific insect behaviors: feeding and locomotion.

  4. Aberrant Wnt signaling pathway in medial temporal lobe structures of Alzheimer's disease

    DEFF Research Database (Denmark)

    Riise, Jesper; Plath, Niels; Pakkenberg, Bente

    2015-01-01

    alterations of the intracellular Wnt pathway signaling components β-catenin, Gsk3β and Tcf7l1/Tcf3 and the phosphorylation state of β-catenin and Gsk3β in the hippocampus suggestive of a link between AD and aberrant canonical activity. Alterations in Gsk3β co-appeared with hippocampal kinase...... on isolated Wnt pathway components. Here, we provide the first comprehensive pathway-focused evaluation of the Wnt pathway in the entorhinal cortex and hippocampus of AD brains. Our data demonstrate altered Wnt pathway gene expression at all levels of the pathway in both medial temporal lobe regions...

  5. Aberrant Regulation of Notch3 Signaling Pathway in Polycystic Kidney Disease.

    Science.gov (United States)

    Idowu, Jessica; Home, Trisha; Patel, Nisha; Magenheimer, Brenda; Tran, Pamela V; Maser, Robin L; Ward, Christopher J; Calvet, James P; Wallace, Darren P; Sharma, Madhulika

    2018-02-20

    Polycystic kidney disease (PKD) is a genetic disorder characterized by fluid-filled cysts in the kidney and liver that ultimately leads to end-stage renal disease. Currently there is no globally approved therapy for PKD. The Notch signaling pathway regulates cellular processes such as proliferation and de-differentiation, which are cellular hallmarks of PKD. Thus we hypothesized that the Notch pathway plays a critical role in PKD. Evaluation of protein expression of Notch signaling components in kidneys of Autosomal Recessive PKD (ARPKD) and Autosomal Dominant PKD (ADPKD) mouse models and of ADPKD patients revealed that Notch pathway members, particularly Notch3, were consistently upregulated or activated in cyst-lining epithelial cells. Notch3 expression correlated with rapidly growing cysts and co-localized with the proliferation marker, PCNA. Importantly, Notch inhibition significantly decreased forskolin-induced Notch3 activation and proliferation of primary human ADPKD cells, and significantly reduced cyst formation and growth of human ADPKD cells cultured in collagen gels. Thus our data indicate that Notch3 is aberrantly activated and facilitates epithelial cell proliferation in PKD, and that inhibition of Notch signaling may prevent cyst formation and growth.

  6. Influence of arsenate and arsenite on signal transduction pathways: an update

    Energy Technology Data Exchange (ETDEWEB)

    Druwe, Ingrid L.; Vaillancourt, Richard R. [The University of Arizona College of Pharmacy, Department of Pharmacology and Toxicology, Tucson, AZ (United States)

    2010-08-15

    Arsenic has been a recognized contaminant and toxicant, as well as a medicinal compound throughout human history. Populations throughout the world are exposed to arsenic and these exposures have been associated with a number of human cancers. Not much is known about the role of arsenic as a human carcinogen and more recently its role in non-cancerous diseases, such as cardiovascular disease, hypertension and diabetes mellitus have been uncovered. The health effects associated with arsenic are numerous and the association between arsenic exposure and human disease has intensified the search for molecular mechanisms that describe the biological activity of arsenic in humans and leads to the aforementioned disease states. Arsenic poses a human health risk due in part to the regulation of cellular signal transduction pathways and over the last few decades, some cellular mechanisms that account for arsenic toxicity, as well as, signal transduction pathways have been discovered. However, given the ubiquitous nature of arsenic in the environment, making sense of all the data remains a challenge. This review will focus on our knowledge of signal transduction pathways that are regulated by arsenic. (orig.)

  7. Elabela-apelin receptor signaling pathway is functional in mammalian systems.

    Science.gov (United States)

    Wang, Zhi; Yu, Daozhan; Wang, Mengqiao; Wang, Qilong; Kouznetsova, Jennifer; Yang, Rongze; Qian, Kun; Wu, Wenjun; Shuldiner, Alan; Sztalryd, Carole; Zou, Minghui; Zheng, Wei; Gong, Da-Wei

    2015-02-02

    Elabela (ELA) or Toddler is a recently discovered hormone which is required for normal development of heart and vasculature through activation of apelin receptor (APJ), a G protein-coupled receptor (GPCR), in zebrafish. The present study explores whether the ELA-APJ signaling pathway is functional in the mammalian system. Using reverse-transcription PCR, we found that ELA is restrictedly expressed in human pluripotent stem cells and adult kidney whereas APJ is more widely expressed. We next studied ELA-APJ signaling pathway in reconstituted mammalian cell systems. Addition of ELA to HEK293 cells over-expressing GFP-AJP fusion protein resulted in rapid internalization of the fusion receptor. In Chinese hamster ovarian (CHO) cells over-expressing human APJ, ELA suppresses cAMP production with EC50 of 11.1 nM, stimulates ERK1/2 phosphorylation with EC50 of 14.3 nM and weakly induces intracellular calcium mobilization. Finally, we tested ELA biological function in human umbilical vascular endothelial cells and showed that ELA induces angiogenesis and relaxes mouse aortic blood vessel in a dose-dependent manner through a mechanism different from apelin. Collectively, we demonstrate that the ELA-AJP signaling pathways are functional in mammalian systems, indicating that ELA likely serves as a hormone regulating the circulation system in adulthood as well as in embryonic development.

  8. The self-renewal signaling pathways utilized by gastric cancer stem cells.

    Science.gov (United States)

    Fu, Ying; Li, Hui; Hao, Xishan

    2017-04-01

    Gastric cancer is a leading cause of cancer-related mortality worldwide. Cancer stem cells are the source of tumor recurrence and metastasis. Self-renewal is a marker of cancer stem cells and also the basis of long-lasting survival and tumor progression. Although the mechanism of gastric cancer stem cell self-renewal is not clear, there are several signaling pathways and environmental factors known to be involved. This mini review describes recent developments in the self-renewal signaling pathway of gastric cancer stem cell research. Advancements made in this field of research will likely support the development of novel therapeutic strategies for gastric cancer.

  9. TGF-β1/Smad3 Pathway Targets PP2A-AMPK-FoxO1 Signaling to Regulate Hepatic Gluconeogenesis*

    Science.gov (United States)

    Yadav, Hariom; Devalaraja, Samir; Chung, Stephanie T.; Rane, Sushil G.

    2017-01-01

    Maintenance of glucose homeostasis is essential for normal physiology. Deviation from normal glucose levels, in either direction, increases susceptibility to serious medical complications such as hypoglycemia and diabetes. Maintenance of glucose homeostasis is achieved via functional interactions among various organs: liver, skeletal muscle, adipose tissue, brain, and the endocrine pancreas. The liver is the primary site of endogenous glucose production, especially during states of prolonged fasting. However, enhanced gluconeogenesis is also a signature feature of type 2 diabetes (T2D). Thus, elucidating the signaling pathways that regulate hepatic gluconeogenesis would allow better insight into the process of normal endogenous glucose production as well as how this process is impaired in T2D. Here we demonstrate that the TGF-β1/Smad3 signaling pathway promotes hepatic gluconeogenesis, both upon prolonged fasting and during T2D. In contrast, genetic and pharmacological inhibition of TGF-β1/Smad3 signals suppressed endogenous glucose production. TGF-β1 and Smad3 signals achieved this effect via the targeting of key regulators of hepatic gluconeogenesis, protein phosphatase 2A (PP2A), AMP-activated protein kinase (AMPK), and FoxO1 proteins. Specifically, TGF-β1 signaling suppressed the LKB1-AMPK axis, thereby facilitating the nuclear translocation of FoxO1 and activation of key gluconeogenic genes, glucose-6-phosphatase and phosphoenolpyruvate carboxykinase. These findings underscore an important role of TGF-β1/Smad3 signaling in hepatic gluconeogenesis, both in normal physiology and in the pathophysiology of metabolic diseases such as diabetes, and are thus of significant medical relevance. PMID:28069811

  10. Responses of the insulin signaling pathways in the brown adipose tissue of rats following cold exposure.

    Science.gov (United States)

    Wang, Xiaofei; Wahl, Richard

    2014-01-01

    The insulin signaling pathway is critical for the control of blood glucose levels. Brown adipose tissue (BAT) has also been implicated as important in glucose homeostasis. The effect of short-term cold exposure on this pathway in BAT has not been explored. We evaluated the effect of 4 hours of cold exposure on the insulin pathway in the BAT of rats. Whole genomic microarray chips were used to examine the transcripts of the pathway in BAT of rats exposed to 4°C and 22°C for 4 hours. The 4 most significantly altered pathways following 4 hours of cold exposure were the insulin signaling pathway, protein kinase A, PI3K/AKT and ERK/MAPK signaling. The insulin signaling pathway was the most affected. In the documented 142 genes of the insulin pathway, 42 transcripts (29.6%) responded significantly to this cold exposure with the least false discovery rate (Benjamini-Hochberg Multiple Testing: -log10 (p-value)  = 7.18). Twenty-seven genes (64%) were up-regulated, including the insulin receptor (Insr), insulin substrates 1 and 2 (Irs1 and Irs2). Fifteen transcripts (36%) were down-regulated. Multiple transcripts of the primary target and secondary effector targets for the insulin signaling were also up-regulated, including those for carbohydrate metabolism. Using western blotting, we demonstrated that the cold induced higher Irs2, Irs1, and Akt-p protein levels in the BAT than in the BAT of controls maintained at room temperature, and higher Akt-p protein level in the muscle. this study demonstrated that 4 hours of cold exposure stimulated the insulin signaling pathway in the BAT and muscle of overnight fasted rats. This raises the possibility that acute cold stimulation may have potential to improve glucose clearance and insulin sensitivity.

  11. [Role and related mechanism of S1P/S1P1 signal pathway during post conditioning of hypertrophic cardiomyocytes].

    Science.gov (United States)

    Bao, X H; Li, H X; Tao, J; Li, X M; Yang, Y N; Ma, Y T; Chen, B D

    2016-05-24

    To study the role and mechanism of sphingosine-1-phosphate (S1P)/ sphingosine-1-phosphate receptor 1(S1P1) signal pathway during post conditioning of hypertrophic cardiomyocytes. Neonatal rat cardiomyocytes were isolated and cultured, then stimulated by norepinephrine (NE) to induce cardiomyocytes hypertrophy. Using tri-gas incubator to create hypoxia and reoxygenation enviroment to mimic ischemia-reperfusion and postconditioning. Hypertrophic cardiomyoctyes were divided into five groups according to the presence or absence of various drugs and postconditiong and relevant signal pathways changes were detected: (1) IPost group (hypoxia+ postconditioning); (2) IPost+ S1P group (cells were pretreated with S1P (1 μmol/L) for 2 h before IPost); (3) IPost+ W-146+ S1P group (cells in IPost+ W-146+ S1P group were pretreated with S1P1 inhibitor W-146 (0.4 μmol/L) for 20 min); (4) IPost+ PD98059+ S1P group (cells in IPost+ S1P group were pretreated with MAPK antagonist PD98059 (125 μmol/L) for 20 min); (5) IPost+ LY-294002+ S1P group (cells in IPost+ S1P group were pretreated with PI3K antagonist LY294002 (0.1 μmol/L) for 20 min). Apoptosis was detected by flow cytometry and protein expression of relevant signal pathways were detected by Western blot. (1)Apoptosis rate was significantly increased in hypoxia/reoxygenation (27.90±4.49)% group compared with normal control group (7.97±2.18)%, which could be significantly reduced in IPost group (15.90±1.77)% (all PS1P and IPost+ S1P+ LY-294002 groups than in IPost and IPost+ S1P+ W-146 and IPost+ S1P+ PD98059 group (all PS1P and IPost+ S1P+ LY-294002 group than in IPost and IPost+ S1P+ W-146 group and IPost+ S1P+ PD98059 group (all PS1P+ W-146 and IPost+ S1P+ PD98059 groups. p-ERK1/2 and p-Akt levels in IPost+ S1P+ W-146 group and IPost+ S1P+ PD98059 were similar as in IPost group. S1P can play protective role on NE induced cardiomyocytes hypertrophy during post conditioning through downregulating caspase-3 expression and

  12. Proteomic analysis of the signaling pathway mediated by the heterotrimeric G? protein Pga1 of Penicillium chrysogenum

    OpenAIRE

    Carrasco-Navarro, Ulises; Vera-Estrella, Rosario; Barkla, Bronwyn J.; Z??iga-Le?n, Eduardo; Reyes-Vivas, Horacio; Fern?ndez, Francisco J.; Fierro, Francisco

    2016-01-01

    Background The heterotrimeric G? protein Pga1-mediated signaling pathway regulates the entire developmental program in Penicillium chrysogenum, from spore germination to the formation of conidia. In addition it participates in the regulation of penicillin biosynthesis. We aimed to advance the understanding of this key signaling pathway using a proteomics approach, a powerful tool to identify effectors participating in signal transduction pathways. Results Penicillium chrysogenum mutants with ...

  13. The ABA-INSENSITIVE-4 (ABI4) transcription factor links redox, hormone and sugar signaling pathways.

    Science.gov (United States)

    Foyer, Christine H; Kerchev, Pavel I; Hancock, Robert D

    2012-02-01

    The cellular reduction-oxidation (redox) hub processes information from metabolism and the environment and so regulates plant growth and defense through integration with the hormone signaling network. One key pathway of redox control involves interactions with ABSCISIC ACID (ABA). Accumulating evidence suggests that the ABA-INSENSITIVE-4 (ABI4) transcription factor plays a key role in transmitting information concerning the abundance of ascorbate and hence the ability of cells to buffer oxidative challenges. ABI4 is required for the ascorbate-dependent control of growth, a process that involves enhancement of salicylic acid (SA) signaling and inhibition of jasmonic acid (JA) signaling pathways. Low redox buffering capacity reinforces SA- JA- interactions through the mediation of ABA and ABI4 to fine-tune plant growth and defense in relation to metabolic cues and environmental challenges. Moreover, ABI4-mediated pathways of sugar sensitivity are also responsive to the abundance of ascorbate, providing evidence of overlap between redox and sugar signaling pathways.

  14. Defocused low-energy shock wave activates adipose tissue-derived stem cells in vitro via multiple signaling pathways.

    Science.gov (United States)

    Xu, Lina; Zhao, Yong; Wang, Muwen; Song, Wei; Li, Bo; Liu, Wei; Jin, Xunbo; Zhang, Haiyang

    2016-12-01

    We found defocused low-energy shock wave (DLSW) could be applied in regenerative medicine by activating mesenchymal stromal cells. However, the possible signaling pathways that participated in this process remain unknown. In the present study, DLSW was applied in cultured rat adipose tissue-derived stem cells (ADSCs) to explore its effect on ADSCs and the activated signaling pathways. After treating with DLSW, the cellular morphology and cytoskeleton of ADSCs were observed. The secretions of ADSCs were detected. The expressions of ADSC surface antigens were analyzed using flow cytometry. The expressions of proliferating cell nuclear antigen and Ki67 were analyzed using western blot. The expression of CXCR2 and the migrations of ADSCs in vitro and in vivo were detected. The phosphorylation of selected signaling pathways with or without inhibitors was also detected. DLSW did not change the morphology and phenotype of ADSCs, and could promote the secretion, proliferation and migration of ADSCs. The phosphorylation levels were significantly higher in mitogen-activated protein kinases (MAPK) pathway, phosphoinositide 3-kinase (PI-3K)/AKT pathway and nuclear factor-kappa B (NF-κB) signaling pathway but not in Janus kinase/signal transducer and activator of transcription (JAK/STAT) pathway. Furthermore, ADSCs were not activated by DLSW after adding the inhibitors of these pathways simultaneously. Our results demonstrated for the first time that DLSW could activate ADSCs through MAPK, PI-3K/AKT and NF-κB signaling pathways. Combination of DLSW and agonists targeting these pathways might improve the efficacy of ADSCs in regenerative medicine in the future. Copyright © 2016 International Society for Cellular Therapy. Published by Elsevier Inc. All rights reserved.

  15. Prevotella intermedia induces prostaglandin E2 via multiple signaling pathways.

    Science.gov (United States)

    Guan, S-M; Fu, S-M; He, J-J; Zhang, M

    2011-01-01

    Prostaglandin E(2) (PGE(2)) plays important roles in the bone resorption of inflammatory diseases such as rheumatoid arthritis and periodontitis via specific prostaglandin receptors (i.e., EP1-EP4). In this study, the authors examined whether Prevotella intermedia regulates PGE(2) production and EP expression in human periodontal ligament fibroblasts (hPDLs); they also explored the potential signaling pathways involved in PGE(2) production. P. intermedia induced PGE(2) production and cyclooxygenase-2 (COX-2) expression in a dose- and time-dependent manner. Indomethacin and NS-398 completely abrogated the P. intermedia-induced PGE(2) production without modulating COX-2 expression. Specific inhibitors of extracellular signal-regulated kinase, c-Jun N-terminal kinase, p38, phosphatidylinositol 3-kinase, and protein kinase C--but not c-AMP and protein kinase A--significantly attenuated the P. intermedia-induced COX-2 and PGE(2) expression. P. intermedia reduced EP1 expression in a concentration- and time-dependent manner. The results indicate that the COX-2-dependent induction of PGE(2) by P. intermedia in hPDLs is mediated by multiple signaling pathways.

  16. Notch pathway signaling in the skin antagonizes Merkel cell development.

    Science.gov (United States)

    Logan, Gregory J; Wright, Margaret C; Kubicki, Adam C; Maricich, Stephen M

    2018-02-15

    Merkel cells are mechanosensitive skin cells derived from the epidermal lineage whose development requires expression of the basic helix-loop-helix transcription factor Atoh1. The genes and pathways involved in regulating Merkel cell development during embryogenesis are poorly understood. Notch pathway signaling antagonizes Atoh1 expression in many developing body regions, so we hypothesized that Notch signaling might inhibit Merkel cell development. We found that conditional, constitutive overexpression of the Notch intracellular domain (NICD) in mouse epidermis significantly decreased Merkel cell numbers in whisker follicles and touch domes of hairy skin. Conversely, conditional deletion of the obligate NICD binding partner RBPj in the epidermis significantly increased Merkel cell numbers in whisker follicles, led to the development of ectopic Merkel cells outside of touch domes in hairy skin epidermis, and altered the distribution of Merkel cells in touch domes. Deletion of the downstream Notch effector gene Hes1 also significantly increased Merkel cell numbers in whisker follicles. Together, these data demonstrate that Notch signaling regulates Merkel cell production and patterning. Copyright © 2018 Elsevier Inc. All rights reserved.

  17. Emerging Role and Therapeutic Implication of Wnt Signaling Pathways in Autoimmune Diseases

    Science.gov (United States)

    Shi, Juan; Chi, Shuhong; Xue, Jing; Yang, Jiali; Li, Feng; Liu, Xiaoming

    2016-01-01

    The Wnt signaling pathway plays a key role in many biological aspects, such as cellular proliferation, tissue regeneration, embryonic development, and other systemic effects. Under a physiological condition, it is tightly controlled at different layers and arrays, and a dysregulated activation of this signaling has been implicated into the pathogenesis of various human disorders, including autoimmune diseases. Despite the fact that therapeutic interventions are available for ameliorating disease manifestations, there is no curative therapy currently available for autoimmune disorders. Increasing lines of evidence have suggested a crucial role of Wnt signaling during the pathogenesis of many autoimmune diseases; in addition, some of microRNAs (miRNAs), a class of small, noncoding RNA molecules capable of transcriptionally regulating gene expression, have also recently been demonstrated to possess both physiological and pathological roles in autoimmune diseases by regulating the Wnt signaling pathway. This review summarizes currently our understanding of the pathogenic roles of Wnt signaling in several major autoimmune disorders and miRNAs, those targeting Wnt signaling in autoimmune diseases, with a focus on the implication of the Wnt signaling as potential biomarkers and therapeutic targets in immune diseases, as well as miRNA-mediated regulation of Wnt signaling activation in the development of autoimmune diseases. PMID:27110577

  18. Emerging Role and Therapeutic Implication of Wnt Signaling Pathways in Autoimmune Diseases

    Directory of Open Access Journals (Sweden)

    Juan Shi

    2016-01-01

    Full Text Available The Wnt signaling pathway plays a key role in many biological aspects, such as cellular proliferation, tissue regeneration, embryonic development, and other systemic effects. Under a physiological condition, it is tightly controlled at different layers and arrays, and a dysregulated activation of this signaling has been implicated into the pathogenesis of various human disorders, including autoimmune diseases. Despite the fact that therapeutic interventions are available for ameliorating disease manifestations, there is no curative therapy currently available for autoimmune disorders. Increasing lines of evidence have suggested a crucial role of Wnt signaling during the pathogenesis of many autoimmune diseases; in addition, some of microRNAs (miRNAs, a class of small, noncoding RNA molecules capable of transcriptionally regulating gene expression, have also recently been demonstrated to possess both physiological and pathological roles in autoimmune diseases by regulating the Wnt signaling pathway. This review summarizes currently our understanding of the pathogenic roles of Wnt signaling in several major autoimmune disorders and miRNAs, those targeting Wnt signaling in autoimmune diseases, with a focus on the implication of the Wnt signaling as potential biomarkers and therapeutic targets in immune diseases, as well as miRNA-mediated regulation of Wnt signaling activation in the development of autoimmune diseases.

  19. Correlated cone noise decreases rod signal contributions to the post-receptoral pathways.

    Science.gov (United States)

    Hathibelagal, Amithavikram R; Feigl, Beatrix; Zele, Andrew J

    2018-04-01

    This study investigated how invisible extrinsic temporal white noise that correlates with the activity of one of the three [magnocellular (MC), parvocellular (PC), or koniocellular (KC)] post-receptoral pathways alters mesopic rod signaling. A four-primary photostimulator provided independent control of the rod and three cone photoreceptor excitations. The rod contributions to the three post-receptoral pathways were estimated by perceptually matching a 20% contrast rod pulse by independently varying the LMS (MC pathway), +L-M (PC pathway), and S-cone (KC pathway) excitations. We show that extrinsic cone noise caused a predominant decrease in the overall magnitude and ratio of the rod contributions to each pathway. Thus, the relative cone activity in the post-receptoral pathways determines the relative mesopic rod inputs to each pathway.

  20. Homocysteine enhances MMP-9 production in murine macrophages via ERK and Akt signaling pathways

    International Nuclear Information System (INIS)

    Lee, Seung Jin; Lee, Yi Sle; Seo, Kyo Won; Bae, Jin Ung; Kim, Gyu Hee; Park, So Youn; Kim, Chi Dae

    2012-01-01

    Homocysteine (Hcy) at elevated levels is an independent risk factor of cardiovascular diseases, including atherosclerosis. In the present study, we investigated the effect of Hcy on the production of matrix metalloproteinases (MMP) in murine macrophages. Among the MMP known to regulate the activities of collagenase and gelatinase, Hcy exclusively increased the gelatinolytic activity of MMP-9 in J774A.1 cells as well as in mouse peritoneal macrophages. Furthermore, this activity was found to be correlated with Western blot findings in J774A.1 cells, which showed that MMP-9 expression was concentration- and time-dependently increased by Hcy. Inhibition of the ERK and Akt pathways led to a significant decrease in Hcy-induced MMP-9 expression, and combined treatment with inhibitors of the ERK and Akt pathways showed an additive effects. Activity assays for ERK and Akt showed that Hcy increased the phosphorylation of both, but these phosphorylation were not affected by inhibitors of the Akt and ERK pathways. In line with these findings, the molecular inhibition of ERK and Akt using siRNA did not affect the Hcy-induced phosphorylation of Akt and ERK, respectively. Taken together, these findings suggest that Hcy enhances MMP-9 production in murine macrophages by separately activating the ERK and Akt signaling pathways. -- Highlights: ► Homocysteine (Hcy) induced MMP-9 production in murine macrophages. ► Hcy induced MMP-9 production through ERK and Akt signaling pathways. ► ERK and Akt signaling pathways were activated by Hcy in murine macrophages. ► ERK and Akt pathways were additively act on Hcy-induced MMP-9 production. ► Hcy enhances MMP-9 production in macrophages via activation of ERK and Akt signaling pathways in an independent manner.

  1. Homocysteine enhances MMP-9 production in murine macrophages via ERK and Akt signaling pathways

    Energy Technology Data Exchange (ETDEWEB)

    Lee, Seung Jin; Lee, Yi Sle; Seo, Kyo Won; Bae, Jin Ung; Kim, Gyu Hee; Park, So Youn; Kim, Chi Dae, E-mail: chidkim@pusan.ac.kr

    2012-04-01

    Homocysteine (Hcy) at elevated levels is an independent risk factor of cardiovascular diseases, including atherosclerosis. In the present study, we investigated the effect of Hcy on the production of matrix metalloproteinases (MMP) in murine macrophages. Among the MMP known to regulate the activities of collagenase and gelatinase, Hcy exclusively increased the gelatinolytic activity of MMP-9 in J774A.1 cells as well as in mouse peritoneal macrophages. Furthermore, this activity was found to be correlated with Western blot findings in J774A.1 cells, which showed that MMP-9 expression was concentration- and time-dependently increased by Hcy. Inhibition of the ERK and Akt pathways led to a significant decrease in Hcy-induced MMP-9 expression, and combined treatment with inhibitors of the ERK and Akt pathways showed an additive effects. Activity assays for ERK and Akt showed that Hcy increased the phosphorylation of both, but these phosphorylation were not affected by inhibitors of the Akt and ERK pathways. In line with these findings, the molecular inhibition of ERK and Akt using siRNA did not affect the Hcy-induced phosphorylation of Akt and ERK, respectively. Taken together, these findings suggest that Hcy enhances MMP-9 production in murine macrophages by separately activating the ERK and Akt signaling pathways. -- Highlights: ► Homocysteine (Hcy) induced MMP-9 production in murine macrophages. ► Hcy induced MMP-9 production through ERK and Akt signaling pathways. ► ERK and Akt signaling pathways were activated by Hcy in murine macrophages. ► ERK and Akt pathways were additively act on Hcy-induced MMP-9 production. ► Hcy enhances MMP-9 production in macrophages via activation of ERK and Akt signaling pathways in an independent manner.

  2. Phosphoproteomic Analysis Identifies Signaling Pathways Regulated by Curcumin in Human Colon Cancer Cells.

    Science.gov (United States)

    Sato, Tatsuhiro; Higuchi, Yutaka; Shibagaki, Yoshio; Hattori, Seisuke

    2017-09-01

    Curcumin, a major polyphenol of the spice turmeric, acts as a potent chemopreventive and chemotherapeutic agent in several cancer types, including colon cancer. Although various proteins have been shown to be affected by curcumin, how curcumin exerts its anticancer activity is not fully understood. Phosphoproteomic analyses were performed using SW480 and SW620 human colon cancer cells to identify curcumin-affected signaling pathways. Curcumin inhibited the growth of the two cell lines in a dose-dependent manner. Thirty-nine curcumin-regulated phosphoproteins were identified, five of which are involved in cancer signaling pathways. Detailed analyses revealed that the mTORC1 and p53 signaling pathways are main targets of curcumin. Our results provide insight into the molecular mechanisms of the anticancer activities of curcumin and future molecular targets for its clinical application. Copyright© 2017, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.

  3. Integrin Activation Contributes to Lower Cisplatin Sensitivity in MV3 Melanoma Cells by Inducing the Wnt Signalling Pathway

    Directory of Open Access Journals (Sweden)

    Maria B. R. Piva

    2017-09-01

    Full Text Available Background: integrins have been associated with the development of chemotherapy resistant tumour cells, mostly those of hematopoietic origin, by mediating the binding to the extracellular matrix. The relevance for solid tumour cells and the underlying mechanisms remain elusive. Methods: using MTT assays, we detected the loss in cisplatin sensitivity of human MV3 melanoma cells upon integrin activation. Underlying cellular pathways were evaluated by flow cytometry. A crosstalk between integrin activation and the canonical wnt signalling pathway was tested by measuring β-catenin activity. Results: MV3 cells display a higher resistance against cisplatin cytotoxicity when cellular integrins were activated by manganese or collagen. Proteome profiler array showed a deregulation of the integrin expression pattern by cisplatin. Integrin activation by manganese induces the phosphorylation of PI3K/AKT. The inhibition of PI3K using BEZ235 strongly increases cell sensitivity to cisplatin, blocking manganese and collagen effects. PI3K/AKT activates wnt signalling by blocking Gsk3-β, which was confirmed by β-catenin up-regulation and nuclear localization. Integrins did not affect E-cadherin expression levels, thus endothelial to mesenchymal transition (EMT can be excluded. Conclusion: This is the first report on an integrin/wnt signalling activation axis addressing the consequences for chemotherapy sensitiveness of melanoma cells, which thus offers novel therapeutic targets for approaches to interfere with chemoresistance.

  4. EG-1 interacts with c-Src and activates its signaling pathway.

    Science.gov (United States)

    Lu, Ming; Zhang, Liping; Sartippour, Maryam R; Norris, Andrew J; Brooks, Mai N

    2006-10-01

    EG-1 is significantly elevated in breast, colorectal, and prostate cancers. Overexpression of EG-1 stimulates cellular proliferation, and targeted inhibition blocks mouse xenograft tumor growth. To further clarify the function of EG-1, we investigated its role in c-Src activation. We observed that EG-1 overexpression results in activation of c-Src, but found no evidence that EG-1 is a direct Src substrate. EG-1 also binds to other members of the Src family. Furthermore, EG-1 shows interaction with multiple other SH3- and WW-containing molecules involved in various signaling pathways. These observations suggest that EG-1 may be involved in signaling pathways including c-Src activation.

  5. Encoding of temporal signals by the TGF-β pathway and implications for embryonic patterning

    Science.gov (United States)

    Sorre, Benoit; Warmflash, Aryeh; Brivanlou, Ali H.; Siggia, Eric D.

    2014-01-01

    Summary Genetics and biochemistry have defined the components and wiring of the signaling pathways that pattern the embryo. Among them, the TGF-β pathway has the potential to behave as a morphogen: invitro experiments have clearly established that it can dictate cell fate in a concentration dependent manner. How morphogens convey positional information in a developing embryo, where signal levels are changing with time, is less understood. Using integrated microfluidic cell culture and time-lapse microscopy, we demonstrate here that the speed of ligand presentation has a key and previously unexpected influence on TGF-β signaling outcomes. The response to a TGF-β concentration step is transient and adaptive, slowly increasing the ligand concentration diminishes the response and well-spaced pulses of ligand combine additively resulting in greater pathway output than with constant stimulation. Our results suggest that in an embryonic context, the speed of change of ligand concentration is an instructive signal for patterning. PMID:25065773

  6. Does a Common Pathway Transduce Symbiotic Signals in Plant-Microbe Interactions?

    Science.gov (United States)

    Genre, Andrea; Russo, Giulia

    2016-01-01

    Recent years have witnessed major advances in our knowledge of plant mutualistic symbioses such as the rhizobium-legume symbiosis (RLS) and arbuscular mycorrhizas (AM). Some of these findings caused the revision of longstanding hypotheses, but one of the most solid theories is that a conserved set of plant proteins rules the transduction of symbiotic signals from beneficial glomeromycetes and rhizobia in a so-called common symbiotic pathway (CSP). Nevertheless, the picture still misses several elements, and a few crucial points remain unclear. How does one common pathway discriminate between - at least - two symbionts? Can we exclude that microbes other than AM fungi and rhizobia also use this pathway to communicate with their host plants? We here discuss the possibility that our current view is biased by a long-lasting focus on legumes, whose ability to develop both AM and RLS is an exception among plants and a recent innovation in their evolution; investigations in non-legumes are starting to place legume symbiotic signaling in a broader perspective. Furthermore, recent studies suggest that CSP proteins act in a wider scenario of symbiotic and non-symbiotic signaling. Overall, evidence is accumulating in favor of distinct activities for CSP proteins in AM and RLS, depending on the molecular and cellular context where they act.

  7. Characterization of Heregulin-Stimulated Signal Transduction Pathways to the Nucleus

    National Research Council Canada - National Science Library

    Wilson, Kristin

    2000-01-01

    ... 40% of breast cancers and correlates with a poor prognosis for women with breast cancer. Mapping the molecular determinants of the heregulin/ErbB2 signaling pathway will be important in determining viable cellular targets for therapeutic intervention...

  8. An interplay between 2 signaling pathways: Melatonin-cAMP and IP{sub 3}–Ca{sup 2+} signaling pathways control intraerythrocytic development of the malaria parasite Plasmodium falciparum

    Energy Technology Data Exchange (ETDEWEB)

    Furuyama, Wakako [National Research Center for Protozoan Diseases, Obihiro University of Agriculture and Veterinary Medicine, Obihiro, Hokkaido 080-8555 (Japan); Enomoto, Masahiro [Princess Margaret Cancer Centre, Department of Medical Biophysics, University of Toronto, M5G1L7 Toronto, Ontario (Canada); Mossaad, Ehab [National Research Center for Protozoan Diseases, Obihiro University of Agriculture and Veterinary Medicine, Obihiro, Hokkaido 080-8555 (Japan); Kawai, Satoru [Laboratory of Tropical Medicine and Parasitology, Dokkyo Medical University, Mibu, Tochigi 321-0293 (Japan); Mikoshiba, Katsuhiko [Laboratory for Developmental Neurobiology, RIKEN Brain Science Institute, Wako, Saitama 351-0198 (Japan); Kawazu, Shin-ichiro, E-mail: skawazu@obihiro.ac.jp [National Research Center for Protozoan Diseases, Obihiro University of Agriculture and Veterinary Medicine, Obihiro, Hokkaido 080-8555 (Japan)

    2014-03-28

    Highlights: • A melatonin receptor antagonist blocked Ca{sup 2+} oscillation in P. falciparum and inhibited parasite growth. • P. falciparum development is controlled by Ca{sup 2+}- and cAMP-signaling pathways. • The cAMP-signaling pathway at ring form and late trophozoite stages governs parasite growth of P. falciparum. - Abstract: Plasmodium falciparum spends most of its asexual life cycle within human erythrocytes, where proliferation and maturation occur. Development into the mature forms of P. falciparum causes severe symptoms due to its distinctive sequestration capability. However, the physiological roles and the molecular mechanisms of signaling pathways that govern development are poorly understood. Our previous study showed that P. falciparum exhibits stage-specific spontaneous Calcium (Ca{sup 2+}) oscillations in ring and early trophozoites, and the latter was essential for parasite development. In this study, we show that luzindole (LZ), a selective melatonin receptor antagonist, inhibits parasite growth. Analyses of development and morphology of LZ-treated P. falciparum revealed that LZ severely disrupted intraerythrocytic maturation, resulting in parasite death. When LZ was added at ring stage, the parasite could not undergo further development, whereas LZ added at the trophozoite stage inhibited development from early into late schizonts. Live-cell Ca{sup 2+} imaging showed that LZ treatment completely abolished Ca{sup 2+} oscillation in the ring forms while having little effect on early trophozoites. Further, the melatonin-induced cAMP increase observed at ring and late trophozoite stage was attenuated by LZ treatment. These suggest that a complex interplay between IP{sub 3}–Ca{sup 2+} and cAMP signaling pathways is involved in intraerythrocytic development of P. falciparum.

  9. Signal Transduction Pathways of TNAP: Molecular Network Analyses.

    Science.gov (United States)

    Négyessy, László; Györffy, Balázs; Hanics, János; Bányai, Mihály; Fonta, Caroline; Bazsó, Fülöp

    2015-01-01

    Despite the growing body of evidence pointing on the involvement of tissue non-specific alkaline phosphatase (TNAP) in brain function and diseases like epilepsy and Alzheimer's disease, our understanding about the role of TNAP in the regulation of neurotransmission is severely limited. The aim of our study was to integrate the fragmented knowledge into a comprehensive view regarding neuronal functions of TNAP using objective tools. As a model we used the signal transduction molecular network of a pyramidal neuron after complementing with TNAP related data and performed the analysis using graph theoretic tools. The analyses show that TNAP is in the crossroad of numerous pathways and therefore is one of the key players of the neuronal signal transduction network. Through many of its connections, most notably with molecules of the purinergic system, TNAP serves as a controller by funnelling signal flow towards a subset of molecules. TNAP also appears as the source of signal to be spread via interactions with molecules involved among others in neurodegeneration. Cluster analyses identified TNAP as part of the second messenger signalling cascade. However, TNAP also forms connections with other functional groups involved in neuronal signal transduction. The results indicate the distinct ways of involvement of TNAP in multiple neuronal functions and diseases.

  10. Role of HIF-1α signaling pathway in osteoarthritis: a systematic review

    Directory of Open Access Journals (Sweden)

    Javier Fernández-Torres

    Full Text Available Abstract Osteoarthritis (OA is the most common form of arthritis and is frequently diagnosed and managed in primary care; it is characterized by loss of articular hyaline cartilage, which is a unique connective tissue that physiologically lacks blood vessels. Articular cartilage survives in a microenvironment devoid of oxygen, which is regulated by hypoxia inducible factor (HIF-1α. HIF-1α is considered the main transcriptional regulator of cellular and developmental response to hypoxia. To date, the relevance of HIF-1α in the assessment of cartilage has increased since its participation is essential in the homeostasis of this tissue. Taking into account the new emerging insights of HIF-1α in the scientific literature in the last years, we focused the present review on the potential role of HIF-1α signaling pathway in OA development, especially in how some genetic factors may influence the maintenance or breakdown of articular cartilage.

  11. Pentagone internalises glypicans to fine-tune multiple signalling pathways

    Science.gov (United States)

    Norman, Mark; Vuilleumier, Robin; Springhorn, Alexander; Gawlik, Jennifer; Pyrowolakis, George

    2016-01-01

    Tight regulation of signalling activity is crucial for proper tissue patterning and growth. Here we investigate the function of Pentagone (Pent), a secreted protein that acts in a regulatory feedback during establishment and maintenance of BMP/Dpp morphogen signalling during Drosophila wing development. We show that Pent internalises the Dpp co-receptors, the glypicans Dally and Dally-like protein (Dlp), and propose that this internalisation is important in the establishment of a long range Dpp gradient. Pent-induced endocytosis and degradation of glypicans requires dynamin- and Rab5, but not clathrin or active BMP signalling. Thus, Pent modifies the ability of cells to trap and transduce BMP by fine-tuning the levels of the BMP reception system at the plasma membrane. In addition, and in accordance with the role of glypicans in multiple signalling pathways, we establish a requirement of Pent for Wg signalling. Our data propose a novel mechanism by which morphogen signalling is regulated. DOI: http://dx.doi.org/10.7554/eLife.13301.001 PMID:27269283

  12. A SNARE-protein has opposing functions in penetration resistance and defence signalling pathways

    DEFF Research Database (Denmark)

    Zhang, Ziguo; Feechan, Angela; Pedersen, Carsten

    2007-01-01

    Penetration resistance is often the first line of defence against fungal pathogens. Subsequently induced defences are mediated by the programmed cell death (PCD) reaction pathway and the salicylic acid (SA), jasmonic acid (JA) and ethylene (ET) signalling pathways. We previously demonstrated...

  13. TGF-β1/Smad3 Pathway Targets PP2A-AMPK-FoxO1 Signaling to Regulate Hepatic Gluconeogenesis.

    Science.gov (United States)

    Yadav, Hariom; Devalaraja, Samir; Chung, Stephanie T; Rane, Sushil G

    2017-02-24

    Maintenance of glucose homeostasis is essential for normal physiology. Deviation from normal glucose levels, in either direction, increases susceptibility to serious medical complications such as hypoglycemia and diabetes. Maintenance of glucose homeostasis is achieved via functional interactions among various organs: liver, skeletal muscle, adipose tissue, brain, and the endocrine pancreas. The liver is the primary site of endogenous glucose production, especially during states of prolonged fasting. However, enhanced gluconeogenesis is also a signature feature of type 2 diabetes (T2D). Thus, elucidating the signaling pathways that regulate hepatic gluconeogenesis would allow better insight into the process of normal endogenous glucose production as well as how this process is impaired in T2D. Here we demonstrate that the TGF-β1/Smad3 signaling pathway promotes hepatic gluconeogenesis, both upon prolonged fasting and during T2D. In contrast, genetic and pharmacological inhibition of TGF-β1/Smad3 signals suppressed endogenous glucose production. TGF-β1 and Smad3 signals achieved this effect via the targeting of key regulators of hepatic gluconeogenesis, protein phosphatase 2A (PP2A), AMP-activated protein kinase (AMPK), and FoxO1 proteins. Specifically, TGF-β1 signaling suppressed the LKB1-AMPK axis, thereby facilitating the nuclear translocation of FoxO1 and activation of key gluconeogenic genes, glucose-6-phosphatase and phosphoenolpyruvate carboxykinase. These findings underscore an important role of TGF-β1/Smad3 signaling in hepatic gluconeogenesis, both in normal physiology and in the pathophysiology of metabolic diseases such as diabetes, and are thus of significant medical relevance. © 2017 by The American Society for Biochemistry and Molecular Biology, Inc.

  14. Semantic Mining based on graph theory and ontologies. Case Study: Cell Signaling Pathways

    Directory of Open Access Journals (Sweden)

    Carlos R. Rangel

    2016-08-01

    Full Text Available In this paper we use concepts from graph theory and cellular biology represented as ontologies, to carry out semantic mining tasks on signaling pathway networks. Specifically, the paper describes the semantic enrichment of signaling pathway networks. A cell signaling network describes the basic cellular activities and their interactions. The main contribution of this paper is in the signaling pathway research area, it proposes a new technique to analyze and understand how changes in these networks may affect the transmission and flow of information, which produce diseases such as cancer and diabetes. Our approach is based on three concepts from graph theory (modularity, clustering and centrality frequently used on social networks analysis. Our approach consists into two phases: the first uses the graph theory concepts to determine the cellular groups in the network, which we will call them communities; the second uses ontologies for the semantic enrichment of the cellular communities. The measures used from the graph theory allow us to determine the set of cells that are close (for example, in a disease, and the main cells in each community. We analyze our approach in two cases: TGF-ß and the Alzheimer Disease.

  15. The cAMP Signaling and MAP Kinase Pathways in Plant Pathogenic Fungi

    NARCIS (Netherlands)

    Mehrabi, R.; Zhao, X.; Kim, Y.; Xu, J.R.

    2009-01-01

    The key components of the well conserved cyclic AMP signaling and MAP kinase pathways have been functionally characterized in the corn smut Ustilago maydis, rice blast fungus Magnaporthe grisea, and a few other fungal pathogens. In general, the cAMP signaling and the MAP kinase cascade homologous to

  16. MGAT1 is a novel transcriptional target of Wnt/β-catenin signaling pathway.

    Science.gov (United States)

    Akiva, Izzet; Birgül Iyison, Necla

    2018-01-08

    The Wnt/β-catenin signaling pathway is an evolutionary conserved pathway, which has important functions in vertebrate early development, axis formation, cellular proliferation and morphogenesis. Additionally, Wnt/β-catenin signaling pathway is one of the most important intracellular pathways that controls cancer progression. To date most of the identified targets of this pathway are shown to harbor tumorigenic properties. We previously showed that Mannosyl glycoprotein acetylglucosaminyl-transferase (MGAT1) enzyme is among the Wnt/β-catenin signaling putative target genes in hepatocellular carcinoma cell lines (Huh7). MGAT1 protein levels were determined by Western Blotting from Huh7 cell lines in which Wnt/β-catenin pathway was activated by means of different approaches such as LiCl treatment and mutant β-catenin overexpression. Luciferase reporter assay was used to analyze the promoter activity of MGAT1. The mRNA levels of MGAT1 were determined by quantitative real-time PCR from Huh7 cells that were treated with either Wnt agonist or GSK-3β inhibitor. Wound healing and XTT cell proliferation assays were performed in order to determine the proliferation and migration capacities of MGAT1 overexpressing stable Huh7 cells. Finally, xenograft experiments were carried out to measure the tumor formation capacities in vivo. In this study we showed that the activation of Wnt/β-catenin pathway culminates in the upregulation of MGAT1 enzyme both at transcriptional and post-transcriptional levels. We also showed that overexpression of the β-catenin gene (CTNNB1) increased the promoter activity of MGAT1. We applied a set of complementary approaches to elucidate the functional importance of MGAT1 as a vital target of Wnt/β-catenin signaling in Huh7 cells. Our analyses related to cell proliferation and migration assays showed that in comparison to the control cells, MGAT1 expressing Huh7 cells have greater proliferative and invasive capabilities. Furthermore, the

  17. Deregulation of Interferon Signaling in Malignant Cells

    Directory of Open Access Journals (Sweden)

    Leonidas C. Platanias

    2010-02-01

    Full Text Available Interferons (IFNs are a family of cytokines with potent antiproliferative, antiviral, and immunomodulatory properties. Much has been learned about IFNs and IFN-activated signaling cascades over the last 50 years. Due to their potent antitumor effects in vitro and in vivo, recombinant IFNs have been used extensively over the years, alone or in combination with other drugs, for the treatment of various malignancies. This review summarizes the current knowledge on IFN signaling components and pathways that are deregulated in human malignancies. The relevance of deregulation of IFN signaling pathways in defective innate immune surveillance and tumorigenesis are discussed.

  18. Intercellular signaling pathways active during and after growth and differentiation of the lumbar vertebral growth plate.

    Science.gov (United States)

    Dahia, Chitra Lekha; Mahoney, Eric J; Durrani, Atiq A; Wylie, Christopher

    2011-06-15

    Vertebral growth plates at different postnatal ages were assessed for active intercellular signaling pathways. To generate a spatial and temporal map of the major signaling pathways active in the postnatal mouse lumbar vertebral growth plate. The growth of all long bones is known to occur by cartilaginous growth plates. The growth plate is composed of layers of chondrocyets that actively proliferate, differentiate, die and, are replaced by bone. The role of major cell signaling pathways has been suggested for regulation of the fetal long bones. But not much is known about the molecular or cellular signals that control the postnatal vertebral growth plate and hence postnatal vertebral bone growth. Understanding such molecular mechanisms will help design therapeutic treatments for vertebral growth disorders such as scoliosis. Antibodies against activated downstream intermediates were used to identify cells in the growth plate responding to BMP, TGFβ, and FGF in cryosections of lumbar vertebrae from different postnatal age mice to identify the zones that were responding to these signals. Reporter mice were used to identify the chondrocytes responding to hedgehog (Ihh), and Wnt signaling. We present a spatial/temporal map of these signaling pathways during growth, and differentiation of the mouse lumbar vertebral growth plate. During growth and differentiation of the vertebral growth plate, its different components respond at different times to different intercellular signaling ligands. Response to most of these signals is dramatically downregulated at the end of vertebral growth.

  19. GAS6/TAM Pathway Signaling in Hemostasis and Thrombosis.

    Science.gov (United States)

    Law, Luke A; Graham, Douglas K; Di Paola, Jorge; Branchford, Brian R

    2018-01-01

    The GAS6/TYRO3-AXL-MERTK (TAM) signaling pathway is essential for full and sustained platelet activation, as well as thrombus stabilization. Inhibition of this pathway decreases platelet aggregation, shape change, clot retraction, aggregate formation under flow conditions, and surface expression of activation markers. Transgenic mice deficient in GAS6, or any of the TAM family of receptors that engage this ligand, exhibit in vivo protection against arterial and venous thrombosis but do not demonstrate either spontaneous or prolonged bleeding compared to their wild-type counterparts. Comparable results are observed in wild-type mice treated with pharmacological inhibitors of the GAS6-TAM pathway. Thus, GAS6/TAM inhibition offers an attractive novel therapeutic option that may allow for a moderate reduction in platelet activation and decreased thrombosis while still permitting the primary hemostatic function of platelet plug formation.

  20. β1-adrenergic receptors activate two distinct signaling pathways in striatal neurons

    Science.gov (United States)

    Meitzen, John; Luoma, Jessie I.; Stern, Christopher M.; Mermelstein, Paul G.

    2010-01-01

    Monoamine action in the dorsal striatum and nucleus accumbens plays essential roles in striatal physiology. Although research often focuses on dopamine and its receptors, norepinephrine and adrenergic receptors are also crucial in regulating striatal function. While noradrenergic neurotransmission has been identified in the striatum, little is known regarding the signaling pathways activated by β-adrenergic receptors in this brain region. Using cultured striatal neurons, we characterized a novel signaling pathway by which activation of β1-adrenergic receptors leads to the rapid phosphorylation of cAMP Response Element Binding Protein (CREB), a transcription-factor implicated as a molecular switch underlying long-term changes in brain function. Norepinephrine-mediated CREB phosphorylation requires β1-adrenergic receptor stimulation of a receptor tyrosine kinase, ultimately leading to the activation of a Ras/Raf/MEK/MAPK/MSK signaling pathway. Activation of β1-adrenergic receptors also induces CRE-dependent transcription and increased c-fos expression. In addition, stimulation of β1-adrenergic receptors produces cAMP production, but surprisingly, β1-adrenergic receptor activation of adenylyl cyclase was not functionally linked to rapid CREB phosphorylation. These findings demonstrate that activation of β1-adrenergic receptors on striatal neurons can stimulate two distinct signaling pathways. These adrenergic actions can produce long-term changes in gene expression, as well as rapidly modulate cellular physiology. By elucidating the mechanisms by which norepinephrine and β1-adrenergic receptor activation affects striatal physiology, we provide the means to more fully understand the role of monoamines in modulating striatal function, specifically how norepinephrine and β1-adrenergic receptors may affect striatal physiology. PMID:21143600

  1. Eight paths of ERK1/2 signalling pathway regulating hepatocyte ...

    Indian Academy of Sciences (India)

    2011-12-05

    Dec 5, 2011 ... This study aims at exploring which paths of ERK1/2 signalling pathway participate in the regulation of rat .... total RNA was used to synthesize the first strand of cDNA. ..... stem cells contribute to regeneration of injured liver.

  2. Agmatine modulates melanogenesis via MITF signaling pathway.

    Science.gov (United States)

    Kwon, Eun-Jeong; Kim, Moon-Moo

    2017-01-01

    Agmatine contained in soybean is also found in Manaca, an anti-aging plant, inhabited in Amazon and induces vasodilation by the promotion of NO synthesis in blood vessel. However, the research of agmatine on melanin synthesis related to hair greying is lacking. The aim of this study was to investigate the melanogenic effect of agmatine via regulation of MITF signaling pathway in B16F1 cells. It was determined whether agmatine regulates melanin synthesis at cellular level in addition to the effect of agmatine on mushroom tyrosinase in vitro in the presence of different concentrations of agmatine. Furthermore, the effect of agmatine on the protein expressions of tyrosinase, TRP-1, TRP-2, BMP-4, BMP-6, C-KIT, p-p38, MITF and C-FOS were examined by western blot analysis. In addition, immunofluorescence staining was carried out to visualize the location of MITF expression in cell. Agmatine at 256μM or more increased melanin synthesis as well as tyrosinase activity. Moreover, whereas agmatine increased the expression levels of TRP-1, BMP-6, p-p38 and MITF, it reduced the expression level of BMP-4. It was also found that agmatine enhanced the expression level of MITF in nucleus. These results suggest that agmatine could induce melanin synthesis though the regulation of MITF transcription factor via BMP-6/p38 signaling pathway. Copyright © 2016 Elsevier B.V. All rights reserved.

  3. EMD self-adaptive selecting relevant modes algorithm for FBG spectrum signal

    Science.gov (United States)

    Chen, Yong; Wu, Chun-ting; Liu, Huan-lin

    2017-07-01

    Noise may reduce the demodulation accuracy of fiber Bragg grating (FBG) sensing signal so as to affect the quality of sensing detection. Thus, the recovery of a signal from observed noisy data is necessary. In this paper, a precise self-adaptive algorithm of selecting relevant modes is proposed to remove the noise of signal. Empirical mode decomposition (EMD) is first used to decompose a signal into a set of modes. The pseudo modes cancellation is introduced to identify and eliminate false modes, and then the Mutual Information (MI) of partial modes is calculated. MI is used to estimate the critical point of high and low frequency components. Simulation results show that the proposed algorithm estimates the critical point more accurately than the traditional algorithms for FBG spectral signal. While, compared to the similar algorithms, the signal noise ratio of the signal can be improved more than 10 dB after processing by the proposed algorithm, and correlation coefficient can be increased by 0.5, so it demonstrates better de-noising effect.

  4. Involvement of wnt signaling pathways in the metamorphosis of the bryozoan bugula neritina

    KAUST Repository

    Wong, Yue Him

    2012-03-20

    In this study, we analyzed the metamorphosis of the marine bryozoan Bugula neritina. We observed the morphogenesis of the ancestrula. We defined three distinct pre-ancestrula stages based on the anatomy of the developing polypide and the overall morphology of pre-ancestrula. We then used an annotation based enrichment analysis tool to analyze the B. neritina transcriptome and identified over-representation of genes related to Wnt signaling pathways, suggesting its involvement in metamorphosis. Finally, we studied the temporal-spatial gene expression studies of several Wnt pathway genes. We found that one of the Wnt ligand, BnWnt10, was expressed spatially opposite to the Wnt antagonist BnsFRP within the blastemas, which is the presumptive polypide. Down-stream components of the canonical Wnt signaling pathway were exclusively expressed in the blastemas. Bn?catenin and BnFz5/8 were exclusively expressed in the blastemas throughout the metamorphosis. Based on the genes expression patterns, we propose that BnWnt10 and BnsFRP may relate to the patterning of the polypide, in which the two genes served as positional signals and contributed to the polarization of the blastemas. Another Wnt ligand, BnWnt6, was expressed in the apical part of the pre-ancestrula epidermis. Overall, our findings suggest that the Wnt signaling pathway may be important to the pattern formation of polypide and the development of epidermis. © 2012 Wong et al.

  5. Involvement of wnt signaling pathways in the metamorphosis of the bryozoan bugula neritina

    KAUST Repository

    Wong, Yue Him; Wang, Hao; Ravasi, Timothy; Qian, Pei-Yuan

    2012-01-01

    In this study, we analyzed the metamorphosis of the marine bryozoan Bugula neritina. We observed the morphogenesis of the ancestrula. We defined three distinct pre-ancestrula stages based on the anatomy of the developing polypide and the overall morphology of pre-ancestrula. We then used an annotation based enrichment analysis tool to analyze the B. neritina transcriptome and identified over-representation of genes related to Wnt signaling pathways, suggesting its involvement in metamorphosis. Finally, we studied the temporal-spatial gene expression studies of several Wnt pathway genes. We found that one of the Wnt ligand, BnWnt10, was expressed spatially opposite to the Wnt antagonist BnsFRP within the blastemas, which is the presumptive polypide. Down-stream components of the canonical Wnt signaling pathway were exclusively expressed in the blastemas. Bn?catenin and BnFz5/8 were exclusively expressed in the blastemas throughout the metamorphosis. Based on the genes expression patterns, we propose that BnWnt10 and BnsFRP may relate to the patterning of the polypide, in which the two genes served as positional signals and contributed to the polarization of the blastemas. Another Wnt ligand, BnWnt6, was expressed in the apical part of the pre-ancestrula epidermis. Overall, our findings suggest that the Wnt signaling pathway may be important to the pattern formation of polypide and the development of epidermis. © 2012 Wong et al.

  6. Directed random walks and constraint programming reveal active pathways in hepatocyte growth factor signaling.

    Science.gov (United States)

    Kittas, Aristotelis; Delobelle, Aurélien; Schmitt, Sabrina; Breuhahn, Kai; Guziolowski, Carito; Grabe, Niels

    2016-01-01

    An effective means to analyze mRNA expression data is to take advantage of established knowledge from pathway databases, using methods such as pathway-enrichment analyses. However, pathway databases are not case-specific and expression data could be used to infer gene-regulation patterns in the context of specific pathways. In addition, canonical pathways may not always describe the signaling mechanisms properly, because interactions can frequently occur between genes in different pathways. Relatively few methods have been proposed to date for generating and analyzing such networks, preserving the causality between gene interactions and reasoning over the qualitative logic of regulatory effects. We present an algorithm (MCWalk) integrated with a logic programming approach, to discover subgraphs in large-scale signaling networks by random walks in a fully automated pipeline. As an exemplary application, we uncover the signal transduction mechanisms in a gene interaction network describing hepatocyte growth factor-stimulated cell migration and proliferation from gene-expression measured with microarray and RT-qPCR using in-house perturbation experiments in a keratinocyte-fibroblast co-culture. The resulting subgraphs illustrate possible associations of hepatocyte growth factor receptor c-Met nodes, differentially expressed genes and cellular states. Using perturbation experiments and Answer Set programming, we are able to select those which are more consistent with the experimental data. We discover key regulator nodes by measuring the frequency with which they are traversed when connecting signaling between receptors and significantly regulated genes and predict their expression-shift consistently with the measured data. The Java implementation of MCWalk is publicly available under the MIT license at: https://bitbucket.org/akittas/biosubg. © 2015 FEBS.

  7. Molecular mechanisms of BMP-induced bone formation: Cross-talk between BMP and NF-κB signaling pathways in osteoblastogenesis

    Directory of Open Access Journals (Sweden)

    Eijiro Jimi

    2010-02-01

    Full Text Available Osteoblasts are bone-forming cells that differentiate from mesenchymal stem cells. Differentiation processes are coordinately and dynamically controlled in the mesenchymal cells by specific signal transduction pathways. Bone morphogenetic proteins (BMPs, members of the TGF-β superfamily, induce not only bone formation in vivo, but also osteoblast differentiation of mesenchymal cells in vitro. BMP signals are transduced from plasma membrane receptors to the nucleus through both Smad-dependent and -independent pathways, and are regulated by many extracellular and intercellular proteins that interact with BMPs or components of BMP signaling pathways. To understand the molecular mechanisms underlying the role of BMPs in osteoblast differentiation, it is important to elucidate the BMP signaling transduction pathways that are active during osteoblast differentiation. In this review, we summarize the BMP signaling pathways that are known to function in osteoblast development. We also describe our recent findings regarding the molecular mechanisms underlying the cross-talk between BMP/Smad and NF-κB pathways in osteoblast differentiation.

  8. The involvement of calcium and MAP kinase signaling pathways in the production of radiation-induced bystander effects.

    LENUS (Irish Health Repository)

    Lyng, F M

    2006-04-01

    Much evidence now exists regarding radiation-induced bystander effects, but the mechanisms involved in the transduction of the signal are still unclear. The mitogen-activated protein kinase (MAPK) pathways have been linked to growth factor-mediated regulation of cellular events such as proliferation, senescence, differentiation and apoptosis. Activation of multiple MAPK pathways such as the ERK, JNK and p38 pathways have been shown to occur after exposure of cells to radiation and a variety of other toxic stresses. Previous studies have shown oxidative stress and calcium signaling to be important in radiation-induced bystander effects. The aim of the present study was to investigate MAPK signaling pathways in bystander cells exposed to irradiated cell conditioned medium (ICCM) and the role of oxidative metabolism and calcium signaling in the induction of bystander responses. Human keratinocytes (HPV-G cell line) were irradiated (0.005-5 Gy) using a cobalt-60 teletherapy unit. The medium was harvested 1 h postirradiation and transferred to recipient HPV-G cells. Phosphorylated forms of p38, JNK and ERK were studied by immunofluorescence 30 min-24 h after exposure to ICCM. Inhibitors of the ERK pathway (PD98059 and U0126), the JNK pathway (SP600125), and the p38 pathway (SB203580) were used to investigate whether bystander-induced cell death could be blocked. Cells were also incubated with ICCM in the presence of superoxide dismutase, catalase, EGTA, verapamil, nifedipine and thapsigargin to investigate whether bystander effects could be inhibited because of the known effects on calcium homeostasis. Activated forms of JNK and ERK proteins were observed after exposure to ICCM. Inhibition of the ERK pathway appeared to increase bystander-induced apoptosis, while inhibition of the JNK pathway appeared to decrease apoptosis. In addition, reactive oxygen species, such as superoxide and hydrogen peroxide, and calcium signaling were found to be important modulators of

  9. Identification of signaling pathways associated with cancer protection in Laron syndrome.

    Science.gov (United States)

    Lapkina-Gendler, Lena; Rotem, Itai; Pasmanik-Chor, Metsada; Gurwitz, David; Sarfstein, Rive; Laron, Zvi; Werner, Haim

    2016-05-01

    The growth hormone (GH)-insulin-like growth factor-1 (IGF1) pathway emerged in recent years as a critical player in cancer biology. Enhanced expression or activation of specific components of the GH-IGF1 axis, including the IGF1 receptor (IGF1R), is consistently associated with a transformed phenotype. Recent epidemiological studies have shown that patients with Laron syndrome (LS), the best-characterized entity among the congenital IGF1 deficiencies, seem to be protected from cancer development. To identify IGF1-dependent genes and signaling pathways associated with cancer protection in LS, we conducted a genome-wide analysis using immortalized lymphoblastoid cells derived from LS patients and healthy controls of the same gender, age range, and ethnic origin. Our analyses identified a collection of genes that are either over- or under-represented in LS-derived lymphoblastoids. Gene differential expression occurs in several gene families, including cell cycle, metabolic control, cytokine-cytokine receptor interaction, Jak-STAT signaling, and PI3K-AKT signaling. Major differences between LS and healthy controls were also noticed in pathways associated with cell cycle distribution, apoptosis, and autophagy. Our results highlight the key role of the GH-IGF1 axis in the initiation and progression of cancer. Furthermore, data are consistent with the concept that homozygous congenital IGF1 deficiency may confer protection against future tumor development. © 2016 Society for Endocrinology.

  10. The regulation of ras-raf signaling pathway on G1 phase of the irradiated cells

    International Nuclear Information System (INIS)

    Guo Dehuang; Dong Bo; Liu Nongle; Wen Gengyun; Luo Qingliang; Mao Bingzhi

    2000-01-01

    Objective: To investigate the way of ras-raf signaling pathway which regulate the G 1 phase in irradiated KG-1 cells. Methods: Blocked the GM-CSF signaling pathway by transfected DN-ras and then momentary transfected cyclin D1 into irradiated KG-1 cells, the effects of cyclin D1 on G 1 phase was examined. Results: The irradiated KG-1 cells transfected DN-ras can't recover form G 1 phase arrest even though the GM-CSF was given,momentary transfected cyclin D1 promote the irradiated KG-1 cells from G 1 arrest. Conclusion: Activation of ras-raf signaling pathway regulate the cell cycle of the irradiated KG-1 cells through promotion the expression of the cyclin D1

  11. Transcription Profiles Reveal Sugar and Hormone Signaling Pathways Mediating Flower Induction in Apple (Malus domestica Borkh.).

    Science.gov (United States)

    Xing, Li-Bo; Zhang, Dong; Li, You-Mei; Shen, Ya-Wen; Zhao, Cai-Ping; Ma, Juan-Juan; An, Na; Han, Ming-Yu

    2015-10-01

    Flower induction in apple (Malus domestica Borkh.) is regulated by complex gene networks that involve multiple signal pathways to ensure flower bud formation in the next year, but the molecular determinants of apple flower induction are still unknown. In this research, transcriptomic profiles from differentiating buds allowed us to identify genes potentially involved in signaling pathways that mediate the regulatory mechanisms of flower induction. A hypothetical model for this regulatory mechanism was obtained by analysis of the available transcriptomic data, suggesting that sugar-, hormone- and flowering-related genes, as well as those involved in cell-cycle induction, participated in the apple flower induction process. Sugar levels and metabolism-related gene expression profiles revealed that sucrose is the initiation signal in flower induction. Complex hormone regulatory networks involved in cytokinin (CK), abscisic acid (ABA) and gibberellic acid pathways also induce apple flower formation. CK plays a key role in the regulation of cell formation and differentiation, and in affecting flowering-related gene expression levels during these processes. Meanwhile, ABA levels and ABA-related gene expression levels gradually increased, as did those of sugar metabolism-related genes, in developing buds, indicating that ABA signals regulate apple flower induction by participating in the sugar-mediated flowering pathway. Furthermore, changes in sugar and starch deposition levels in buds can be affected by ABA content and the expression of the genes involved in the ABA signaling pathway. Thus, multiple pathways, which are mainly mediated by crosstalk between sugar and hormone signals, regulate the molecular network involved in bud growth and flower induction in apple trees. © The Author 2015. Published by Oxford University Press on behalf of Japanese Society of Plant Physiologists.

  12. A hepatic amino acid/mTOR/S6K-dependent signalling pathway modulates systemic lipid metabolism via neuronal signals.

    Science.gov (United States)

    Uno, Kenji; Yamada, Tetsuya; Ishigaki, Yasushi; Imai, Junta; Hasegawa, Yutaka; Sawada, Shojiro; Kaneko, Keizo; Ono, Hiraku; Asano, Tomoichiro; Oka, Yoshitomo; Katagiri, Hideki

    2015-08-13

    Metabolism is coordinated among tissues and organs via neuronal signals. Levels of circulating amino acids (AAs), which are elevated in obesity, activate the intracellular target of rapamycin complex-1 (mTORC1)/S6kinase (S6K) pathway in the liver. Here we demonstrate that hepatic AA/mTORC1/S6K signalling modulates systemic lipid metabolism via a mechanism involving neuronal inter-tissue communication. Hepatic expression of an AA transporter, SNAT2, activates the mTORC1/S6K pathway, and markedly elevates serum triglycerides (TGs), while downregulating adipose lipoprotein lipase (LPL). Hepatic Rheb or active-S6K expression have similar metabolic effects, whereas hepatic expression of dominant-negative-S6K inhibits TG elevation in SNAT2 mice. Denervation, pharmacological deafferentation and β-blocker administration suppress obesity-related hypertriglyceridemia with adipose LPL upregulation, suggesting that signals are transduced between liver and adipose tissue via a neuronal pathway consisting of afferent vagal and efferent sympathetic nerves. Thus, the neuronal mechanism uncovered here serves to coordinate amino acid and lipid levels and contributes to the development of obesity-related hypertriglyceridemia.

  13. A systems biology approach for pathway level analysis

    OpenAIRE

    Draghici, Sorin; Khatri, Purvesh; Tarca, Adi Laurentiu; Amin, Kashyap; Done, Arina; Voichita, Calin; Georgescu, Constantin; Romero, Roberto

    2007-01-01

    A common challenge in the analysis of genomics data is trying to understand the underlying phenomenon in the context of all complex interactions taking place on various signaling pathways. A statistical approach using various models is universally used to identify the most relevant pathways in a given experiment. Here, we show that the existing pathway analysis methods fail to take into consideration important biological aspects and may provide incorrect results in certain situations. By usin...

  14. Coordinated induction of GST and MRP2 by cAMP in Caco-2 cells: Role of protein kinase A signaling pathway and toxicological relevance

    International Nuclear Information System (INIS)

    Arana, Maite Rocío; Tocchetti, Guillermo Nicolás; Domizi, Pablo; Arias, Agostina; Rigalli, Juan Pablo; Ruiz, María Laura

    2015-01-01

    The cAMP pathway is a universal signaling pathway regulating many cellular processes including metabolic routes, growth and differentiation. However, its effects on xenobiotic biotransformation and transport systems are poorly characterized. The effect of cAMP on expression and activity of GST and MRP2 was evaluated in Caco-2 cells, a model of intestinal epithelium. Cells incubated with the cAMP permeable analog dibutyryl cyclic AMP (db-cAMP: 1,10,100 μM) for 48 h exhibited a dose–response increase in GST class α and MRP2 protein expression. Incubation with forskolin, an activator of adenylyl cyclase, confirmed the association between intracellular cAMP and upregulation of MRP2. Consistent with increased expression of GSTα and MRP2, db-cAMP enhanced their activities, as well as cytoprotection against the common substrate 1-chloro-2,4-dinitrobenzene. Pretreatment with protein kinase A (PKA) inhibitors totally abolished upregulation of MRP2 and GSTα induced by db-cAMP. In silico analysis together with experiments consisting of treatment with db-cAMP of Caco-2 cells transfected with a reporter construct containing CRE and AP-1 sites evidenced participation of these sites in MRP2 upregulation. Further studies involving the transcription factors CREB and AP-1 (c-JUN, c-FOS and ATF2) demonstrated increased levels of total c-JUN and phosphorylation of c-JUN and ATF2 by db-cAMP, which were suppressed by a PKA inhibitor. Co-immunoprecipitation and ChIP assay studies demonstrated that db-cAMP increased c-JUN/ATF2 interaction, with further recruitment to the region of the MRP2 promoter containing CRE and AP-1 sites. We conclude that cAMP induces GSTα and MRP2 expression and activity in Caco-2 cells via the PKA pathway, thus regulating detoxification of specific xenobiotics. - Highlights: • cAMP positively modulates the expression and activity of GST and MRP2 in Caco-2 cells. • Such induction resulted in increased cytoprotection against chemical injury. • PKA

  15. Coordinated induction of GST and MRP2 by cAMP in Caco-2 cells: Role of protein kinase A signaling pathway and toxicological relevance

    Energy Technology Data Exchange (ETDEWEB)

    Arana, Maite Rocío, E-mail: arana@ifise-conicet.gov.ar [Instituto de Fisiología Experimental (CONICET), Facultad de Ciencias Bioquímicas y Farmacéuticas (UNR), Suipacha 570, 2000 Rosario (Argentina); Tocchetti, Guillermo Nicolás, E-mail: gtocchetti@live.com.ar [Instituto de Fisiología Experimental (CONICET), Facultad de Ciencias Bioquímicas y Farmacéuticas (UNR), Suipacha 570, 2000 Rosario (Argentina); Domizi, Pablo, E-mail: domizi@ibr-conicet.gov.ar [Instituto de Biología Molecular y Celular de Rosario (CONICET), Facultad de Ciencias Bioquímicas y Farmacéuticas (UNR), Suipacha 570, 2000 Rosario (Argentina); Arias, Agostina, E-mail: agoarias@yahoo.com.ar [Instituto de Fisiología Experimental (CONICET), Facultad de Ciencias Bioquímicas y Farmacéuticas (UNR), Suipacha 570, 2000 Rosario (Argentina); Rigalli, Juan Pablo, E-mail: jprigalli@gmail.com [Instituto de Fisiología Experimental (CONICET), Facultad de Ciencias Bioquímicas y Farmacéuticas (UNR), Suipacha 570, 2000 Rosario (Argentina); Ruiz, María Laura, E-mail: ruiz@ifise-conicet.gov.ar [Instituto de Fisiología Experimental (CONICET), Facultad de Ciencias Bioquímicas y Farmacéuticas (UNR), Suipacha 570, 2000 Rosario (Argentina); and others

    2015-09-01

    The cAMP pathway is a universal signaling pathway regulating many cellular processes including metabolic routes, growth and differentiation. However, its effects on xenobiotic biotransformation and transport systems are poorly characterized. The effect of cAMP on expression and activity of GST and MRP2 was evaluated in Caco-2 cells, a model of intestinal epithelium. Cells incubated with the cAMP permeable analog dibutyryl cyclic AMP (db-cAMP: 1,10,100 μM) for 48 h exhibited a dose–response increase in GST class α and MRP2 protein expression. Incubation with forskolin, an activator of adenylyl cyclase, confirmed the association between intracellular cAMP and upregulation of MRP2. Consistent with increased expression of GSTα and MRP2, db-cAMP enhanced their activities, as well as cytoprotection against the common substrate 1-chloro-2,4-dinitrobenzene. Pretreatment with protein kinase A (PKA) inhibitors totally abolished upregulation of MRP2 and GSTα induced by db-cAMP. In silico analysis together with experiments consisting of treatment with db-cAMP of Caco-2 cells transfected with a reporter construct containing CRE and AP-1 sites evidenced participation of these sites in MRP2 upregulation. Further studies involving the transcription factors CREB and AP-1 (c-JUN, c-FOS and ATF2) demonstrated increased levels of total c-JUN and phosphorylation of c-JUN and ATF2 by db-cAMP, which were suppressed by a PKA inhibitor. Co-immunoprecipitation and ChIP assay studies demonstrated that db-cAMP increased c-JUN/ATF2 interaction, with further recruitment to the region of the MRP2 promoter containing CRE and AP-1 sites. We conclude that cAMP induces GSTα and MRP2 expression and activity in Caco-2 cells via the PKA pathway, thus regulating detoxification of specific xenobiotics. - Highlights: • cAMP positively modulates the expression and activity of GST and MRP2 in Caco-2 cells. • Such induction resulted in increased cytoprotection against chemical injury. • PKA

  16. UTP-induced ATP release is a fine-tuned signalling pathway in osteocytes

    DEFF Research Database (Denmark)

    Kringelbach, Tina M.; Aslan, Derya; Novak, Ivana

    2014-01-01

    Osteocytes reside as a cellular network throughout the mineralised matrix of bone and are considered the primary mechanosensors of this tissue. They sense mechanical stimulation such as fluid flow and are able to regulate osteoblast and osteoclast functions on the bone surface. Previously, we fou...... signals may be propagated by P2 receptor activation and further ATP release in the osteocyte network and implicate purinergic signalling as a central signalling pathway in osteocyte mechanotransduction....

  17. Development of steroid signaling pathways during primordial follicle formation in the human fetal ovary.

    Science.gov (United States)

    Fowler, Paul A; Anderson, Richard A; Saunders, Philippa T; Kinnell, Hazel; Mason, J Ian; Evans, Dean B; Bhattacharya, Siladitya; Flannigan, Samantha; Franks, Stephen; Monteiro, Ana; O'Shaughnessy, Peter J

    2011-06-01

    Ovarian primordial follicle formation is critical for subsequent human female fertility. It is likely that steroid, and especially estrogen, signaling is required for this process, but details of the pathways involved are currently lacking. The aim was to identify and characterize key members of the steroid-signaling pathway expressed in the second trimester human fetal ovary. We conducted an observational study of the female fetus, quantifying and localizing steroid-signaling pathway members. The study was conducted at the Universities of Aberdeen, Edinburgh, and Glasgow. Ovaries were collected from 43 morphologically normal human female fetuses from women undergoing elective termination of second trimester pregnancies. We measured mRNA transcript levels and immunolocalized key steroidogenic enzymes and steroid receptors, including those encoded by ESR2, AR, and CYP19A1. Levels of mRNA encoding the steroidogenic apparatus and steroid receptors increased across the second trimester. CYP19A1 transcript increased 4.7-fold during this period with intense immunostaining for CYP19A detected in pregranulosa cells around primordial follicles and somatic cells around oocyte nests. ESR2 was localized primarily to germ cells, but androgen receptor was exclusively expressed in somatic cells. CYP17A1 and HSD3B2 were also localized to oocytes, whereas CYP11A1 was detected in oocytes and some pregranulosa cells. The human fetal ovary expresses the machinery to produce and detect multiple steroid signaling pathways, including estrogenic signaling, with the oocyte acting as a key component. This study provides a step-change in our understanding of local dynamics of steroid hormone signaling during the key period of human primordial follicle formation.

  18. NF-kappaB signaling: a tale of two pathways in skeletal myogenesis.

    Science.gov (United States)

    Bakkar, Nadine; Guttridge, Denis C

    2010-04-01

    NF-kappaB is a ubiquitiously expressed transcription factor that plays vital roles in innate immunity and other processes involving cellular survival, proliferation, and differentiation. Activation of NF-kappaB is controlled by an IkappaB kinase (IKK) complex that can direct either canonical (classical) NF-kappaB signaling by degrading the IkappaB inhibitor and releasing p65/p50 dimers to the nucleus, or causes p100 processing and nuclear translocation of RelB/p52 via a noncanonical (alternative) pathway. Under physiological conditions, NF-kappaB activity is transiently regulated, whereas constitutive activation of this transcription factor typically in the classical pathway is associated with a multitude of disease conditions, including those related to skeletal muscle. How NF-kappaB functions in muscle diseases is currently under intense investigation. Insight into this role of NF-kappaB may be gained by understanding at a more basic level how this transcription factor contributes to skeletal muscle cell differentiation. Recent data from knockout mice support that the classical NF-kappaB pathway functions as an inhibitor of skeletal myogenesis and muscle regeneration acting through multiple mechanisms. In contrast, alternative NF-kappaB signaling does not appear to be required for myofiber conversion, but instead functions in myotube homeostasis by regulating mitochondrial biogenesis. Additional knowledge of these signaling pathways in skeletal myogenesis should aid in the development of specific inhibitors that may be useful in treatments of muscle disorders.

  19. Analysis of porcine granulosa cell death signaling pathways induced by vinclozolin.

    Science.gov (United States)

    Knet, Malgorzata; Wartalski, Kamil; Hoja-Lukowicz, Dorota; Tabarowski, Zbigniew; Slomczynska, Maria; Duda, Malgorzata

    2015-10-01

    Recent studies suggest that disturbing androgen-signaling pathways in porcine ovarian follicles may cause granulosa cell (GC) death. For this reason, we investigated which apoptotic pathway is initiated after GC exposure to an environmental antiandrogen, vinclozolin (Vnz), in vitro. Immunocytochemistry, Western blots, and fluorometric assays were used to quantify caspase-3 and -9 expression and activity. To elucidate the specific mechanism of Vnz action and toxicity, GCs were assessed for viability, cytotoxicity, and apoptotic activity using the ApoTox-Glo Triplex Assay. To further determine the mechanism of GC death induced by Vnz, we used the Apoptosis Antibody Array Kit. In response to Vnz stimulus, we found an increased level of caspase-3 protein expression (P ≤ 0.001) and an increase in caspase-3 proteolytic activity (P ≤ 0.001), confirming that Vnz is a potent proapoptotic factor. The strong immunoreaction of caspase-9 after Vnz treatment (P ≤ 0.001) suggests that intrinsic mitochondrial apoptosis pathway was activated during GC death. On the other hand, caspase-8, being a part of the extrinsic receptor pathway, was also activated (P ≤ 0.001). Therefore, it is possible that Vnz induces porcine granulosal apoptosis also through a parallel pathway. Activation of these two pathways was confirmed by the Apoptosis Antibody Array Kit. In conclusion, it is possible that the intrinsic signaling pathway may not act as an initial trigger for GC apoptosis but might contribute to the amplification and propagation of apoptotic cell death in the granulosa layer after treatment with this antiandrogen. Moreover, Vnz disturbs the physiological process of programmed cell death. Consequently, this could explain why atretic follicles are rapidly removed and suggests that normal function of the ovarian follicle may be destroyed. Copyright © 2015 Elsevier Inc. All rights reserved.

  20. MiR-9-5p promotes MSC migration by activating β-catenin signaling pathway.

    Science.gov (United States)

    Li, Xianyang; He, Lihong; Yue, Qing; Lu, Junhou; Kang, Naixin; Xu, Xiaojing; Wang, Huihui; Zhang, Huanxiang

    2017-07-01

    Mesenchymal stem cells (MSCs) have the potential to treat various tissue damages, but the very limited number of cells that migrate to the damaged region strongly restricts their therapeutic applications. Full understanding of mechanisms regulating MSC migration will help to improve their migration ability and therapeutic effects. Increasing evidence shows that microRNAs play important roles in the regulation of MSC migration. In the present study, we reported that miR-9-5p was upregulated in hepatocyte growth factor -treated MSCs and in MSCs with high migration ability. Overexpression of miR-9-5p promoted MSC migration, whereas inhibition of endogenous miR-9-5p decreased MSC migration. To elucidate the underlying mechanism, we screened the target genes of miR-9-5p and report for the first time that CK1α and GSK3β, two inhibitors of β-catenin signaling pathway, were direct targets of miR-9-5p in MSCs and that overexpression of miR-9-5p upregulated β-catenin signaling pathway. In line with these data, inhibition of β-catenin signaling pathway by FH535 decreased the miR-9-5p-promoted migration of MSCs, while activation of β-catenin signaling pathway by LiCl rescued the impaired migration of MSCs triggered by miR-9-5p inhibitor. Furthermore, the formation and distribution of focal adhesions as well as the reorganization of F-actin were affected by the expression of miR-9-5p. Collectively, these results demonstrate that miR-9-5p promotes MSC migration by upregulating β-catenin signaling pathway, shedding light on the optimization of MSCs for cell replacement therapy through manipulating the expression level of miR-9-5p. Copyright © 2017 the American Physiological Society.

  1. Crosstalk between autophagy and inflammatory signalling pathways: balancing defence and homeostasis.

    Science.gov (United States)

    Cadwell, Ken

    2016-11-01

    Autophagy has broad functions in immunity, ranging from cell-autonomous defence to coordination of complex multicellular immune responses. The successful resolution of infection and avoidance of autoimmunity necessitates efficient and timely communication between autophagy and pathways that sense the immune environment. The recent literature indicates that a variety of immune mediators induce or repress autophagy. It is also becoming increasingly clear that immune signalling cascades are subject to regulation by autophagy, and that a return to homeostasis following a robust immune response is critically dependent on this pathway. Importantly, examples of non-canonical forms of autophagy in mediating immunity are pervasive. In this article, the progress in elucidating mechanisms of crosstalk between autophagy and inflammatory signalling cascades is reviewed. Improved mechanistic understanding of the autophagy machinery offers hope for treating infectious and inflammatory diseases.

  2. The effect of aquaporin 5 overexpression on the Ras signaling pathway

    International Nuclear Information System (INIS)

    Woo, Janghee; Lee, Juna; Kim, Myoung Sook; Jang, Se Jin; Sidransky, David; Moon, Chulso

    2008-01-01

    Human aquaporin 5 (AQP5) has been shown to be overexpressed in multiple cancers, such as pancreatic cancer and colon cancer. Furthermore, it has been reported that ectopic expression of AQP5 leads to many phenotypic changes characteristic of transformation. However, the biochemical mechanism leading to transformation in AQP5-overexpressing cells has not been clearly elucidated. In this report, the overexpression of AQP5 in NIH3T3 cells demonstrated a significant effect on Ras activity and, thus, cell proliferation. Furthermore, this influence was shown to be mediated by phosphorylation of the PKA consensus site of AQP5. This is the first evidence demonstrating an association between AQP5 and a signaling pathway, namely the Ras signal transduction pathway, which may be the basis of the oncogenic properties seen in AQP-overexpressing cells

  3. Signaling pathway underlying the octopaminergic modulation of myogenic contraction in the cricket lateral oviduct.

    Science.gov (United States)

    Tamashiro, Hirotake; Yoshino, Masami

    2014-12-01

    Octopamine (OA), a biogenic monoamine, is a neurotransmitter and neuromodulator in invertebrates. Here, we report the effect of OA on the spontaneous rhythmic contractions (SRCs) of the lateral oviduct of the cricket Gryllus bimaculatus and the possible signaling pathway involved. Application of OA increased both the frequency and amplitude of SRCs in a dose-dependent manner. The effect of OA was inhibited by subsequent application of the OA receptor antagonist epinastine, indicating that the action of OA is mediated by OA receptor. To investigate the predominant signaling pathway underlying the action of OA, we first examined a possible involvement of the cAMP/cAMP-dependent protein kinase A (PKA) signaling pathway. Application of the membrane-permeable cAMP analog 8-Br-cAMP had little effect on SRCs and the effect of OA was not influenced by subsequent application of the PKA inhibitor H89, indicating that the cAMP/PKA signaling pathway is not the predominant pathway in the action of OA. Next, we examined a possible involvement of the second messenger inositol 1,4,5-trisphosphate in the action of OA. The effect of OA on SRCs was inhibited by subsequent application of the phosphoinositide-specific phospholipase C (PLC) inhibitor U73122, indicating that the PLC pathway is involved in the action of OA. The OA-induced increase in the frequency of SRCs was inhibited by pretreatment of the cell with the ryanodine receptor antagonist tetracaine but was not significantly affected by the IP3 receptor antagonist 2-aminoethoxydiphenyl borate (2-APB). On the other hand, the OA-induced increase in the amplitude of SRCs was inhibited by pretreatment of the cells with 2-APB but was not significantly affected by tetracaine. Taken together, these results suggest that the OA-induced excitatory effect on SRCs is mediated by the PLC signaling pathway: Ca2+ release from IP3 receptors may contribute to the modulation of the amplitude of SRCs, whereas Ca2+ release from ryanodine

  4. NK cell activation: distinct stimulatory pathways counterbalancing inhibitory signals.

    Science.gov (United States)

    Bakker, A B; Wu, J; Phillips, J H; Lanier, L L

    2000-01-01

    A delicate balance between positive and negative signals regulates NK cell effector function. Activation of NK cells may be initiated by the triggering of multiple adhesion or costimulatory molecules, and can be counterbalanced by inhibitory signals induced by receptors for MHC class I. A common pathway of inhibitory signaling is provided by immunoreceptor tyrosine-based inhibitory motifs (ITIMs) in the cytoplasmic domains of these receptors which mediate the recruitment of SH2 domain-bearing tyrosine phosphate-1 (SHP-1). In contrast to the extensive progress that has been made regarding the negative regulation of NK cell function, our knowledge of the signals that activate NK cells is still poor. Recent studies of the activating receptor complexes have shed new light on the induction of NK cell effector function. Several NK receptors using novel adaptors with immunoreceptor tyrosine-based activation motifs (ITAMs) and with PI 3-kinase recruiting motifs have been implicated in NK cell stimulation.

  5. Proteomics and pathway analysis identifies JNK signaling as critical for high linear energy transfer radiation-induced apoptosis in non-small lung cancer cells.

    Science.gov (United States)

    Ståhl, Sara; Fung, Eva; Adams, Christopher; Lengqvist, Johan; Mörk, Birgitta; Stenerlöw, Bo; Lewensohn, Rolf; Lehtiö, Janne; Zubarev, Roman; Viktorsson, Kristina

    2009-05-01

    During the past decade, we have witnessed an explosive increase in generation of large proteomics data sets, not least in cancer research. There is a growing need to extract and correctly interpret information from such data sets to generate biologically relevant hypotheses. A pathway search engine (PSE) has recently been developed as a novel tool intended to meet these requirements. Ionizing radiation (IR) is an anticancer treatment modality that triggers multiple signal transduction networks. In this work, we show that high linear energy transfer (LET) IR induces apoptosis in a non-small cell lung cancer cell line, U-1810, whereas low LET IR does not. PSE was applied to study changes in pathway status between high and low LET IR to find pathway candidates of importance for high LET-induced apoptosis. Such pathways are potential clinical targets, and they were further validated in vitro. We used an unsupervised shotgun proteomics approach where high resolution mass spectrometry coupled to nanoflow liquid chromatography determined the identity and relative abundance of expressed proteins. Based on the proteomics data, PSE suggested the JNK pathway (p = 6.10(-6)) as a key event in response to high LET IR. In addition, the Fas pathway was found to be activated (p = 3.10(-5)) and the p38 pathway was found to be deactivated (p = 0.001) compared with untreated cells. Antibody-based analyses confirmed that high LET IR caused an increase in phosphorylation of JNK. Moreover pharmacological inhibition of JNK blocked high LET-induced apoptotic signaling. In contrast, neither an activation of p38 nor a role for p38 in high LET IR-induced apoptotic signaling was found. We conclude that, in contrast to conventional low LET IR, high LET IR can trigger activation of the JNK pathway, which in turn is critical for induction of apoptosis in these cells. Thus PSE predictions were largely confirmed, and PSE was proven to be a useful hypothesis-generating tool.

  6. Selection of personalized patient therapy through the use of knowledge-based computational models that identify tumor-driving signal transduction pathways.

    Science.gov (United States)

    Verhaegh, Wim; van Ooijen, Henk; Inda, Márcia A; Hatzis, Pantelis; Versteeg, Rogier; Smid, Marcel; Martens, John; Foekens, John; van de Wiel, Paul; Clevers, Hans; van de Stolpe, Anja

    2014-06-01

    Increasing knowledge about signal transduction pathways as drivers of cancer growth has elicited the development of "targeted drugs," which inhibit aberrant signaling pathways. They require a companion diagnostic test that identifies the tumor-driving pathway; however, currently available tests like estrogen receptor (ER) protein expression for hormonal treatment of breast cancer do not reliably predict therapy response, at least in part because they do not adequately assess functional pathway activity. We describe a novel approach to predict signaling pathway activity based on knowledge-based Bayesian computational models, which interpret quantitative transcriptome data as the functional output of an active signaling pathway, by using expression levels of transcriptional target genes. Following calibration on only a small number of cell lines or cohorts of patient data, they provide a reliable assessment of signaling pathway activity in tumors of different tissue origin. As proof of principle, models for the canonical Wnt and ER pathways are presented, including initial clinical validation on independent datasets from various cancer types. ©2014 American Association for Cancer Research.

  7. Resveratrol and Calcium Signaling: Molecular Mechanisms and Clinical Relevance

    Directory of Open Access Journals (Sweden)

    Audrey E. McCalley

    2014-06-01

    Full Text Available Resveratrol is a naturally occurring compound contributing to cellular defense mechanisms in plants. Its use as a nutritional component and/or supplement in a number of diseases, disorders, and syndromes such as chronic diseases of the central nervous system, cancer, inflammatory diseases, diabetes, and cardiovascular diseases has prompted great interest in the underlying molecular mechanisms of action. The present review focuses on resveratrol, specifically its isomer trans-resveratrol, and its effects on intracellular calcium signaling mechanisms. As resveratrol’s mechanisms of action are likely pleiotropic, its effects and interactions with key signaling proteins controlling cellular calcium homeostasis are reviewed and discussed. The clinical relevance of resveratrol’s actions on excitable cells, transformed or cancer cells, immune cells and retinal pigment epithelial cells are contrasted with a review of the molecular mechanisms affecting calcium signaling proteins on the plasma membrane, cytoplasm, endoplasmic reticulum, and mitochondria. The present review emphasizes the correlation between molecular mechanisms of action that have recently been identified for resveratrol and their clinical implications.

  8. Signaling transduction pathways involved in basophil adhesion and histamine release

    DEFF Research Database (Denmark)

    Sha, Quan; Poulsen, Lars K.; Gerwien, Jens

    2006-01-01

    Little is known about basophil with respect to the different signaling transduction pathways involved in spontaneous, cytokine or anti-IgE induced adhesion and how this compares to IgE-dependent and IgE-independent mediator secretion. The purpose of the present study was to investigate the roles...... of beta1 and beta2 integrins in basophil adhesion as well as hosphatidylinositol 3-kinase (PI3K), src-kinases and extracellular signal regulated kinase (ERK) 1/2 in basophil adhesion and histamine release (HR)....

  9. MAPKs are essential upstream signaling pathways in proteolytic cartilage degradation--divergence in pathways leading to aggrecanase and MMP-mediated articular cartilage degradation

    DEFF Research Database (Denmark)

    Sondergaard, B-C; Schultz, N; Madsen, S H

    2010-01-01

    Matrix metalloproteinases (MMPs) and aggrecanases are essential players in cartilage degradation. However, the signaling pathways that results in MMP and/or aggrecanase synthesis and activation are not well understood. We investigated the molecular events leading to MMP- and aggrecanase-mediated ......Matrix metalloproteinases (MMPs) and aggrecanases are essential players in cartilage degradation. However, the signaling pathways that results in MMP and/or aggrecanase synthesis and activation are not well understood. We investigated the molecular events leading to MMP- and aggrecanase......-mediated cartilage degradation....

  10. The DAF-7/TGF-β signaling pathway regulates abundance of the C. elegans glutamate receptor GLR-1

    Science.gov (United States)

    McGehee, Annette M.; Moss, Benjamin J.; Juo, Peter

    2015-01-01

    Transforming growth factor-β (TGF-β) family signaling pathways have roles in both neuronal development and the regulation of synaptic function. Here we identify a novel role for the C. elegans DAF-7/TGF-β signaling pathway in the regulation of the AMPA-type glutamate receptor GLR-1. We found that the abundance of GLR-1 increases at synapses in the ventral nerve cord (VNC) of animals with loss-of-function mutations in multiple DAF-7/TGF-β pathway components including the TGF-β ligand DAF-7, the type I receptor DAF-1, and the Smads DAF-8 and DAF-14. The GLR-1 defect can be rescued by expression of daf-8 specifically in glr-1-expressing interneurons. The effect on GLR-1 was specific for the DAF-7 pathway because mutations in the DBL-1/TGF-β family pathway did not increase GLR-1 levels in the VNC. Immunoblot analysis indicates that total levels of GLR-1 protein are increased in neurons of DAF-7/TGF-β pathway mutants. The increased abundance of GLR-1 in the VNC of daf-7 pathway mutants is dependent on the transcriptional regulator DAF-3/Smad suggesting that DAF-3-dependent transcription controls GLR-1 levels. Furthermore, we found that glr-1 transcription is increased in daf-7 mutants based on a glr-1 transcriptional reporter. Together these results suggest that the DAF-7/TGF-β signaling pathway functions in neurons and negatively regulates the abundance of GLR-1, in part, by controlling transcription of the receptor itself. Finally, DAF-7/TGF-β pathway mutants exhibit changes in spontaneous locomotion that are dependent on endogenous GLR-1 and consistent with increased glutamatergic signaling. These results reveal a novel mechanism by which TGF-β signaling functions in the nervous system to regulate behavior. PMID:26054666

  11. The DAF-7/TGF-β signaling pathway regulates abundance of the Caenorhabditis elegans glutamate receptor GLR-1.

    Science.gov (United States)

    McGehee, Annette M; Moss, Benjamin J; Juo, Peter

    2015-07-01

    Transforming growth factor-β (TGF-β) family signaling pathways have roles in both neuronal development and the regulation of synaptic function. Here we identify a novel role for the Caenorhabditis elegans DAF-7/TGF-β signaling pathway in the regulation of the AMPA-type glutamate receptor GLR-1. We found that the abundance of GLR-1 increases at synapses in the ventral nerve cord (VNC) of animals with loss-of-function mutations in multiple DAF-7/TGF-β pathway components including the TGF-β ligand DAF-7, the type I receptor DAF-1, and the Smads DAF-8 and DAF-14. The GLR-1 defect can be rescued by expression of daf-8 specifically in glr-1-expressing interneurons. The effect on GLR-1 was specific for the DAF-7 pathway because mutations in the DBL-1/TGF-β family pathway did not increase GLR-1 levels in the VNC. Immunoblot analysis indicates that total levels of GLR-1 protein are increased in neurons of DAF-7/TGF-β pathway mutants. The increased abundance of GLR-1 in the VNC of daf-7 pathway mutants is dependent on the transcriptional regulator DAF-3/Smad suggesting that DAF-3-dependent transcription controls GLR-1 levels. Furthermore, we found that glr-1 transcription is increased in daf-7 mutants based on a glr-1 transcriptional reporter. Together these results suggest that the DAF-7/TGF-β signaling pathway functions in neurons and negatively regulates the abundance of GLR-1, in part, by controlling transcription of the receptor itself. Finally, DAF-7/TGF-β pathway mutants exhibit changes in spontaneous locomotion that are dependent on endogenous GLR-1 and consistent with increased glutamatergic signaling. These results reveal a novel mechanism by which TGF-β signaling functions in the nervous system to regulate behavior. Copyright © 2015 Elsevier Inc. All rights reserved.

  12. Signal transduction pathways involved in mechanotransduction in bone cells

    International Nuclear Information System (INIS)

    Liedert, Astrid; Kaspar, Daniela; Blakytny, Robert; Claes, Lutz; Ignatius, Anita

    2006-01-01

    Several in vivo and in vitro studies with different loading regimens showed that mechanical stimuli have an influence on proliferation and differentiation of bone cells. Prerequisite for this influence is the transduction of mechanical signals into the cell, a phenomenon that is termed mechanotransduction, which is essential for the maintenance of skeletal homeostasis in adults. Mechanoreceptors, such as the integrins, cadherins, and stretch-activated Ca 2+ channels, together with various signal transduction pathways, are involved in the mechanotransduction process that ultimately regulates gene expression in the nucleus. Mechanotransduction itself is considered to be regulated by hormones, the extracellular matrix of the osteoblastic cells and the mode of the mechanical stimulus

  13. MicroRNA-200a suppresses the Wnt/β-catenin signaling pathway by interacting with β-catenin.

    Science.gov (United States)

    Su, Juan; Zhang, Anling; Shi, Zhendong; Ma, Feifei; Pu, Peiyu; Wang, Tao; Zhang, Jie; Kang, Chunsheng; Zhang, Qingyu

    2012-04-01

    The Wnt/β-catenin signaling pathway is crucial for human organ development and is involved in tumor progression of many cancers. Accumulating evidence suggests that the expression of β-catenin is, in part, regulated by specific microRNAs (miRNAs). The purpose of this study was to determine the expression of a recently identified epithelial to mesenchymal transition (EMT)-associated tumor suppressor microRNA (miR)-200a, in cancer cells. We also aimed to identify specific miR-200a target genes and to investigate the antitumor effects of miR-200a on the Wnt/β-catenin signaling pathway. We employed TOP/FOP flash luciferase assays to identify the effect of miR-200a on the Wnt/β-catenin pathway and we confirmed our observations using fluorescence microscopy. To determine target genes of miR-200a, a 3' untranslated region (3' UTR) luciferase assay was performed. Cell viability, invasion and wound healing assays were carried out for functional analysis after miRNA transfection. We further investigated the role of miR-200a in EMT by Western blot analysis. We found fluctuation in the expression of miR-200a that was accompanied by changes in the expression of members of the Wnt/β-catenin signaling pathway. We also determined that miR-200a can directly interact with the 3' UTR of CTNNB1 (the gene that encodes β-catenin) to suppress Wnt/β-catenin signaling. MiR-200a could also influence the biological activities of SGC790 and U251 cells. Our results demonstrate that miR-200a is a new tumor suppressor that can regulate the activity of the Wnt/β-catenin signaling pathway via two mechanisms. MiR-200a is a candidate target for tumor treatment via its regulation of the Wnt/β-catenin signaling pathway.

  14. Pathways to Advancing Aging Policy-Relevant Research in Academic Settings.

    Science.gov (United States)

    Kietzman, Kathryn G; Troy, Lisa M; Green, Carmen R; Wallace, Steven P

    2016-01-01

    Policy-level changes have a significant influence on the health and well-being of aging populations. Yet there is often a gap between scientific knowledge and policy action. Although previous research has identified barriers and facilitators to effective knowledge translation, little attention has been given to the role of academic institutions in knowledge generation. This exploratory focus group study examines barriers and pathways to developing and maintaining an aging policy-relevant research agenda in academic settings, and additional challenges associated with minority group membership in this pursuit. Participants were personally committed to conducting policy-relevant research despite institutional barriers such as fewer funding opportunities and less value attributed to their research, particularly in the context of tenure and promotion. Although many viewed their research as an opportunity to make a difference, especially for underserved older adult populations, a number of minority group participants expressed that their policy research interests were marginalized. Participants offer individual and institutional-level strategies for addressing barriers, including collaborating with community members and colleagues and engaging mentors within and outside of their academic institutions. Reframing the valuation of policy research through the diversification of funding and publishing opportunities can better support scholars engaged in aging policy-relevant research.

  15. Changes of TSPO-mediated mitophagy signaling pathway in learned helplessness mice.

    Science.gov (United States)

    Li, Dongmei; Zheng, Ji; Wang, Mingyang; Feng, Lu; Ren, Zhili; Liu, Yanyong; Yang, Nan; Zuo, Pingping

    2016-11-30

    Low response rate was witnessed with the present monoaminergic based antidepressants, urging a need for new therapeutic target identification. Accumulated evidences strongly suggest that mitochondrial deficit is implicated in major depression and 18kDa translocator protein (TSPO) plays an important role in regulating mitochondrial function. However the changes of TSPO and TSPO mediated mitophagy pathway in the depressive brain is unclear. In present study, a well validated animal model of depression, learned helplessness (LH), was employed to investigate the relevant changes. Significant behavioral changes were observed in the LH mice. Results showed that TSPO and other mitophagy related proteins, such as VDAC1, Pink1 and Beclin1 were significantly decreased by LH challenge. Moreover, KIFC2, relevant to the mitochondrial transport and Snap25, relevant to neurotransmitter vesicle release, were also obviously down-regulated in the LH mice, which further rendered supportive evidence for the existing mitochondrial dysfunction in LH mice. Present results demonstrated that LH induced depressive symptoms and affected TSPO-mediated mitophagy pathway, indicating a potential target candidate for depression treatment. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

  16. Deficient brain insulin signalling pathway in Alzheimer’s disease and diabetes

    Science.gov (United States)

    Liu, Ying; Liu, Fei; Grundke-Iqbal, Inge; Iqbal, Khalid; Gong, Cheng-Xin

    2015-01-01

    Brain glucose metabolism is impaired in Alzheimer’s disease (AD), the most common form of dementia. Type 2 diabetes mellitus (T2DM) is reported to increase the risk for dementia, including AD, but the underlying mechanism is not understood. Here, we investigated the brain insulin–PI3K–AKT signalling pathway in the autopsied frontal cortices from nine AD, 10 T2DM, eight T2DM–AD and seven control cases. We found decreases in the levels and activities of several components of the insulin–PI3K–AKT signalling pathway in AD and T2DM cases. The deficiency of insulin–PI3K–AKT signalling was more severe in individuals with both T2DM and AD (T2DM–AD). This decrease in insulin–PI3K–AKT signalling could lead to activation of glycogen synthase kinase-3β, the major tau kinase. The levels and the activation of the insulin–PI3K–AKT signalling components correlated negatively with the level of tau phosphorylation and positively with protein O-GlcNAcylation, suggesting that impaired insulin–PI3K–AKT signalling might contribute to neurodegeneration in AD through down-regulation of O-GlcNAcylation and the consequent promotion of abnormal tau hyperphosphorylation and neurodegeneration. The decrease in brain insulin–PI3K–AKT signalling also correlated with the activation of calpain I in the brain, suggesting that the decrease might be caused by calpain over-activation. Our findings provide novel insight into the molecular mechanism by which type 2 diabetes mellitus increases the risk for developing cognitive impairment and dementia in Alzheimer’s disease. PMID:21598254

  17. Using answer set programming to integrate RNA expression with signalling pathway information to infer how mutations affect ageing.

    Science.gov (United States)

    Papatheodorou, Irene; Ziehm, Matthias; Wieser, Daniela; Alic, Nazif; Partridge, Linda; Thornton, Janet M

    2012-01-01

    A challenge of systems biology is to integrate incomplete knowledge on pathways with existing experimental data sets and relate these to measured phenotypes. Research on ageing often generates such incomplete data, creating difficulties in integrating RNA expression with information about biological processes and the phenotypes of ageing, including longevity. Here, we develop a logic-based method that employs Answer Set Programming, and use it to infer signalling effects of genetic perturbations, based on a model of the insulin signalling pathway. We apply our method to RNA expression data from Drosophila mutants in the insulin pathway that alter lifespan, in a foxo dependent fashion. We use this information to deduce how the pathway influences lifespan in the mutant animals. We also develop a method for inferring the largest common sub-paths within each of our signalling predictions. Our comparisons reveal consistent homeostatic mechanisms across both long- and short-lived mutants. The transcriptional changes observed in each mutation usually provide negative feedback to signalling predicted for that mutation. We also identify an S6K-mediated feedback in two long-lived mutants that suggests a crosstalk between these pathways in mutants of the insulin pathway, in vivo. By formulating the problem as a logic-based theory in a qualitative fashion, we are able to use the efficient search facilities of Answer Set Programming, allowing us to explore larger pathways, combine molecular changes with pathways and phenotype and infer effects on signalling in in vivo, whole-organism, mutants, where direct signalling stimulation assays are difficult to perform. Our methods are available in the web-service NetEffects: http://www.ebi.ac.uk/thornton-srv/software/NetEffects.

  18. Domain altering SNPs in the human proteome and their impact on signaling pathways.

    Directory of Open Access Journals (Sweden)

    Yichuan Liu

    Full Text Available Single nucleotide polymorphisms (SNPs constitute an important mode of genetic variations observed in the human genome. A small fraction of SNPs, about four thousand out of the ten million, has been associated with genetic disorders and complex diseases. The present study focuses on SNPs that fall on protein domains, 3D structures that facilitate connectivity of proteins in cell signaling and metabolic pathways. We scanned the human proteome using the PROSITE web tool and identified proteins with SNP containing domains. We showed that SNPs that fall on protein domains are highly statistically enriched among SNPs linked to hereditary disorders and complex diseases. Proteins whose domains are dramatically altered by the presence of an SNP are even more likely to be present among proteins linked to hereditary disorders. Proteins with domain-altering SNPs comprise highly connected nodes in cellular pathways such as the focal adhesion, the axon guidance pathway and the autoimmune disease pathways. Statistical enrichment of domain/motif signatures in interacting protein pairs indicates extensive loss of connectivity of cell signaling pathways due to domain-altering SNPs, potentially leading to hereditary disorders.

  19. The Drosophila rolled locus encodes a MAP kinase required in the sevenless signal transduction pathway.

    OpenAIRE

    Biggs, W H; Zavitz, K H; Dickson, B; van der Straten, A; Brunner, D; Hafen, E; Zipursky, S L

    1994-01-01

    Mitogen-activated protein (MAP) kinases have been proposed to play a critical role in receptor tyrosine kinase (RTK)-mediated signal transduction pathways. Although genetic and biochemical studies of RTK pathways in Caenorhabditis elegans, Drosophila melanogaster and mammals have revealed remarkable similarities, a genetic requirement for MAP kinases in RTK signaling has not been established. During retinal development in Drosophila, the sevenless (Sev) RTK is required for development of the ...

  20. EGF signalling pathway regulates colon cancer stem cell proliferation and apoptosis.

    Science.gov (United States)

    Feng, Y; Dai, X; Li, X; Wang, H; Liu, J; Zhang, J; Du, Y; Xia, L

    2012-10-01

    Cancer stem cells (CSCs) compose a subpopulation of cells within a tumour that can self-renew and proliferate. Growth factors such as epidermal growth factor (EGF) and basic fibroblast growth factor (b-FGF) promote cancer stem cell proliferation in many solid tumours. This study assesses whether EGF, bFGF and IGF signalling pathways are essential for colon CSC proliferation and self-renewal. Colon CSCs were cultured in serum-free medium (SFM) with one of the following growth factors: EGF, bFGF or IGF. Characteristics of CSC gene expression were evaluated by real time PCR. Tumourigenicity of CSCs was determined using a xenograft model in vivo. Effects of EGF receptor inhibitors, Gefitinib and PD153035, on CSC proliferation, apoptosis and signalling were evaluated using fluorescence-activated cell sorting and western blotting. Colon cancer cell HCT116 transformed to CSCs in SFM. Compared to other growth factors, EGF was essential to support proliferation of CSCs that expressed higher levels of progenitor genes (Musashi-1, LGR5) and lower levels of differential genes (CK20). CSCs promoted more rapid tumour growth than regular cancer cells in xenografts. EGFR inhibitors suppressed proliferation and induced apoptosis of CSCs by inhibiting autophosphorylation of EGFR and downstream signalling proteins, such as Akt kinase, extracellular signal-regulated kinase 1/2 (ERK 1/2). This study indicates that EGF signalling was essential for formation and maintenance of colon CSCs. Inhibition of the EGF signalling pathway may provide a useful strategy for treatment of colon cancer. © 2012 Blackwell Publishing Ltd.

  1. Distinct Calcium Signaling Pathways Regulate Calmodulin Gene Expression in Tobacco1

    Science.gov (United States)

    van der Luit, Arnold H.; Olivari, Claudio; Haley, Ann; Knight, Marc R.; Trewavas, Anthony J.

    1999-01-01

    Cold shock and wind stimuli initiate Ca2+ transients in transgenic tobacco (Nicotiana plumbaginifolia) seedlings (named MAQ 2.4) containing cytoplasmic aequorin. To investigate whether these stimuli initiate Ca2+ pathways that are spatially distinct, stress-induced nuclear and cytoplasmic Ca2+ transients and the expression of a stress-induced calmodulin gene were compared. Tobacco seedlings were transformed with a construct that encodes a fusion protein between nucleoplasmin (a major oocyte nuclear protein) and aequorin. Immunocytochemical evidence indicated targeting of the fusion protein to the nucleus in these plants, which were named MAQ 7.11. Comparison between MAQ 7.11 and MAQ 2.4 seedlings confirmed that wind stimuli and cold shock invoke separate Ca2+ signaling pathways. Partial cDNAs encoding two tobacco calmodulin genes, NpCaM-1 and NpCaM-2, were identified and shown to have distinct nucleotide sequences that encode identical polypeptides. Expression of NpCaM-1, but not NpCaM-2, responded to wind and cold shock stimulation. Comparison of the Ca2+ dynamics with NpCaM-1 expression after stimulation suggested that wind-induced NpCaM-1 expression is regulated by a Ca2+ signaling pathway operational predominantly in the nucleus. In contrast, expression of NpCaM-1 in response to cold shock is regulated by a pathway operational predominantly in the cytoplasm. PMID:10557218

  2. A Wnt1 regulated Frizzled-1/β-Catenin signaling pathway as a candidate regulatory circuit controlling mesencephalic dopaminergic neuron-astrocyte crosstalk: Therapeutical relevance for neuron survival and neuroprotection

    Directory of Open Access Journals (Sweden)

    Pluchino Stefano

    2011-07-01

    Full Text Available Abstract Background Dopamine-synthesizing (dopaminergic, DA neurons in the ventral midbrain (VM constitute a pivotal neuronal population controlling motor behaviors, cognitive and affective brain functions, which generation critically relies on the activation of Wingless-type MMTV integration site (Wnt/β-catenin pathway in their progenitors. In Parkinson's disease, DA cell bodies within the substantia nigra pars compacta (SNpc progressively degenerate, with causes and mechanisms poorly understood. Emerging evidence suggests that Wnt signaling via Frizzled (Fzd receptors may play a role in different degenerative states, but little is known about Wnt signaling in the adult midbrain. Using in vitro and in vivo model systems of DA degeneration, along with functional studies in both intact and SN lesioned mice, we herein highlight an intrinsic Wnt1/Fzd-1/β-catenin tone critically contributing to the survival and protection of adult midbrain DA neurons. Results In vitro experiments identifie Fzd-1 receptor expression at a mRNA and protein levels in dopamine transporter (DAT expressing neurons, and demonstrate the ability of exogenous Wnt1 to exert robust neuroprotective effects against Caspase-3 activation, the loss of tyrosine hydroxylase-positive (TH+ neurons and [3H] dopamine uptake induced by different DA-specific insults, including serum and growth factor deprivation, 6-hydroxydopamine and MPTP/MPP+. Co-culture of DA neurons with midbrain astrocytes phenocopies Wnt1 neuroprotective effects, whereas RNA interference-mediated knockdown of Wnt1 in midbrain astrocytes markedly reduces astrocyte-induced TH+ neuroprotection. Likewise, silencing β-catenin mRNA or knocking down Fzd-1 receptor expression in mesencephalic neurons counteract astrocyte-induced TH+ neuroprotection. In vivo experiments document Fzd-1 co-localization with TH+ neurons within the intact SNpc and blockade of Fzd/β-catenin signaling by unilateral infusion of a Fzd

  3. The signaling pathways by which the Fas/FasL system accelerates oocyte aging.

    Science.gov (United States)

    Zhu, Jiang; Lin, Fei-Hu; Zhang, Jie; Lin, Juan; Li, Hong; Li, You-Wei; Tan, Xiu-Wen; Tan, Jing-He

    2016-02-01

    In spite of great efforts, the mechanisms for postovulatory oocyte aging are not fully understood. Although our previous work showed that the FasL/Fas signaling facilitated oocyte aging, the intra-oocyte signaling pathways are unknown. Furthermore, the mechanisms by which oxidative stress facilitates oocyte aging and the causal relationship between Ca2+ rises and caspase-3 activation and between the cell cycle and apoptosis during oocyte aging need detailed investigations. Our aim was to address these issues by studying the intra-oocyte signaling pathways for Fas/FasL to accelerate oocyte aging. The results indicated that sFasL released by cumulus cells activated Fas on the oocyte by increasing reactive oxygen species via activating NADPH oxidase. The activated Fas triggered Ca2+ release from the endoplasmic reticulum by activating phospholipase C-γ pathway and cytochrome c pathway. The cytoplasmic Ca2+ rises activated calcium/calmodulin-dependent protein kinase II (CaMKII) and caspase-3. While activated CaMKII increased oocyte susceptibility to activation by inactivating maturation-promoting factor (MPF) through cyclin B degradation, the activated caspase-3 facilitated further Ca2+releasing that activates more caspase-3 leading to oocyte fragmentation. Furthermore, caspase-3 activation and fragmentation were prevented in oocytes with a high MPF activity, suggesting that an oocyte must be in interphase to undergo apoptosis.

  4. Epidermal wound repair is regulated by the planar cell polarity signaling pathway.

    Science.gov (United States)

    Caddy, Jacinta; Wilanowski, Tomasz; Darido, Charbel; Dworkin, Sebastian; Ting, Stephen B; Zhao, Quan; Rank, Gerhard; Auden, Alana; Srivastava, Seema; Papenfuss, Tony A; Murdoch, Jennifer N; Humbert, Patrick O; Parekh, Vishwas; Boulos, Nidal; Weber, Thomas; Zuo, Jian; Cunningham, John M; Jane, Stephen M

    2010-07-20

    The mammalian PCP pathway regulates diverse developmental processes requiring coordinated cellular movement, including neural tube closure and cochlear stereociliary orientation. Here, we show that epidermal wound repair is regulated by PCP signaling. Mice carrying mutant alleles of PCP genes Vangl2, Celsr1, PTK7, and Scrb1, and the transcription factor Grhl3, interact genetically, exhibiting failed wound healing, neural tube defects, and disordered cochlear polarity. Using phylogenetic analysis, ChIP, and gene expression in Grhl3(-)(/-) mice, we identified RhoGEF19, a homolog of a RhoA activator involved in PCP signaling in Xenopus, as a direct target of GRHL3. Knockdown of Grhl3 or RhoGEF19 in keratinocytes induced defects in actin polymerization, cellular polarity, and wound healing, and re-expression of RhoGEF19 rescued these defects in Grhl3-kd cells. These results define a role for Grhl3 in PCP signaling and broadly implicate this pathway in epidermal repair. (c) 2010 Elsevier Inc. All rights reserved.

  5. Neuroprotective effect of rapamycin on spinal cord injury via activation of the Wnt/β-catenin signaling pathway

    Directory of Open Access Journals (Sweden)

    Kai Gao

    2015-01-01

    Full Text Available The Wnt/β-catenin signaling pathway plays a crucial role in neural development, axonal guidance, neuropathic pain remission and neuronal survival. In this study, we initially examined the effect of rapamycin on the Wnt/β-catenin signaling pathway after spinal cord injury, by intraperitoneally injecting spinal cord injured rats with rapamycin over 2 days. Western blot analysis and immunofluorescence staining were used to detect the expression levels of β-catenin protein, ca-spase-3 protein and brain-derived neurotrophic factor protein, components of the Wnt/β-catenin signaling pathway. Rapamycin increased the levels of β-catenin and brain-derived neurotrophic factor in the injured spinal cord, improved the pathological morphology at the injury site, reduced the loss of motor neurons, and promoted motor functional recovery in rats after spinal cord injury. Our experimental findings suggest that the neuroprotective effect of rapamycin intervention is mediated through activation of the Wnt/β-catenin signaling pathway after spinal cord injury.

  6. Improved Protein Arrays for Quantitative Systems Analysis of the Dynamics of Signaling Pathway Interactions

    Energy Technology Data Exchange (ETDEWEB)

    Yang, Chin-Rang [National Inst. of Health (NIH), Bethesda, MD (United States). National Heart, Lung and Blood Inst.

    2013-12-11

    Astronauts and workers in nuclear plants who repeatedly exposed to low doses of ionizing radiation (IR, <10 cGy) are likely to incur specific changes in signal transduction and gene expression in various tissues of their body. Remarkable advances in high throughput genomics and proteomics technologies enable researchers to broaden their focus from examining single gene/protein kinetics to better understanding global gene/protein expression profiling and biological pathway analyses, namely Systems Biology. An ultimate goal of systems biology is to develop dynamic mathematical models of interacting biological systems capable of simulating living systems in a computer. This Glue Grant is to complement Dr. Boothman’s existing DOE grant (No. DE-FG02-06ER64186) entitled “The IGF1/IGF-1R-MAPK-Secretory Clusterin (sCLU) Pathway: Mediator of a Low Dose IR-Inducible Bystander Effect” to develop sensitive and quantitative proteomic technology that suitable for low dose radiobiology researches. An improved version of quantitative protein array platform utilizing linear Quantum dot signaling for systematically measuring protein levels and phosphorylation states for systems biology modeling is presented. The signals are amplified by a confocal laser Quantum dot scanner resulting in ~1000-fold more sensitivity than traditional Western blots and show the good linearity that is impossible for the signals of HRP-amplification. Therefore this improved protein array technology is suitable to detect weak responses of low dose radiation. Software is developed to facilitate the quantitative readout of signaling network activities. Kinetics of EGFRvIII mutant signaling was analyzed to quantify cross-talks between EGFR and other signaling pathways.

  7. NAViGaTing the micronome--using multiple microRNA prediction databases to identify signalling pathway-associated microRNAs.

    Directory of Open Access Journals (Sweden)

    Elize A Shirdel

    2011-02-01

    Full Text Available MicroRNAs are a class of small RNAs known to regulate gene expression at the transcript level, the protein level, or both. Since microRNA binding is sequence-based but possibly structure-specific, work in this area has resulted in multiple databases storing predicted microRNA:target relationships computed using diverse algorithms. We integrate prediction databases, compare predictions to in vitro data, and use cross-database predictions to model the microRNA:transcript interactome--referred to as the micronome--to study microRNA involvement in well-known signalling pathways as well as associations with disease. We make this data freely available with a flexible user interface as our microRNA Data Integration Portal--mirDIP (http://ophid.utoronto.ca/mirDIP.mirDIP integrates prediction databases to elucidate accurate microRNA:target relationships. Using NAViGaTOR to produce interaction networks implicating microRNAs in literature-based, KEGG-based and Reactome-based pathways, we find these signalling pathway networks have significantly more microRNA involvement compared to chance (p<0.05, suggesting microRNAs co-target many genes in a given pathway. Further examination of the micronome shows two distinct classes of microRNAs; universe microRNAs, which are involved in many signalling pathways; and intra-pathway microRNAs, which target multiple genes within one signalling pathway. We find universe microRNAs to have more targets (p<0.0001, to be more studied (p<0.0002, and to have higher degree in the KEGG cancer pathway (p<0.0001, compared to intra-pathway microRNAs.Our pathway-based analysis of mirDIP data suggests microRNAs are involved in intra-pathway signalling. We identify two distinct classes of microRNAs, suggesting a hierarchical organization of microRNAs co-targeting genes both within and between pathways, and implying differential involvement of universe and intra-pathway microRNAs at the disease level.

  8. MicroRNA-gene signaling pathways in pancreatic cancer

    Directory of Open Access Journals (Sweden)

    Alexandra Drakaki

    2013-10-01

    Full Text Available Pancreatic cancer is the fourth most frequent cause of cancer-related deaths and is characterized by early metastasis and pronounced resistance to chemotherapy and radiation therapy. Despite extensive esearch efforts, there is not any substantial progress regarding the identification of novel drugs against pancreatic cancer. Although the introduction of the chemotherapeutic agent gemcitabine improved clinical response, the prognosis of these patients remained extremely poor with a 5-year survival rate of 3-5%. Thus, the identification of the novel molecular pathways involved in pancreatic oncogenesis and the development of new and potent therapeutic options are highly desirable. Here, we describe how microRNAs control signaling pathways that are frequently deregulated during pancreatic oncogenesis. In addition, we provide evidence that microRNAs could be potentially used as novel pancreatic cancer therapeutics through reversal of chemotherapy and radiotherapy resistance or regulation of essential molecular pathways. Further studies should integrate the deregulated genes and microRNAs into molecular networks in order to identify the central regulators of pancreatic oncogenesis. Targeting these central regulators could lead to the development of novel targeted therapeutic approaches for pancreatic cancer patients.

  9. Interleukin-2 signaling pathway analysis by quantitative phosphoproteomics

    DEFF Research Database (Denmark)

    Osinalde, Nerea; Moss, Helle; Arrizabalaga, Onetsine

    2011-01-01

    among which 79 were found with increased abundance in the tyrosine-phosphorylated complexes, including several previously not reported IL-2 downstream effectors. Combinatorial site-specific phosphoproteomic analysis resulted in identification of 99 phosphorylated sites mapping to the identified proteins...... with increased abundance in the tyrosine-phosphorylated complexes, of which 34 were not previously described. In addition, chemical inhibition of the identified IL-2-mediated JAK, PI3K and MAPK signaling pathways, resulted in distinct alteration on the IL-2 dependent proliferation....

  10. Failure of signal transduction pathway of DNA damage in hereditary microcephaly

    International Nuclear Information System (INIS)

    Miyamoto, Tatsuo; Matsuura, Shinya

    2009-01-01

    Mechanisms underlying the brain size determination are considered from an aspect of DNA-damage signaling recently revealed by studies on hereditary microcephaly (M), in relation to the radiation-induced M. International Commission of Radiological Protection (ICRP) assesses the risk of M by in utero exposure as 40%/Sv, the threshold dose is about 0.2 Gy (deterministic effect), A-bomb M is conceived to be due to the exposure at 8-5 weeks of gestation, and M is induced by radiation at 10 days after fertilization in the mouse. Recent studies on causing genes of M have revealed its particular connection with signaling pathways: in ataxia-telangiectasia (AT), genes of ATM; in Seckel syndrome, of ATR (AT and Rad3-related) and pericentrin (PCNT); Nijmegen syndrome (NBS), of NBS1; NBS-like disease, of Rad50 and Mre11; AT-like disease, of Mre11; Lig4 syndrome, of Lig4; immunodeficiency combined with M, of XLF; primary M, of MCPH1, ASPM, CdkRap2, CENP-J and STIL. Single and double strand breaks of DNA respectively activate the signaling pathway of ATR where PCNT and MCPH1 participate, and pathway of ATM where NBS1, Mre11 and Rad50 do. PCNT is a major protein, pericentrin, composing the centrosome, of which defect results in the Seckel disease with spindle dysfunction. At present, M can be thus said to be of the cellular common features of failure of ATM/ATR signaling and of dysfunction of centrosome. As well, ASPM gene expression is recently reported to be suppressed by radiation. Thus future studies on M will spread to wider biological field of cell and development as well as radiation and inheritance. (K.T.)

  11. Yeast signaling pathways in the oxidative stress response

    Energy Technology Data Exchange (ETDEWEB)

    Ikner, Aminah [Section of Microbiology, Division of Biological Sciences, University of California, Davis, CA 95616 (United States); Shiozaki, Kazuhiro [Section of Microbiology, Division of Biological Sciences, University of California, Davis, CA 95616 (United States)]. E-mail: kshiozaki@ucdavis.edu

    2005-01-06

    Oxidative stress that generates the reactive oxygen species (ROS) is one of the major causes of DNA damage and mutations. The 'DNA damage checkpoint' that arrests cell cycle and repairs damaged DNA has been a focus of recent studies, and the genetically amenable model systems provided by yeasts have been playing a leading role in the eukaryotic checkpoint research. However, means to eliminate ROS are likely to be as important as the DNA repair mechanisms in order to suppress mutations in the chromosomal DNA, and yeasts also serve as excellent models to understand how eukaryotes combat oxidative stress. In this article, we present an overview of the signaling pathways that sense oxidative stress and induce expression of various anti-oxidant genes in the budding yeast Saccharomyces cerevisiae, the fission yeast Schizosaccharomyces pombe and the pathogenic yeast Candida albicans. Three conserved signaling modules have been identified in the oxidative stress response of these diverse yeast species: the stress-responsive MAP kinase cascade, the multistep phosphorelay and the AP-1-like transcription factor. The structure and function of these signaling modules are discussed.

  12. Yeast signaling pathways in the oxidative stress response

    International Nuclear Information System (INIS)

    Ikner, Aminah; Shiozaki, Kazuhiro

    2005-01-01

    Oxidative stress that generates the reactive oxygen species (ROS) is one of the major causes of DNA damage and mutations. The 'DNA damage checkpoint' that arrests cell cycle and repairs damaged DNA has been a focus of recent studies, and the genetically amenable model systems provided by yeasts have been playing a leading role in the eukaryotic checkpoint research. However, means to eliminate ROS are likely to be as important as the DNA repair mechanisms in order to suppress mutations in the chromosomal DNA, and yeasts also serve as excellent models to understand how eukaryotes combat oxidative stress. In this article, we present an overview of the signaling pathways that sense oxidative stress and induce expression of various anti-oxidant genes in the budding yeast Saccharomyces cerevisiae, the fission yeast Schizosaccharomyces pombe and the pathogenic yeast Candida albicans. Three conserved signaling modules have been identified in the oxidative stress response of these diverse yeast species: the stress-responsive MAP kinase cascade, the multistep phosphorelay and the AP-1-like transcription factor. The structure and function of these signaling modules are discussed

  13. Molecular pathway profiling of T lymphocyte signal transduction pathways; Th1 and Th2 genomic fingerprints are defined by TCR and CD28-mediated signaling

    NARCIS (Netherlands)

    Smeets, Ruben L.; Fleuren, Wilco W. M.; He, Xuehui; Vink, Paul M.; Wijnands, Frank; Gorecka, Monika; Klop, Henri; Bauerschmidt, Sussane; Garritsen, Anja; Koenen, Hans J. P. M.; Joosten, Irma; Boots, Annemieke M. H.; Alkema, Wynand

    2012-01-01

    Background: T lymphocytes are orchestrators of adaptive immunity. Naive T cells may differentiate into Th1, Th2, Th17 or iTreg phenotypes, depending on environmental co-stimulatory signals. To identify genes and pathways involved in differentiation of Jurkat T cells towards Th1 and Th2 subtypes we

  14. Molecular pathway profiling of T lymphocyte signal transduction pathways; Th1 and Th2 genomic fingerprints are defined by TCR and CD28-mediated signaling.

    NARCIS (Netherlands)

    Smeets, R.L.; Fleuren, W.W.M.; He, X.; Vink, P.M.; Wijnands, F.; Gorecka, M.; Klop, H.; Bauerschmidt, S.; Garritsen, A.; Koenen, H.J.P.M.; Joosten, I.; Boots, A.M.H.; Alkema, W.

    2012-01-01

    BACKGROUND: T lymphocytes are orchestrators of adaptive immunity. Naive T cells may differentiate into Th1, Th2, Th17 or iTreg phenotypes, depending on environmental co-stimulatory signals. To identify genes and pathways involved in differentiation of Jurkat T cells towards Th1 and Th2 subtypes we

  15. Possible involvement of the JAK/STAT signaling pathway in N-acetylcysteine-mediated antidepressant-like effects

    OpenAIRE

    Al-Samhari, Marwa M; Al-Rasheed, Nouf M; Al-Rejaie, Salim; Al-Rasheed, Nawal M; Hasan, Iman H; Mahmoud, Ayman M; Dzimiri, Nduna

    2015-01-01

    Advances in depression research have targeted inflammation and oxidative stress to develop novel types of treatment. The JAK/STAT signaling pathway plays pivotal roles in immune and inflammatory responses. The present study was designed to investigate the effects of N-acetylcysteine, a putative precursor of the antioxidant glutathione, in an animal model of depression, with an emphasis on the JAK/STAT signaling pathway. Fluoxetine, a classical antidepressant drug was also under investigation....

  16. Proteomics and Pathway Analysis Identifies JNK Signaling as Critical for High Linear Energy Transfer Radiation-induced Apoptosis in Non-small Lung Cancer Cells*S⃞

    Science.gov (United States)

    Ståhl, Sara; Fung, Eva; Adams, Christopher; Lengqvist, Johan; Mörk, Birgitta; Stenerlöw, Bo; Lewensohn, Rolf; Lehtiö, Janne; Zubarev, Roman; Viktorsson, Kristina

    2009-01-01

    During the past decade, we have witnessed an explosive increase in generation of large proteomics data sets, not least in cancer research. There is a growing need to extract and correctly interpret information from such data sets to generate biologically relevant hypotheses. A pathway search engine (PSE) has recently been developed as a novel tool intended to meet these requirements. Ionizing radiation (IR) is an anticancer treatment modality that triggers multiple signal transduction networks. In this work, we show that high linear energy transfer (LET) IR induces apoptosis in a non-small cell lung cancer cell line, U-1810, whereas low LET IR does not. PSE was applied to study changes in pathway status between high and low LET IR to find pathway candidates of importance for high LET-induced apoptosis. Such pathways are potential clinical targets, and they were further validated in vitro. We used an unsupervised shotgun proteomics approach where high resolution mass spectrometry coupled to nanoflow liquid chromatography determined the identity and relative abundance of expressed proteins. Based on the proteomics data, PSE suggested the JNK pathway (p = 6·10−6) as a key event in response to high LET IR. In addition, the Fas pathway was found to be activated (p = 3·10−5) and the p38 pathway was found to be deactivated (p = 0.001) compared with untreated cells. Antibody-based analyses confirmed that high LET IR caused an increase in phosphorylation of JNK. Moreover pharmacological inhibition of JNK blocked high LET-induced apoptotic signaling. In contrast, neither an activation of p38 nor a role for p38 in high LET IR-induced apoptotic signaling was found. We conclude that, in contrast to conventional low LET IR, high LET IR can trigger activation of the JNK pathway, which in turn is critical for induction of apoptosis in these cells. Thus PSE predictions were largely confirmed, and PSE was proven to be a useful hypothesis-generating tool. PMID:19168796

  17. Sotos syndrome is associated with deregulation of the MAPK/ERK-signaling pathway.

    Directory of Open Access Journals (Sweden)

    Remco Visser

    Full Text Available Sotos syndrome (SoS is characterized by tall stature, characteristic craniofacial features and mental retardation. It is caused by haploinsufficiency of the NSD1 gene. In this study, our objective was to identify downstream effectors of NSD1 and to map these effectors in signaling pathways associated with growth. Genome-wide expression studies were performed on dermal fibroblasts from SoS patients with a confirmed NSD1 abnormality. To substantiate those results, phosphorylation, siRNA and transfection experiments were performed. A significant association was demonstrated with the Mitogen-Activated Protein Kinase (MAPK pathway. Members of the fibroblast growth factor family such as FGF4 and FGF13 contributed strongly to the differential expression in this pathway. In addition, a diminished activity state of the MAPK/ERK pathway was demonstrated in SoS. The Ras Interacting Protein 1 (RASIP1 was identified to exhibit upregulated expression in SoS. It was shown that RASIP1 dose-dependently potentiated bFGF induced expression of the MAPK responsive SBE reporter providing further support for a link between NSD1 and the MAPK/ERK signaling pathway. Additionally, we demonstrated NSD1 expression in the terminally differentiated hypertrophic chondrocytes of normal human epiphyseal growth plates. In short stature syndromes such as hypochondroplasia and Noonan syndrome, the activation level of the FGF-MAPK/ERK-pathway in epiphyseal growth plates is a determining factor for statural growth. In analogy, we propose that deregulation of the MAPK/ERK pathway in SoS results in altered hypertrophic differentiation of NSD1 expressing chondrocytes and may be a determining factor in statural overgrowth and accelerated skeletal maturation in SoS.

  18. The Impact of Hedgehog Signaling Pathway on DNA Repair Mechanisms in Human Cancer

    International Nuclear Information System (INIS)

    Meng, Erhong; Hanna, Ann; Samant, Rajeev S.; Shevde, Lalita A.

    2015-01-01

    Defined cellular mechanisms have evolved that recognize and repair DNA to protect the integrity of its structure and sequence when encountering assaults from endogenous and exogenous sources. There are five major DNA repair pathways: mismatch repair, nucleotide excision repair, direct repair, base excision repair and DNA double strand break repair (including non-homologous end joining and homologous recombination repair). Aberrant activation of the Hedgehog (Hh) signaling pathway is a feature of many cancer types. The Hh pathway has been documented to be indispensable for epithelial-mesenchymal transition, invasion and metastasis, cancer stemness, and chemoresistance. The functional transcription activators of the Hh pathway include the GLI proteins. Inhibition of the activity of GLI can interfere with almost all DNA repair types in human cancer, indicating that Hh/GLI functions may play an important role in enabling tumor cells to survive lethal types of DNA damage induced by chemotherapy and radiotherapy. Thus, Hh signaling presents an important therapeutic target to overcome DNA repair-enabled multi-drug resistance and consequently increase chemotherapeutic response in the treatment of cancer

  19. The Impact of Hedgehog Signaling Pathway on DNA Repair Mechanisms in Human Cancer

    Energy Technology Data Exchange (ETDEWEB)

    Meng, Erhong; Hanna, Ann; Samant, Rajeev S.; Shevde, Lalita A., E-mail: lsamant@uab.edu [Department of Pathology, Comprehensive Cancer Center, University of Alabama at Birmingham, WTI320D, 1824 6th Avenue South, Birmingham, AL 35233 (United States)

    2015-07-21

    Defined cellular mechanisms have evolved that recognize and repair DNA to protect the integrity of its structure and sequence when encountering assaults from endogenous and exogenous sources. There are five major DNA repair pathways: mismatch repair, nucleotide excision repair, direct repair, base excision repair and DNA double strand break repair (including non-homologous end joining and homologous recombination repair). Aberrant activation of the Hedgehog (Hh) signaling pathway is a feature of many cancer types. The Hh pathway has been documented to be indispensable for epithelial-mesenchymal transition, invasion and metastasis, cancer stemness, and chemoresistance. The functional transcription activators of the Hh pathway include the GLI proteins. Inhibition of the activity of GLI can interfere with almost all DNA repair types in human cancer, indicating that Hh/GLI functions may play an important role in enabling tumor cells to survive lethal types of DNA damage induced by chemotherapy and radiotherapy. Thus, Hh signaling presents an important therapeutic target to overcome DNA repair-enabled multi-drug resistance and consequently increase chemotherapeutic response in the treatment of cancer.

  20. Protein conservation and variation suggest mechanisms of cell type-specific modulation of signaling pathways.

    Directory of Open Access Journals (Sweden)

    Martin H Schaefer

    2014-06-01

    Full Text Available Many proteins and signaling pathways are present in most cell types and tissues and yet perform specialized functions. To elucidate mechanisms by which these ubiquitous pathways are modulated, we overlaid information about cross-cell line protein abundance and variability, and evolutionary conservation onto functional pathway components and topological layers in the pathway hierarchy. We found that the input (receptors and the output (transcription factors layers evolve more rapidly than proteins in the intermediary transmission layer. In contrast, protein expression variability decreases from the input to the output layer. We observed that the differences in protein variability between the input and transmission layer can be attributed to both the network position and the tendency of variable proteins to physically interact with constitutively expressed proteins. Differences in protein expression variability and conservation are also accompanied by the tendency of conserved and constitutively expressed proteins to acquire somatic mutations, while germline mutations tend to occur in cell type-specific proteins. Thus, conserved core proteins in the transmission layer could perform a fundamental role in most cell types and are therefore less tolerant to germline mutations. In summary, we propose that the core signal transmission machinery is largely modulated by a variable input layer through physical protein interactions. We hypothesize that the bow-tie organization of cellular signaling on the level of protein abundance variability contributes to the specificity of the signal response in different cell types.

  1. Research advances in sorafenib-induced apoptotic signaling pathways in liver cancer cells

    Directory of Open Access Journals (Sweden)

    ZHANG Chaoya

    2016-04-01

    Full Text Available Currently, sorafenib is the multi-target inhibitor for the treatment of advanced primary liver cancer, and can effectively prolong the progression-free survival and overall survival in patients with advanced primary liver cancer. The application of sorafenib in the targeted therapy for liver cancer has become a hot topic. Major targets or signaling pathways include Raf/Mek/Erk, Jak/Stat, PI3K/Akt/mTOR, VEGFR and PDGFR, STAT, microRNA, Wnt/β-catenin, autolysosome, and tumor-related proteins, and sorafenib can regulate the proliferation, differentiation, metastasis, and apoptosis of liver cancer cells through these targets. This article reviews the current research on the action of sorafenib on these targets or signaling pathways to provide useful references for further clinical research on sorafenib.

  2. Effects of matrine on JAK-STAT signaling transduction pathways in ...

    African Journals Online (AJOL)

    The current study aims to investigate the effects of matrine on the JAK-STAT signaling transduction pathways in bleomycin (BLM)-induced pulmonary fibrosis (PF) and to explore its action mechanism. A total of 72 male C57BL/6 mice were randomized into the control, model, and treatment groups. PF models were ...

  3. Combined EGFR and VEGFR versus single EGFR signaling pathways inhibition therapy for NSCLC: a systematic review and meta-analysis.

    Directory of Open Access Journals (Sweden)

    Xinji Zhang

    Full Text Available BACKGROUND: Lung cancer is a heterogeneous disease with multiple signaling pathways influencing tumor cell survival and proliferation, and it is likely that blocking only one of these pathways allows others to act as salvage or escape mechanisms for cancer cells. Whether combined inhibition therapy has greater anti-tumor activity than single inhibition therapy is a matter of debate. Hence, a meta-analysis comparing therapy inhibiting both VEGFR and EGFR signaling pathways with that inhibiting EGFR signaling pathway alone was performed. METHODOLOGY AND PRINCIPAL FINDINGS: We searched PubMed, EMBASE database and the proceedings of major conferences for relevant clinical trials. Outcomes analyzed were objective tumor response rate (ORR, progression-free survival (PFS, overall survival (OS and toxicity. Besides, subgroup analyses were performed to investigate whether the combined inhibition therapy is best performed using combination of selective agents or a single agent with multiple targets. Six trials recruiting 3,302 patients were included in the analysis. Combined inhibition therapy was associated with a 3% improvement in OS as compared with single-targeted therapy, but this difference was not statistically significant (HR, 0.97; 95% CI, 0.89-1.05; P=0.472. Patients receiving combined inhibition therapy had significant longer PFS than the group with single-targeted therapy (HR, 0.80; 95% CI, 0.67-0.95; P=0.011. There was no difference in the ORR between the groups (OR, 1.44; 95% CI, 0.95-2.18; P=0.085. Subgroup analysis revealed that combined inhibition therapy using combination regimens was associated with statistically significant improvement in both ORR and PFS. Toxicity was greater in combined inhibition therapy. CONCLUSIONS: There is no evidence to support the use of combined inhibition therapy in unselected patients with advanced NSCLC. However, given the significant advantage in ORR and PFS, combined inhibition therapy using combination

  4. Curcumin ameliorates insulin signalling pathway in brain of Alzheimer's disease transgenic mice.

    Science.gov (United States)

    Feng, Hui-Li; Dang, Hui-Zi; Fan, Hui; Chen, Xiao-Pei; Rao, Ying-Xue; Ren, Ying; Yang, Jin-Duo; Shi, Jing; Wang, Peng-Wen; Tian, Jin-Zhou

    2016-12-01

    Deficits in glucose, impaired insulin signalling and brain insulin resistance are common in the pathogenesis of Alzheimer's disease (AD); therefore, some scholars even called AD type 3 diabetes mellitus. Curcumin can reduce the amyloid pathology in AD. Moreover, it is a well-known fact that curcumin has anti-oxidant and anti-inflammatory properties. However, whether or not curcumin could regulate the insulin signal transduction pathway in AD remains unclear. In this study, we used APPswe/PS1dE9 double transgenic mice as the AD model to investigate the mechanisms and the effects of curcumin on AD. Immunohistochemical (IHC) staining and a western blot analysis were used to test the major proteins in the insulin signal transduction pathway. After the administration of curcumin for 6 months, the results showed that the expression of an insulin receptor (InR) and insulin receptor substrate (IRS)-1 decreased in the hippocampal CA1 area of the APPswe/PS1dE9 double transgenic mice, while the expression of phosphatidylinositol-3 kinase (PI3K), phosphorylated PI3K (p-PI3K), serine-threonine kinase (AKT) and phosphorylated AKT (p-AKT) increased. Among the curcumin groups, the medium-dose group was the most effective one. Thus, we believe that curcumin may be a potential therapeutic agent that can regulate the critical molecules in brain insulin signalling pathways. Furthermore, curcumin could be adopted as one of the AD treatments to improve a patient's learning and memory ability. © The Author(s) 2016.

  5. Peroxisome Proliferator-Activated Receptor and Vitamin D Receptor Signaling Pathways in Cancer Cells

    Directory of Open Access Journals (Sweden)

    Yasuko Kitagishi

    2013-10-01

    Full Text Available Peroxisome proliferator-activated receptors (PPARs are members of the superfamily of nuclear hormone receptors, which respond to specific ligands such as polyunsaturated fatty acids by altering gene expression. Three subtypes of this receptor have been discovered, each evolving to achieve different biological functions. Like other nuclear receptors, the transcriptional activity of PPARs is affected not only by ligand-stimulation, but also by cross-talk with other molecules. For example, both PPARs and the RXRs are ligand-activated transcription factors that coordinately regulate gene expression. In addition, PPARs and vitamin D receptor (VDR signaling pathways regulate a multitude of genes that are of importance for cellular functions including cell proliferation and cell differentiation. Interaction of the PPARs and VDR signaling pathways has been shown at the level of molecular cross-regulation of their transcription factor. A variety of ligands influencing the PPARs and VDR signaling pathways have been shown to reveal chemopreventive potential by mediating tumor suppressive activities in human cancers. Use of these compounds may represent a potential novel strategy to prevent cancers. This review summarizes the roles of the PPARs and the VDR in pathogenesis and progression of cancer.

  6. Peroxisome Proliferator-Activated Receptor and Vitamin D Receptor Signaling Pathways in Cancer Cells

    Energy Technology Data Exchange (ETDEWEB)

    Matsuda, Satoru, E-mail: smatsuda@cc.nara-wu.ac.jp; Kitagishi, Yasuko [Department of Food Science and Nutrition, Nara Women’s University, Kita-Uoya Nishimachi, Nara 630-8506 (Japan)

    2013-10-21

    Peroxisome proliferator-activated receptors (PPARs) are members of the superfamily of nuclear hormone receptors, which respond to specific ligands such as polyunsaturated fatty acids by altering gene expression. Three subtypes of this receptor have been discovered, each evolving to achieve different biological functions. Like other nuclear receptors, the transcriptional activity of PPARs is affected not only by ligand-stimulation, but also by cross-talk with other molecules. For example, both PPARs and the RXRs are ligand-activated transcription factors that coordinately regulate gene expression. In addition, PPARs and vitamin D receptor (VDR) signaling pathways regulate a multitude of genes that are of importance for cellular functions including cell proliferation and cell differentiation. Interaction of the PPARs and VDR signaling pathways has been shown at the level of molecular cross-regulation of their transcription factor. A variety of ligands influencing the PPARs and VDR signaling pathways have been shown to reveal chemopreventive potential by mediating tumor suppressive activities in human cancers. Use of these compounds may represent a potential novel strategy to prevent cancers. This review summarizes the roles of the PPARs and the VDR in pathogenesis and progression of cancer.

  7. Peroxisome Proliferator-Activated Receptor and Vitamin D Receptor Signaling Pathways in Cancer Cells

    International Nuclear Information System (INIS)

    Matsuda, Satoru; Kitagishi, Yasuko

    2013-01-01

    Peroxisome proliferator-activated receptors (PPARs) are members of the superfamily of nuclear hormone receptors, which respond to specific ligands such as polyunsaturated fatty acids by altering gene expression. Three subtypes of this receptor have been discovered, each evolving to achieve different biological functions. Like other nuclear receptors, the transcriptional activity of PPARs is affected not only by ligand-stimulation, but also by cross-talk with other molecules. For example, both PPARs and the RXRs are ligand-activated transcription factors that coordinately regulate gene expression. In addition, PPARs and vitamin D receptor (VDR) signaling pathways regulate a multitude of genes that are of importance for cellular functions including cell proliferation and cell differentiation. Interaction of the PPARs and VDR signaling pathways has been shown at the level of molecular cross-regulation of their transcription factor. A variety of ligands influencing the PPARs and VDR signaling pathways have been shown to reveal chemopreventive potential by mediating tumor suppressive activities in human cancers. Use of these compounds may represent a potential novel strategy to prevent cancers. This review summarizes the roles of the PPARs and the VDR in pathogenesis and progression of cancer

  8. Regulatory Mechanisms of the Ihh/PTHrP Signaling Pathway in Fibrochondrocytes in Entheses of Pig Achilles Tendon

    Directory of Open Access Journals (Sweden)

    Xuesong Han

    2016-01-01

    Full Text Available This study is aimed at exploring the effect of stress stimulation on the proliferation and differentiation of fibrochondrocytes in entheses mediated via the Indian hedgehog (Ihh/parathyroid hormone-related protein (PTHrP signaling pathway. Differential stress stimulation on fibrochondrocytes in entheses was imposed. Gene expression and protein levels of signaling molecules including collagen type I (Col I, Col II, Col X, Ihh, and PTHrP in the cytoplasm of fibrochondrocytes were detected. Ihh signal blocking group was set up using Ihh signaling pathway-specific blocking agent cyclopamine. PTHrP enhancement group was set up using PTHrP reagent. Ihh/PTHrP double intervention group, as well as control group, was included to study the regulatory mechanisms of the Ihh/PTHrP signaling pathway in fibrochondrocytes. Under low cyclic stress tensile (CTS, PTHrP, Col I, and Col II gene expression and protein synthesis increased. Under high CTS, Ihh and Col X gene expression and protein synthesis increased. Blocking Ihh signaling with cyclopamine resulted in reduced PTHrP gene expression and protein synthesis and increased Col X gene expression and protein synthesis. Ihh and PTHrP coregulate fibrochondrocyte proliferation and differentiation in entheses through negative feedback regulation. Fibrochondrocyte is affected by the CTS. This phenomenon is regulated by stress stimulation through the Ihh/PTHrP signaling pathway.

  9. Regulatory Mechanisms of the Ihh/PTHrP Signaling Pathway in Fibrochondrocytes in Entheses of Pig Achilles Tendon.

    Science.gov (United States)

    Han, Xuesong; Zhuang, Yanfeng; Zhang, Zhihong; Guo, Lin; Wang, Wanming

    2016-01-01

    This study is aimed at exploring the effect of stress stimulation on the proliferation and differentiation of fibrochondrocytes in entheses mediated via the Indian hedgehog (Ihh)/parathyroid hormone-related protein (PTHrP) signaling pathway. Differential stress stimulation on fibrochondrocytes in entheses was imposed. Gene expression and protein levels of signaling molecules including collagen type I (Col I), Col II, Col X, Ihh, and PTHrP in the cytoplasm of fibrochondrocytes were detected. Ihh signal blocking group was set up using Ihh signaling pathway-specific blocking agent cyclopamine. PTHrP enhancement group was set up using PTHrP reagent. Ihh/PTHrP double intervention group, as well as control group, was included to study the regulatory mechanisms of the Ihh/PTHrP signaling pathway in fibrochondrocytes. Under low cyclic stress tensile (CTS), PTHrP, Col I, and Col II gene expression and protein synthesis increased. Under high CTS, Ihh and Col X gene expression and protein synthesis increased. Blocking Ihh signaling with cyclopamine resulted in reduced PTHrP gene expression and protein synthesis and increased Col X gene expression and protein synthesis. Ihh and PTHrP coregulate fibrochondrocyte proliferation and differentiation in entheses through negative feedback regulation. Fibrochondrocyte is affected by the CTS. This phenomenon is regulated by stress stimulation through the Ihh/PTHrP signaling pathway.

  10. The canonical Wnt signaling pathway promotes chondrocyte differentiation in a Sox9-dependent manner

    International Nuclear Information System (INIS)

    Yano, Fumiko; Kugimiya, Fumitaka; Ohba, Shinsuke; Ikeda, Toshiyuki; Chikuda, Hirotaka; Ogasawara, Toru; Ogata, Naoshi; Takato, Tsuyoshi; Nakamura, Kozo; Kawaguchi, Hiroshi; Chung, Ung-il

    2005-01-01

    To better understand the role of the canonical Wnt signaling pathway in cartilage development, we adenovirally expressed a constitutively active (Canada) or a dominant negative (dn) form of lymphoid enhancer factor-1 (LEF-1), the main nuclear effector of the pathway, in undifferentiated mesenchymal cells, chondrogenic cells, and primary chondrocytes, and examined the expression of markers for chondrogenic differentiation and hypertrophy. caLEF-1 and LiCl, an activator of the canonical pathway, promoted both chondrogenic differentiation and hypertrophy, whereas dnLEF-1 and the gene silencing of β-catenin suppressed LiCl-promoted effects. To investigate whether these effects were dependent on Sox9, a master regulator of cartilage development, we stimulated Sox9-deficient ES cells with the pathway. caLEF-1 and LiCl promoted both chondrogenic differentiation and hypertrophy in wild-type, but not in Sox9-deficient, cells. The response of Sox9-deficient cells was restored by the adenoviral expression of Sox9. Thus, the canonical Wnt signaling pathway promotes chondrocyte differentiation in a Sox9-dependent manner

  11. A pivotal role of the jasmonic acid signal pathway in mediating radiation-induced bystander effects in Arabidopsis thaliana

    Energy Technology Data Exchange (ETDEWEB)

    Wang, Ting; Xu, Wei; Deng, Chenguang; Xu, Shaoxin; Li, Fanghua; Wu, Yuejin; Wu, Lijun [Key Laboratory of Ion Beam Bioengineering, Hefei Institutes of Physical Science, Chinese Academy of Sciences, Hefei 230031 (China); Key Laboratory of Environmental Toxicology and Pollution Control Technology of Anhui Province, Hefei 230031 (China); Bian, Po, E-mail: bianpo@ipp.ac.cn [Key Laboratory of Ion Beam Bioengineering, Hefei Institutes of Physical Science, Chinese Academy of Sciences, Hefei 230031 (China); Key Laboratory of Environmental Toxicology and Pollution Control Technology of Anhui Province, Hefei 230031 (China)

    2016-09-15

    Highlights: • The JA signal pathway plays a pivotal role in mediating radiation-induced bystander effects in Arabidopsis thaliana. • The JA signal pathway is involved in both the generation of bystander signals in irradiated roots and radiation responses in bystander aerial plants. • Over-accumulation of endogenous JA enhances the radiosensitivity of plants in terms of RIBE. - Abstract: Although radiation-induced bystander effects (RIBE) in Arabidopsis thaliana have been well demonstrated in vivo, little is known about their underlying mechanisms, particularly with regard to the participating signaling molecules and signaling pathways. In higher plants, jasmonic acid (JA) and its bioactive derivatives are well accepted as systemic signal transducers that are produced in response to various environmental stresses. It is therefore speculated that the JA signal pathway might play a potential role in mediating radiation-induced bystander signaling of root-to-shoot. In the present study, pretreatment of seedlings with Salicylhydroxamic acid, an inhibitor of lipoxigenase (LOX) in JA biosynthesis, significantly suppressed RIBE-mediated expression of the AtRAD54 gene. After root irradiation, the aerial parts of A. thaliana mutants deficient in JA biosynthesis (aos) and signaling cascades (jar1-1) showed suppressed induction of the AtRAD54 and AtRAD51 genes and TSI and 180-bp repeats, which have been extensively used as endpoints of bystander genetic and epigenetic effects in plants. These results suggest an involvement of the JA signal pathway in the RIBE of plants. Using the root micro-grafting technique, the JA signal pathway was shown to participate in both the generation of bystander signals in irradiated root cells and radiation responses in the bystander aerial parts of plants. The over-accumulation of endogenous JA in mutant fatty acid oxygenation up-regulated 2 (fou2), in which mutation of the Two Pore Channel 1 (TPC1) gene up-regulates expression of the LOX

  12. Nasopharyngeal Carcinoma Signaling Pathway: An Update on Molecular Biomarkers

    Directory of Open Access Journals (Sweden)

    Warut Tulalamba

    2012-01-01

    Full Text Available Nasopharyngeal carcinoma (NPC is an uncommon cancer, which has a distinctive ethnic and geographic distribution. Etiology of NPC is considered to be related with a complex interaction of environmental and genetic factors as well as Epstein-Barr virus infection. Since NPC is located in the silent painless area, the disease is usually therefore diagnosed at the advanced stages; hence early detection of NPC is difficult. Furthermore, understanding in molecular pathogenesis is still lacking, pondering the identification of effective prognostic and diagnostic biomarkers. Dysregulation of signaling molecules in intracellular signal transduction, which regulate cell proliferation, apoptosis, and adhesion, underlines the basis of NPC pathogenesis. In this paper, the molecular signaling pathways in the NPC are discussed for the holistic view of NPC development and progression. The important insights toward NPC pathogenesis may offer strategies for identification of novel biomarkers for diagnosis and prognosis.

  13. Up-regulation of abscisic acid signaling pathway facilitates aphid xylem absorption and osmoregulation under drought stress.

    Science.gov (United States)

    Guo, Huijuan; Sun, Yucheng; Peng, Xinhong; Wang, Qinyang; Harris, Marvin; Ge, Feng

    2016-02-01

    The activation of the abscisic acid (ABA) signaling pathway reduces water loss from plants challenged by drought stress. The effect of drought-induced ABA signaling on the defense and nutrition allocation of plants is largely unknown. We postulated that these changes can affect herbivorous insects. We studied the effects of drought on different feeding stages of pea aphids in the wild-type A17 of Medicago truncatula and ABA signaling pathway mutant sta-1. We examined the impact of drought on plant water status, induced plant defense signaling via the abscisic acid (ABA), jasmonic acid (JA), and salicylic acid (SA) pathways, and on the host nutritional quality in terms of leaf free amino acid content. During the penetration phase of aphid feeding, drought decreased epidermis/mesophyll resistance but increased mesophyll/phloem resistance of A17 but not sta-1 plants. Quantification of transcripts associated with ABA, JA and SA signaling indicated that the drought-induced up-regulation of ABA signaling decreased the SA-dependent defense but increased the JA-dependent defense in A17 plants. During the phloem-feeding phase, drought had little effect on the amino acid concentrations and the associated aphid phloem-feeding parameters in both plant genotypes. In the xylem absorption stage, drought decreased xylem absorption time of aphids in both genotypes because of decreased water potential. Nevertheless, the activation of the ABA signaling pathway increased water-use efficiency of A17 plants by decreasing the stomatal aperture and transpiration rate. In contrast, the water potential of sta-1 plants (unable to close stomata) was too low to support xylem absorption activity of aphids; the aphids on sta-1 plants had the highest hemolymph osmolarity and lowest abundance under drought conditions. Taken together this study illustrates the significance of cross-talk between biotic-abiotic signaling pathways in plant-aphid interaction, and reveals the mechanisms leading to alter

  14. Interleukin-6 receptor pathways in coronary heart disease

    DEFF Research Database (Denmark)

    Sarwar, Nadeem; Butterworth, Adam S; Freitag, Daniel F

    2012-01-01

    Persistent inflammation has been proposed to contribute to various stages in the pathogenesis of cardiovascular disease. Interleukin-6 receptor (IL6R) signalling propagates downstream inflammation cascades. To assess whether this pathway is causally relevant to coronary heart disease, we studied ...

  15. An alternative mode of CD43 signal transduction activates pro-survival pathways of T lymphocytes.

    Science.gov (United States)

    Bravo-Adame, Maria Elena; Vera-Estrella, Rosario; Barkla, Bronwyn J; Martínez-Campos, Cecilia; Flores-Alcantar, Angel; Ocelotl-Oviedo, Jose Pablo; Pedraza-Alva, Gustavo; Rosenstein, Yvonne

    2017-01-01

    CD43 is one of the most abundant co-stimulatory molecules on a T-cell surface; it transduces activation signals through its cytoplasmic domain, contributing to modulation of the outcome of T-cell responses. The aim of this study was to uncover new signalling pathways regulated by this sialomucin. Analysis of changes in protein abundance allowed us to identify pyruvate kinase isozyme M2 (PKM2), an enzyme of the glycolytic pathway, as an element potentially participating in the signalling cascade resulting from the engagement of CD43 and the T-cell receptor (TCR). We found that the glycolytic activity of this enzyme was not significantly increased in response to TCR+CD43 co-stimulation, but that PKM2 was tyrosine phosphorylated, suggesting that it was performing moonlight functions. We report that phosphorylation of both Y 105 of PKM2 and of Y 705 of signal transducer and activator of transcription 3 was induced in response to TCR+CD43 co-stimulation, resulting in activation of the mitogen-activated protein kinase kinase 5/extracellular signal-regulated kinase 5 (MEK5/ERK5) pathway. ERK5 and the cAMP response element binding protein (CREB) were activated, and c-Myc and nuclear factor-κB (p65) nuclear localization, as well as Bad phosphorylation, were augmented. Consistent with this, expression of human CD43 in a murine T-cell hybridoma favoured cell survival. Altogether, our data highlight novel signalling pathways for the CD43 molecule in T lymphocytes, and underscore a role for CD43 in promoting cell survival through non-glycolytic functions of metabolic enzymes. © 2016 John Wiley & Sons Ltd.

  16. In vivo relevance for photoprotection by the vitamin D rapid response pathway.

    Science.gov (United States)

    Dixon, K M; Deo, S S; Norman, A W; Bishop, J E; Halliday, G M; Reeve, V E; Mason, R S

    2007-03-01

    Vitamin D is produced by exposure of 7-dehydrocholesterol in the skin to UV irradiation (UVR) and further converted in the skin to the biologically active metabolite, 1,25-dihydroxyvitamin D(3) (1,25(OH)(2)D(3)) and other compounds. UVR also results in DNA damage producing cyclobutane pyrimidine dimers (CPD). We previously reported that 1,25(OH)(2)D(3) at picomolar concentrations, protects human skin cells from UVR-induced apoptosis, and decreases CPD in surviving cells. 1,25(OH)(2)D(3) has been shown to generate biological responses via two pathways-the classical steroid receptor/genomic pathway or a rapid, non-genomic pathway mediated by a putative membrane receptor. Whether the rapid response pathway is physiologically relevant is unclear. A cis-locked, rapid-acting agonist 1,25(OH)(2)lumisterol(3) (JN), entirely mimicked the actions of 1,25(OH)(2)D(3) to reduce fibroblast and keratinocyte loss and CPD damage after UVR. The effects of 1,25(OH)(2)D(3) were abolished by a rapid-acting antagonist, but not by a genomic antagonist. Skh:hr1 mice exposed to three times the minimal erythemal dose of solar-simulated UVR and treated topically with 1,25(OH)(2)D(3) or JN immediately after UVR showed reduction in UVR-induced UVR-induced sunburn cells (pphotoprotective effects via the rapid pathway and raise the possibility that other D compounds produced in skin may contribute to the photoprotective effects.

  17. Possible involvement of the JAK/STAT signaling pathway in N-acetylcysteine-mediated antidepressant-like effects.

    Science.gov (United States)

    Al-Samhari, Marwa M; Al-Rasheed, Nouf M; Al-Rejaie, Salim; Al-Rasheed, Nawal M; Hasan, Iman H; Mahmoud, Ayman M; Dzimiri, Nduna

    2016-03-01

    Advances in depression research have targeted inflammation and oxidative stress to develop novel types of treatment. The JAK/STAT signaling pathway plays pivotal roles in immune and inflammatory responses. The present study was designed to investigate the effects of N-acetylcysteine, a putative precursor of the antioxidant glutathione, in an animal model of depression, with an emphasis on the JAK/STAT signaling pathway. Fluoxetine, a classical antidepressant drug was also under investigation. Male Wistar rats were subjected to forced swimming test and given N-acetylcysteine and fluoxetine immediately after the pre-test session, 5 h later and 1 h before the test session of the forced swimming test. N-acetylcysteine decreased immobility time (P acetylcysteine produced significant (P acetylcysteine significantly (P acetylcysteine. Therefore, depression research may target the JAK/STAT signaling pathway to provide a novel effective therapy. © 2015 by the Society for Experimental Biology and Medicine.

  18. Integrated analysis of breast cancer cell lines reveals unique signaling pathways

    Energy Technology Data Exchange (ETDEWEB)

    Heiser, Laura M.; Wang, Nicholas J.; Talcott, Carolyn L.; Laderoute, Keith R.; Knapp, Merrill; Guan, Yinghui; Hu, Zhi; Ziyad, Safiyyah; Weber, Barbara L.; Laquerre, Sylvie; Jackson, Jeffrey R.; Wooster, Richard F.; Kuo, Wen-Lin; Gray, Joe W.; Spellman, Paul T.

    2009-03-31

    Cancer is a heterogeneous disease resulting from the accumulation of genetic defects that negatively impact control of cell division, motility, adhesion and apoptosis. Deregulation in signaling along the EGFR-MAPK pathway is common in breast cancer, though the manner in which deregulation occurs varies between both individuals and cancer subtypes. We were interested in identifying subnetworks within the EGFR-MAPK pathway that are similarly deregulated across subsets of breast cancers. To that end, we mapped genomic, transcriptional and proteomic profiles for 30 breast cancer cell lines onto a curated Pathway Logic symbolic systems model of EGFR-MEK signaling. This model was comprised of 539 molecular states and 396 rules governing signaling between active states. We analyzed these models and identified several subtype specific subnetworks, including one that suggested PAK1 is particularly important in regulating the MAPK cascade when it is over-expressed. We hypothesized that PAK1 overexpressing cell lines would have increased sensitivity to MEK inhibitors. We tested this experimentally by measuring quantitative responses of 20 breast cancer cell lines to three MEK inhibitors. We found that PAK1 over-expressing luminal breast cancer cell lines are significantly more sensitive to MEK inhibition as compared to those that express PAK1 at low levels. This indicates that PAK1 over-expression may be a useful clinical marker to identify patient populations that may be sensitive to MEK inhibitors. All together, our results support the utility of symbolic system biology models for identification of therapeutic approaches that will be effective against breast cancer subsets.

  19. Integrated analysis of breast cancer cell lines reveals unique signaling pathways.

    Science.gov (United States)

    Heiser, Laura M; Wang, Nicholas J; Talcott, Carolyn L; Laderoute, Keith R; Knapp, Merrill; Guan, Yinghui; Hu, Zhi; Ziyad, Safiyyah; Weber, Barbara L; Laquerre, Sylvie; Jackson, Jeffrey R; Wooster, Richard F; Kuo, Wen Lin; Gray, Joe W; Spellman, Paul T

    2009-01-01

    Cancer is a heterogeneous disease resulting from the accumulation of genetic defects that negatively impact control of cell division, motility, adhesion and apoptosis. Deregulation in signaling along the EgfR-MAPK pathway is common in breast cancer, though the manner in which deregulation occurs varies between both individuals and cancer subtypes. We were interested in identifying subnetworks within the EgfR-MAPK pathway that are similarly deregulated across subsets of breast cancers. To that end, we mapped genomic, transcriptional and proteomic profiles for 30 breast cancer cell lines onto a curated Pathway Logic symbolic systems model of EgfR-MAPK signaling. This model was composed of 539 molecular states and 396 rules governing signaling between active states. We analyzed these models and identified several subtype-specific subnetworks, including one that suggested Pak1 is particularly important in regulating the MAPK cascade when it is over-expressed. We hypothesized that Pak1 over-expressing cell lines would have increased sensitivity to Mek inhibitors. We tested this experimentally by measuring quantitative responses of 20 breast cancer cell lines to three Mek inhibitors. We found that Pak1 over-expressing luminal breast cancer cell lines are significantly more sensitive to Mek inhibition compared to those that express Pak1 at low levels. This indicates that Pak1 over-expression may be a useful clinical marker to identify patient populations that may be sensitive to Mek inhibitors. All together, our results support the utility of symbolic system biology models for identification of therapeutic approaches that will be effective against breast cancer subsets.

  20. Transforming growth factor β-induced expression of chondroitin sulfate proteoglycans is mediated through non-Smad signaling pathways.

    Science.gov (United States)

    Jahan, Naima; Hannila, Sari S

    2015-01-01

    The expression of chondroitin sulfate proteoglycans (CSPGs) by reactive astrocytes is a major factor contributing to glial scarring and regenerative failure after spinal cord injury, but the molecular mechanisms underlying CSPG expression remain largely undefined. One contributing factor is transforming growth factor β (TGFβ), which is upregulated after injury and has been shown to induce expression of CSPGs in vitro. TGFβ typically mediates its effects through the Smad2/3 signaling pathway, and it has been suggested that this pathway is responsible for CSPG expression. However, there is evidence that TGFβ can also activate non-Smad signaling pathways. In this study, we report that TGFβ-induced expression of three different CSPGs--neurocan, brevican, and aggrecan--is mediated through non-Smad signaling pathways. We observed significant increases in TGFβ-induced expression of neurocan, brevican, and aggrecan following siRNA knockdown of Smad2 or Smad4, which indicates that Smad signaling is not required for the expression of these CSPGs. In addition, we show that neurocan, aggrecan, and brevican levels are significantly reduced when TGFβ is administered in the presence of either the PI3K inhibitor LY294002 or the mTOR inhibitor rapamycin, but not the MEK1/2 inhibitor U0126. This suggests that TGFβ mediates this effect through non-Smad-dependent activation of the PI3K-Akt-mTOR signaling pathway, and targeting this pathway may therefore be an effective means of reducing CSPG expression in the injured CNS. Copyright © 2014 Elsevier Inc. All rights reserved.

  1. The role of the stress-activated protein kinase (SAPK/JNK) signaling pathway in radiation-induced apoptosis

    International Nuclear Information System (INIS)

    Verheij, M.; Ruiter, G.A.; Zerp, S.F.; Bartelink, H.; Blitterswijk, W.J. van; Fuks, Z.; Haimovitz-Friedman, A.

    1998-01-01

    Ionizing radiation, like a variety of other cellular stress factors, initiates apoptosis, or programmed cell death, in many cell systems. This mode of radiation-induced cell kill should be distinguished from clonogenic cell death due to unrepaired DNA damage. Ionizing radiation not only exerts its effect on the nuclear DNA, but also at the plasma membrane level where it may activate multiple signal transduction pathways. One of these pathways is the stress-activated protein kinase (SAPK) cascade which transduces death signals from the cell membrane to the nucleus. This review discusses recent evidence on the critical role of this signaling system in radiation- and stress-induced apoptosis. An improved understanding of the mechanisms involved in radiation-induced apoptosis may ultimately provide novel strategies of intervention in specific signal transduction pathways to favorably alter the therapeutic ratio in the treatment of human malignancies. (Copyright (c) 1998 Elsevier Science B.V., Amsterdam. All rights reserved.)

  2. Polyclonal immune responses to antigens associated with cancer signaling pathways and new strategies to enhance cancer vaccines.

    Science.gov (United States)

    Clay, Timothy M; Osada, Takuya; Hartman, Zachary C; Hobeika, Amy; Devi, Gayathri; Morse, Michael A; Lyerly, H Kim

    2011-04-01

    Aberrant signaling pathways are a hallmark of cancer. A variety of strategies for inhibiting signaling pathways have been developed, but monoclonal antibodies against receptor tyrosine kinases have been among the most successful. A challenge for these therapies is therapeutic unresponsiveness and acquired resistance due to mutations in the receptors, upregulation of alternate growth and survival pathways, or inadequate function of the monoclonal antibodies. Vaccines are able to induce polyclonal responses that can have a multitude of affects against the target molecule. We began to explore therapeutic vaccine development to antigens associated with these signaling pathways. We provide an illustrative example in developing therapeutic cancer vaccines inducing polyclonal adaptive immune responses targeting the ErbB family member HER2. Further, we will discuss new strategies to augment the clinical efficacy of cancer vaccines by enhancing vaccine immunogenicity and reversing the immunosuppressive tumor microenvironment.

  3. Inhibition of Wnt Signaling Pathways Impairs Chlamydia trachomatis Infection in Endometrial Epithelial Cells.

    Science.gov (United States)

    Kintner, Jennifer; Moore, Cheryl G; Whittimore, Judy D; Butler, Megan; Hall, Jennifer V

    2017-01-01

    Chlamydia trachomatis infections represent the predominant cause of bacterial sexually transmitted infections. As an obligate intracellular bacterium, C. trachomatis is dependent on the host cell for survival, propagation, and transmission. Thus, factors that affect the host cell, including nutrition, cell cycle, and environmental signals, have the potential to impact chlamydial development. Previous studies have demonstrated that activation of Wnt/β-catenin signaling benefits C. trachomatis infections in fallopian tube epithelia. In cervical epithelial cells chlamydiae sequester β-catenin within the inclusion. These data indicate that chlamydiae interact with the Wnt signaling pathway in both the upper and lower female genital tract (FGT). However, hormonal activation of canonical and non-canonical Wnt signaling pathways is an essential component of cyclic remodeling in another prominent area of the FGT, the endometrium. Given this information, we hypothesized that Wnt signaling would impact chlamydial infection in endometrial epithelial cells. To investigate this hypothesis, we analyzed the effect of Wnt inhibition on chlamydial inclusion development and elementary body (EB) production in two endometrial cell lines, Ishikawa (IK) and Hec-1B, in nonpolarized cell culture and in a polarized endometrial epithelial (IK)/stromal (SHT-290) cell co-culture model. Inhibition of Wnt by the small molecule inhibitor (IWP2) significantly decreased inclusion size in IK and IK/SHT-290 cultures ( p Wnt inhibition caused chlamydiae to become aberrant in morphology. EB formation was also impaired in IK, Hec-1B and IK/SHT-290 cultures regardless of whether Wnt inhibition occurred throughout, in the middle (24 hpi) or late (36 hpi) during the development cycle. Overall, these data lead us to conclude that Wnt signaling in the endometrium is a key host pathway for the proper development of C. trachomatis .

  4. Combinatory annotation of cell membrane receptors and signalling pathways of Bombyx mori prothoracic glands

    Science.gov (United States)

    Moulos, Panagiotis; Samiotaki, Martina; Panayotou, George; Dedos, Skarlatos G.

    2016-01-01

    The cells of prothoracic glands (PG) are the main site of synthesis and secretion of ecdysteroids, the biochemical products of cholesterol conversion to steroids that shape the morphogenic development of insects. Despite the availability of genome sequences from several insect species and the extensive knowledge of certain signalling pathways that underpin ecdysteroidogenesis, the spectrum of signalling molecules and ecdysteroidogenic cascades is still not fully comprehensive. To fill this gap and obtain the complete list of cell membrane receptors expressed in PG cells, we used combinatory bioinformatic, proteomic and transcriptomic analysis and quantitative PCR to annotate and determine the expression profiles of genes identified as putative cell membrane receptors of the model insect species, Bombyx mori, and subsequently enrich the repertoire of signalling pathways that are present in its PG cells. The genome annotation dataset we report here highlights modules and pathways that may be directly involved in ecdysteroidogenesis and aims to disseminate data and assist other researchers in the discovery of the role of such receptors and their ligands. PMID:27576083

  5. Melatonin attenuates angiotensin II-induced cardiomyocyte hypertrophy through the CyPA/CD147 signaling pathway.

    Science.gov (United States)

    Su, Hongyan; Li, Jingyuan; Chen, Tongshuai; Li, Na; Xiao, Jie; Wang, Shujian; Guo, Xiaobin; Yang, Yi; Bu, Peili

    2016-11-01

    Melatonin is well known for its cardioprotective effects; however, whether melatonin exerts therapeutic effects on cardiomyocyte hypertrophy remains to be investigated, as do the mechanisms underlying these effects, if they exist. Cyclophilin A (CyPA) and its corresponding receptor, CD147, which exists in a variety of cells, play crucial roles in modulating reactive oxygen species (ROS) production. In this study, we explored the role of the CyPA/CD147 signaling pathway in angiotensin II (Ang II)-induced cardiomyocyte hypertrophy and the protective effects exerted by melatonin against Ang II-induced injury in cultured H9C2 cells. Cyclosporine A, a specific CyPA/CD147 signaling pathway inhibitor, was used to manipulate CyPA/CD147 activity. H9C2 cells were then subjected to Ang II or CyPA treatment in either the absence or presence of melatonin. Our results indicate that Ang II induces cardiomyocyte hypertrophy through the CyPA/CD147 signaling pathway and promotes ROS production, which can be blocked by melatonin pretreatment in a concentration-dependent manner, in cultured H9C2 cells and that CyPA/CD147 signaling pathway inhibition protects against Ang II-induced cardiomyocyte hypertrophy. The protective effects of melatonin against Ang II-induced cardiomyocyte hypertrophy depend at least partially on CyPA/CD147 inhibition.

  6. Genital Sensory Stimulation Shifts Estradiol Intraoviductal Signaling from Nongenomic to Genomic Pathways, Independently from Prolactin Surges

    Directory of Open Access Journals (Sweden)

    C PEÑARROJA-MATUTAN0

    2007-01-01

    Full Text Available Estradiol (E2 accelerates oviductal egg transport through nongenomic pathways involving oviductal protein phosphorylation in non-mated rats, and through genomic pathways in mated rats. Here we investigated the ability of cervico-vaginal stimulation (CVS to switch the mode of action of E2 in the absence of other male-associated components. Pro-estrous rats were subjected to CVS with a glass rod and 12 hours later were injected subcutaneously with E2 and intrabursally with the RNA synthesis inhibitor Actinomycin D or the protein phosphorylation inhibitor H-89. The number of eggs in the oviduct, assessed 24 h later, showed that Actinomycin D, but not H-89 blocked the E2-induced egg transport acceleration. This clearly indicates that CVS alone, without other mating-associated signals, is able to shift E2 signaling from nongenomic to genomic pathways. Since mating and CVS activate a neuroendocrine reflex that causes iterative prolactin (PRL surges, the involvement of PRL pathway in this phenomenon was evaluated. Prolactin receptor mRNA and protein expression in the rat oviduct was demonstrated by RT-PCR and Western blot, but their levels were not different on day 2 of the cycle (C2 or pregnancy (P2. Activated ST AT 5a/b (phosphorylated was detected by Western blot on P2 in the ovary, but not in the oviduct, showing that mating does not stimulate this PRL signalling pathway in the oviduct. Other rats subjected to CVS in the evening of pro-estrus were treated with bromoergocriptine to suppress PRL surges. In these rats, H-89 did not block the E2-induced acceleration of egg transport suggesting that PRL surges are not essential to shift E2 signaling pathways in the oviduct. We conclude that CVS is one of the components of mating that shifts E2 signaling in the oviduct from nongenomic to genomic pathways, and this effect is independent of PRL surges elicited by mating

  7. Modeling of coupled differential equations for cellular chemical signaling pathways: Implications for assay protocols utilized in cellular engineering.

    Science.gov (United States)

    O'Clock, George D

    2016-08-01

    Cellular engineering involves modification and control of cell properties, and requires an understanding of fundamentals and mechanisms of action for cellular derived product development. One of the keys to success in cellular engineering involves the quality and validity of results obtained from cell chemical signaling pathway assays. The accuracy of the assay data cannot be verified or assured if the effect of positive feedback, nonlinearities, and interrelationships between cell chemical signaling pathway elements are not understood, modeled, and simulated. Nonlinearities and positive feedback in the cell chemical signaling pathway can produce significant aberrations in assay data collection. Simulating the pathway can reveal potential instability problems that will affect assay results. A simulation, using an electrical analog for the coupled differential equations representing each segment of the pathway, provides an excellent tool for assay validation purposes. With this approach, voltages represent pathway enzyme concentrations and operational amplifier feedback resistance and input resistance values determine pathway gain and rate constants. The understanding provided by pathway modeling and simulation is strategically important in order to establish experimental controls for assay protocol structure, time frames specified between assays, and assay concentration variation limits; to ensure accuracy and reproducibility of results.

  8. Aberrant signaling pathways in medulloblastomas: a stem cell connection

    Directory of Open Access Journals (Sweden)

    Carolina Oliveira Rodini

    2010-12-01

    Full Text Available Medulloblastoma is a highly malignant primary tumor of the central nervous system. It represents the most frequent type of solid tumor and the leading cause of death related to cancer in early childhood. Current treatment includes surgery, chemotherapy and radiotherapy which may lead to severe cognitive impairment and secondary brain tumors. New perspectives for therapeutic development have emerged with the identification of stem-like cells displaying high tumorigenic potential and increased radio- and chemo-resistance in gliomas. Under the cancer stem cell hypothesis, transformation of neural stem cells and/or granular neuron progenitors of the cerebellum are though to be involved in medulloblastoma development. Dissecting the genetic and molecular alterations associated with this process should significantly impact both basic and applied cancer research. Based on cumulative evidences in the fields of genetics and molecular biology of medulloblastomas, we discuss the possible involvement of developmental signaling pathways as critical biochemical switches determining normal neurogenesis or tumorigenesis. From the clinical viewpoint, modulation of signaling pathways such as TGFβ, regulating neural stem cell proliferation and tumor development, might be attempted as an alternative strategy for future drug development aiming at more efficient therapies and improved clinical outcome of patients with pediatric brain cancers.

  9. Global microRNA profiles and signaling pathways in the development of cardiac hypertrophy

    Energy Technology Data Exchange (ETDEWEB)

    Feng, H.J.; Ouyang, W.; Liu, J.H.; Sun, Y.G.; Hu, R.; Huang, L.H.; Xian, J.L. [Southern Medical University, Department of Nuclear Medicine, Zhujiang Hospital, Guangzhou, China, Department of Nuclear Medicine, Zhujiang Hospital, Southern Medical University, Guangzhou (China); Jing, C.F.; Zhou, M.J. [Sun Yat-Sen University, South China Sea Marine Biotechnology, National Engineering Research Center, Guangzhou, China, National Engineering Research Center, South China Sea Marine Biotechnology, Sun Yat-Sen University, Guangzhou (China)

    2014-04-11

    Hypertrophy is a major predictor of progressive heart disease and has an adverse prognosis. MicroRNAs (miRNAs) that accumulate during the course of cardiac hypertrophy may participate in the process. However, the nature of any interaction between a hypertrophy-specific signaling pathway and aberrant expression of miRNAs remains unclear. In this study, Spague Dawley male rats were treated with transverse aortic constriction (TAC) surgery to mimic pathological hypertrophy. Hearts were isolated from TAC and sham operated rats (n=5 for each group at 5, 10, 15, and 20 days after surgery) for miRNA microarray assay. The miRNAs dysexpressed during hypertrophy were further analyzed using a combination of bioinformatics algorithms in order to predict possible targets. Increased expression of the target genes identified in diverse signaling pathways was also analyzed. Two sets of miRNAs were identified, showing different expression patterns during hypertrophy. Bioinformatics analysis suggested the miRNAs may regulate multiple hypertrophy-specific signaling pathways by targeting the member genes and the interaction of miRNA and mRNA might form a network that leads to cardiac hypertrophy. In addition, the multifold changes in several miRNAs suggested that upregulation of rno-miR-331*, rno-miR-3596b, rno-miR-3557-5p and downregulation of rno-miR-10a, miR-221, miR-190, miR-451 could be seen as biomarkers of prognosis in clinical therapy of heart failure. This study described, for the first time, a potential mechanism of cardiac hypertrophy involving multiple signaling pathways that control up- and downregulation of miRNAs. It represents a first step in the systematic discovery of miRNA function in cardiovascular hypertrophy.

  10. Identification of DreI as an antiviral factor regulated by RLR signaling pathway.

    Directory of Open Access Journals (Sweden)

    Shun Li

    Full Text Available BACKGROUND: Retinoic acid-inducible gene I (RIG-I-like receptors (RLRs had been demonstrated to prime interferon (IFN response against viral infection via the conserved RLR signaling in fish, and a novel fish-specific gene, the grass carp reovirus (GCRV-induced gene 2 (Gig2, had been suggested to play important role in host antiviral response. METHODOLOGY/PRINCIPAL FINDINGS: In this study, we cloned and characterized zebrafish Gig2 homolog (named Danio rerio Gig2-I, DreI, and revealed its antiviral role and expressional regulation signaling pathway. RT-PCR, Western blot and promoter activity assay indicate that DreI can be induced by poly I:C, spring viremia of carp virus (SVCV and recombinant IFN (rIFN, showing that DreI is a typical ISG. Using the pivotal signaling molecules of RLR pathway, including RIG-I, MDA5 and IRF3 from crucian carp, it is found that DreI expression is regulated by RLR cascade and IRF3 plays an important role in this regulation. Furthermore, promoter mutation assay confirms that the IFN-stimulated regulatory elements (ISRE in the 5' flanking region of DreI is essential for its induction. Finally, overexpression of DreI leads to establish a strong antiviral state against SVCV and Rana grylio virus (RGV infection in EPC (Epithelioma papulosum cyprinid cells. CONCLUSIONS/SIGNIFICANCE: These data indicate that DreI is an antiviral protein, which is regulated by RLR signaling pathway.

  11. The hippo pathway promotes Notch signaling in regulation of cell differentiation, proliferation, and oocyte polarity.

    Directory of Open Access Journals (Sweden)

    Jianzhong Yu

    2008-03-01

    Full Text Available Specification of the anterior-posterior axis in Drosophila oocytes requires proper communication between the germ-line cells and the somatically derived follicular epithelial cells. Multiple signaling pathways, including Notch, contribute to oocyte polarity formation by controlling the temporal and spatial pattern of follicle cell differentiation and proliferation. Here we show that the newly identified Hippo tumor-suppressor pathway plays a crucial role in the posterior follicle cells in the regulation of oocyte polarity. Disruption of the Hippo pathway, including major components Hippo, Salvador, and Warts, results in aberrant follicle-cell differentiation and proliferation and dramatic disruption of the oocyte anterior-posterior axis. These phenotypes are related to defective Notch signaling in follicle cells, because misexpression of a constitutively active form of Notch alleviates the oocyte polarity defects. We also find that follicle cells defective in Hippo signaling accumulate the Notch receptor and display defects in endocytosis markers. Our findings suggest that the interaction between Hippo and classic developmental pathways such as Notch is critical to spatial and temporal regulation of differentiation and proliferation and is essential for development of the body axes in Drosophila.

  12. Integrated QSAR study for inhibitors of Hedgehog Signal Pathway against multiple cell lines:a collaborative filtering method.

    Science.gov (United States)

    Gao, Jun; Che, Dongsheng; Zheng, Vincent W; Zhu, Ruixin; Liu, Qi

    2012-07-31

    The Hedgehog Signaling Pathway is one of signaling pathways that are very important to embryonic development. The participation of inhibitors in the Hedgehog Signal Pathway can control cell growth and death, and searching novel inhibitors to the functioning of the pathway are in a great demand. As the matter of fact, effective inhibitors could provide efficient therapies for a wide range of malignancies, and targeting such pathway in cells represents a promising new paradigm for cell growth and death control. Current research mainly focuses on the syntheses of the inhibitors of cyclopamine derivatives, which bind specifically to the Smo protein, and can be used for cancer therapy. While quantitatively structure-activity relationship (QSAR) studies have been performed for these compounds among different cell lines, none of them have achieved acceptable results in the prediction of activity values of new compounds. In this study, we proposed a novel collaborative QSAR model for inhibitors of the Hedgehog Signaling Pathway by integration the information from multiple cell lines. Such a model is expected to substantially improve the QSAR ability from single cell lines, and provide useful clues in developing clinically effective inhibitors and modifications of parent lead compounds for target on the Hedgehog Signaling Pathway. In this study, we have presented: (1) a collaborative QSAR model, which is used to integrate information among multiple cell lines to boost the QSAR results, rather than only a single cell line QSAR modeling. Our experiments have shown that the performance of our model is significantly better than single cell line QSAR methods; and (2) an efficient feature selection strategy under such collaborative environment, which can derive the commonly important features related to the entire given cell lines, while simultaneously showing their specific contributions to a specific cell-line. Based on feature selection results, we have proposed several

  13. Integration of Signaling Pathways with the Epigenetic Machinery in the Maintenance of Stem Cells

    Directory of Open Access Journals (Sweden)

    Luca Fagnocchi

    2016-01-01

    Full Text Available Stem cells balance their self-renewal and differentiation potential by integrating environmental signals with the transcriptional regulatory network. The maintenance of cell identity and/or cell lineage commitment relies on the interplay of multiple factors including signaling pathways, transcription factors, and the epigenetic machinery. These regulatory modules are strongly interconnected and they influence the pattern of gene expression of stem cells, thus guiding their cellular fate. Embryonic stem cells (ESCs represent an invaluable tool to study this interplay, being able to indefinitely self-renew and to differentiate towards all three embryonic germ layers in response to developmental cues. In this review, we highlight those mechanisms of signaling to chromatin, which regulate chromatin modifying enzymes, histone modifications, and nucleosome occupancy. In addition, we report the molecular mechanisms through which signaling pathways affect both the epigenetic and the transcriptional state of ESCs, thereby influencing their cell identity. We propose that the dynamic nature of oscillating signaling and the different regulatory network topologies through which those signals are encoded determine specific gene expression programs, leading to the fluctuation of ESCs among multiple pluripotent states or to the establishment of the necessary conditions to exit pluripotency.

  14. PathText: a text mining integrator for biological pathway visualizations

    Science.gov (United States)

    Kemper, Brian; Matsuzaki, Takuya; Matsuoka, Yukiko; Tsuruoka, Yoshimasa; Kitano, Hiroaki; Ananiadou, Sophia; Tsujii, Jun'ichi

    2010-01-01

    Motivation: Metabolic and signaling pathways are an increasingly important part of organizing knowledge in systems biology. They serve to integrate collective interpretations of facts scattered throughout literature. Biologists construct a pathway by reading a large number of articles and interpreting them as a consistent network, but most of the models constructed currently lack direct links to those articles. Biologists who want to check the original articles have to spend substantial amounts of time to collect relevant articles and identify the sections relevant to the pathway. Furthermore, with the scientific literature expanding by several thousand papers per week, keeping a model relevant requires a continuous curation effort. In this article, we present a system designed to integrate a pathway visualizer, text mining systems and annotation tools into a seamless environment. This will enable biologists to freely move between parts of a pathway and relevant sections of articles, as well as identify relevant papers from large text bases. The system, PathText, is developed by Systems Biology Institute, Okinawa Institute of Science and Technology, National Centre for Text Mining (University of Manchester) and the University of Tokyo, and is being used by groups of biologists from these locations. Contact: brian@monrovian.com. PMID:20529930

  15. Utilizing ras signaling pathway to direct selective replication of herpes simplex virus-1.

    Directory of Open Access Journals (Sweden)

    Weihong Pan

    Full Text Available Re-engineering the tropism of viruses is an attractive translational strategy for targeting cancer cells. The Ras signal transduction pathway is a central hub for a variety of pro-oncogenic events with a fundamental role in normal and neoplastic physiology. In this work we were interested in linking Ras activation to HSV-1 replication in a direct manner in order to generate a novel oncolytic herpes virus which can target cancer cells. To establish such link, we developed a mutant HSV-1 in which the expression of ICP4 (infected cell protein-4, a viral protein necessary for replication is controlled by activation of ELK, a transcription factor down-stream of the Ras pathway and mainly activated by ERK (extracellular signal-regulated kinase, an important Ras effector pathway. This mutant HSV-1 was named as Signal-Smart 1 (SS1. A series of prostate cells were infected with the SS1 virus. Cells with elevated levels of ELK activation were preferentially infected by the SS1 virus, as demonstrated by increased levels of viral progeny, herpetic glycoprotein C and overall SS1 viral protein production. Upon exposure to SS1, the proliferation, invasiveness and colony formation capabilities of prostate cancer cells with increased ELK activation were significantly decreased (p<0.05, while the rate of apoptosis/necrosis in these cells was increased. Additionally, high Ras signaling cells infected with SS1 showed a prominent arrest in the G1 phase of the cell cycle as compared to cells exposed to parental HSV-1. The results of this study reveal the potential for re-modeling the host-herpes interaction to specifically interfere with the life of cancer cells with increased Ras signaling. SS1 also serves as a "prototype" for development of a family of signal-smart viruses which can target cancer cells on the basis of their signaling portfolio.

  16. Signaling pathway-focused gene expression profiling in pressure overloaded hearts

    Directory of Open Access Journals (Sweden)

    Marco Musumeci

    2011-01-01

    Full Text Available The β-blocker propranolol displays antihypertrophic and antifibrotic properties in the heart subjected to pressure overload. Yet the underlying mechanisms responsible for these important effects remain to be completely understood. The purpose of this study was to determine signaling pathway-focused gene expression profile associated with the antihypertrophic action of propranolol in pressure overloaded hearts. To address this question, a focused real-time PCR array was used to screen left ventricular RNA expression of 84 gene transcripts representative of 18 different signaling pathways in C57BL/6 mice subjected to transverse aortic constriction (TAC or sham surgery. On the surgery day, mice received either propranolol (80 mg/kg/day or vehicle for 14 days. TAC caused a 49% increase in the left ventricular weight-to-body weight (LVW/BW ratio without changing gene expression. Propranolol blunted LVW/BW ratio increase by approximately 50% while causing about a 3-fold increase in the expression of two genes, namely Brca1 and Cdkn2a, belonging to the TGF-beta and estrogen pathways, respectively. In conclusion, after 2 weeks of pressure overload, TAC hearts show a gene expression profile superimposable to that of sham hearts. Conversely, propranolol treatment is associated with an increased expression of genes which negatively regulate cell cycle progression. It remains to be established whether a mechanistic link between gene expression changes and the antihypertrophic action of propranolol occurs.

  17. Romidepsin targets multiple survival signaling pathways in malignant T cells

    International Nuclear Information System (INIS)

    Valdez, B C; Brammer, J E; Li, Y; Murray, D; Liu, Y; Hosing, C; Nieto, Y; Champlin, R E; Andersson, B S

    2015-01-01

    Romidepsin is a cyclic molecule that inhibits histone deacetylases. It is Food and Drug Administration-approved for treatment of cutaneous and peripheral T-cell lymphoma, but its precise mechanism of action against malignant T cells is unknown. To better understand the biological effects of romidepsin in these cells, we exposed PEER and SUPT1 T-cell lines, and a primary sample from T-cell lymphoma patient (Patient J) to romidepsin. We then examined the consequences in some key oncogenic signaling pathways. Romidepsin displayed IC 50 values of 10.8, 7.9 and 7.0 nm in PEER, SUPT1 and Patient J cells, respectively. Strong inhibition of histone deacetylases and demethylases, increased production of reactive oxygen species and decreased mitochondrial membrane potential were observed, which may contribute to the observed DNA-damage response and apoptosis. The stress-activated protein kinase/c-Jun N-terminal kinase signaling pathway and unfolded protein response in the endoplasmic reticulum were activated, whereas the phosphatidylinositol 3-kinase/AKT/mammalian target of rapamycin (PI3K/AKT/mTOR) and β-catenin pro-survival pathways were inhibited. The decreased level of β-catenin correlated with the upregulation of its inhibitor SFRP1 through romidepsin-mediated hypomethylation of its gene promoter. Our results provide new insights into how romidepsin invokes malignant T-cell killing, show evidence of its associated DNA hypomethylating activity and offer a rationale for the development of romidepsin-containing combination therapies

  18. Schisantherin A suppresses osteoclast formation and wear particle-induced osteolysis via modulating RANKL signaling pathways

    Energy Technology Data Exchange (ETDEWEB)

    He, Yi; Zhang, Qing; Shen, Yi; Chen, Xia; Zhou, Feng; Peng, Dan, E-mail: xyeypd@163.com

    2014-07-04

    Highlights: • Schisantherin A suppresses osteoclasts formation and function in vitro. • Schisantherin A impairs RANKL signaling pathway. • Schisantherin A suppresses osteolysis in vivo. • Schisantherin A may be used for treating osteoclast related diseases. - Abstract: Receptor activator of NF-κB ligand (RANKL) plays critical role in osteoclastogenesis. Targeting RANKL signaling pathways has been a promising strategy for treating osteoclast related bone diseases such as osteoporosis and aseptic prosthetic loosening. Schisantherin A (SA), a dibenzocyclooctadiene lignan isolated from the fruit of Schisandra sphenanthera, has been used as an antitussive, tonic, and sedative agent, but its effect on osteoclasts has been hitherto unknown. In the present study, SA was found to inhibit RANKL-induced osteoclast formation and bone resorption. The osteoclastic specific marker genes induced by RANKL including c-Src, SA inhibited OSCAR, cathepsin K and TRAP in a dose dependent manner. Further signal transduction studies revealed that SA down-regulate RANKL-induced nuclear factor-kappaB (NF-κB) signaling activation by suppressing the phosphorylation and degradation of IκBα, and subsequently preventing the NF-κB transcriptional activity. Moreover, SA also decreased the RANKL-induced MAPKs signaling pathway, including JNK and ERK1/2 posphorylation while had no obvious effects on p38 activation. Finally, SA suppressed the NF-κB and MAPKs subsequent gene expression of NFATc1 and c-Fos. In vivo studies, SA inhibited osteoclast function and exhibited bone protection effect in wear-particle-induced bone erosion model. Taken together, SA could attenuate osteoclast formation and wear particle-induced osteolysis by mediating RANKL signaling pathways. These data indicated that SA is a promising therapeutic natural compound for the treatment of osteoclast-related prosthesis loosening.

  19. SPAG6 regulates cell apoptosis through the TRAIL signal pathway in myelodysplastic syndromes.

    Science.gov (United States)

    Li, Xinxin; Yang, Bihui; Wang, Li; Chen, Liping; Luo, Xiaohua; Liu, Lin

    2017-05-01

    Myelodysplastic syndromes (MDSs) are a group of malignant clone hematopoietic stem-cell diseases, and the evolution and progression of MDS depend on the abnormal apoptosis of bone marrow cells. Our previous studies have indicated that sperm-associated antigen 6 (SPAG6), located in the uniparental disomy regions of myeloid cells, is overexpressed in patients with MDS as compared to controls, and SPAG6 can inhibit apoptosis of SKM-1. However, the concrete mechanism is still unclear. In the present study, it was found that the TNF-related apoptosis-inducing ligand (TRAIL)signal pathway was activated when the expression of SPAG6 was inhibited by SPAG6-shRNA lentivirus in SKM-1 cells. Additionally, the results of flow cytometry, Cell Counting Kit-8 assay and western blot analysis implied that the TRAIL signal pathway could be inhibited by a high expression of SPAG6. However, SPAG6 cannot influence the expression of TRAIL death receptors, except for FADD. Additionally the interaction between FADD and TRAIL death receptors also increased in SKM-1 cells infected with SPAG6-shRNA lentivirus. Thus, our study demonstrates that SPAG6 may regulate apoptosis in SKM-1 through the TRAIL signal pathway, indicating that SPAG6 could be a potential therapeutic target.

  20. Genetic Variants in the Wnt/β-Catenin Signaling Pathway as Indicators of Bladder Cancer Risk.

    Science.gov (United States)

    Pierzynski, Jeanne A; Hildebrandt, Michelle A; Kamat, Ashish M; Lin, Jie; Ye, Yuanqing; Dinney, Colin P N; Wu, Xifeng

    2015-12-01

    Genetic factors that influence bladder cancer risk remain largely unknown. Previous research has suggested that there is a strong genetic component underlying the risk of bladder cancer. The Wnt/β-catenin signaling pathway is a key modulator of cellular proliferation through its regulation of stem cell homeostasis. Furthermore, variants in the Wnt/β-catenin signaling pathway have been implicated in the development of other cancers, leading us to believe that this pathway may have a vital role in bladder cancer development. A total of 230 single nucleotide polymorphisms in 40 genes in the Wnt/β-catenin signaling pathway were genotyped in 803 bladder cancer cases and 803 healthy controls. A total of 20 single nucleotide polymorphisms were nominally significant for risk. Individuals with 2 variants of LRP6: rs10743980 were associated with a decreased risk of bladder cancer in the recessive model in the initial analysis (OR 0.76, 95% CI 0.58-0.99, p=0.039). This was validated using the bladder genome-wide association study chip (OR 0.51, 95% CI 0.27-1.00, p=0.049 and for combined analysis p=0.007). Together these findings implicate variants in the Wnt/β-catenin stem cell pathway as having a role in bladder cancer etiology. Copyright © 2015 American Urological Association Education and Research, Inc. Published by Elsevier Inc. All rights reserved.

  1. Leptin and glucocorticoid signaling pathways in the hypothalamus of female and male fructose-fed rats

    Directory of Open Access Journals (Sweden)

    Vojnović-Milutinović Danijela

    2014-01-01

    Full Text Available Alterations in leptin and glucocorticoid signaling pathways in the hypothalamus of male and female rats subjected to a fructose-enriched diet were studied. The level of expression of the key components of the leptin signaling pathway (neuropeptide Y /NPY/ and suppressor of cytokine signaling 3 /SOCS3/, and the glucocorticoid signaling pathway (glucocorticoid receptor /GR/, 11β-hydroxysteroid dehydrogenase type 1 /11βHSD1/ and hexose-6-phosphate dehydrogenase /H6PDH/ did not differ between fructose-fed rats and control animals of both genders. However, in females, a fructose-enriched diet provoked increases in the adiposity index, plasma leptin and triglyceride concentrations, and displayed a tendency to decrease the leptin receptor (ObRb protein and mRNA levels. In male rats, the fructose diet caused elevations in plasma non-esterified fatty acids and triglycerides, as well as in both plasma and hypothalamic leptin concentrations. Our results suggest that a fructose-enriched diet can induce hyperleptinemia in both female and male rats, but with a more pronounced effect on hypothalamic leptin sensitivity in females, probably contributing to the observed development of visceral adiposity. [Projekat Ministarstva nauke Republike Srbije, br. III41009

  2. Inflammation activates the interferon signaling pathways in taste bud cells.

    Science.gov (United States)

    Wang, Hong; Zhou, Minliang; Brand, Joseph; Huang, Liquan

    2007-10-03

    Patients with viral and bacterial infections or other inflammatory illnesses often experience taste dysfunctions. The agents responsible for these taste disorders are thought to be related to infection-induced inflammation, but the mechanisms are not known. As a first step in characterizing the possible role of inflammation in taste disorders, we report here evidence for the presence of interferon (IFN)-mediated signaling pathways in taste bud cells. IFN receptors, particularly the IFN-gamma receptor IFNGR1, are coexpressed with the taste cell-type markers neuronal cell adhesion molecule and alpha-gustducin, suggesting that both the taste receptor cells and synapse-forming cells in the taste bud can be stimulated by IFN. Incubation of taste bud-containing lingual epithelia with recombinant IFN-alpha and IFN-gamma triggered the IFN-mediated signaling cascades, resulting in the phosphorylation of the downstream STAT1 (signal transducer and activator of transcription protein 1) transcription factor. Intraperitoneal injection of lipopolysaccharide or polyinosinic:polycytidylic acid into mice, mimicking bacterial and viral infections, respectively, altered gene expression patterns in taste bud cells. Furthermore, the systemic administration of either IFN-alpha or IFN-gamma significantly increased the number of taste bud cells undergoing programmed cell death. These findings suggest that bacterial and viral infection-induced IFNs can act directly on taste bud cells, affecting their cellular function in taste transduction, and that IFN-induced apoptosis in taste buds may cause abnormal cell turnover and skew the representation of different taste bud cell types, leading to the development of taste disorders. To our knowledge, this is the first study providing direct evidence that inflammation can affect taste buds through cytokine signaling pathways.

  3. In Vivo Characterization of Intracellular Signaling Pathways Activated by the Nerve Agent Sarin

    National Research Council Canada - National Science Library

    Shih, Tsung-Ming A; Snyder, Gretchen L; Hendrick, Joseph P; Fienberg, Allen A; McDonough, John H

    2004-01-01

    ..., an excessive stimulation of nicotinic and muscarinic receptors. Preliminary evidence using diverse OPs indicates that the DARPP-32/PP-1 signaling pathway is activated by nicotinic receptor stimulation...

  4. Hydrogen peroxide induces activation of insulin signaling pathway via AMP-dependent kinase in podocytes

    International Nuclear Information System (INIS)

    Piwkowska, Agnieszka; Rogacka, Dorota; Angielski, Stefan; Jankowski, Maciej

    2012-01-01

    Highlights: ► H 2 O 2 activates the insulin signaling pathway and glucose uptake in podocytes. ► H 2 O 2 induces time-dependent changes in AMPK phosphorylation. ► H 2 O 2 enhances insulin signaling pathways via AMPK activation. ► H 2 O 2 stimulation of glucose uptake is AMPK-dependent. -- Abstract: Podocytes are cells that form the glomerular filtration barrier in the kidney. Insulin signaling in podocytes is critical for normal kidney function. Insulin signaling is regulated by oxidative stress and intracellular energy levels. We cultured rat podocytes to investigate the effects of hydrogen peroxide (H 2 O 2 ) on the phosphorylation of proximal and distal elements of insulin signaling. We also investigated H 2 O 2 -induced intracellular changes in the distribution of protein kinase B (Akt). Western blots showed that H 2 O 2 (100 μM) induced rapid, transient phosphorylation of the insulin receptor (IR), the IR substrate-1 (IRS1), and Akt with peak activities at 5 min (Δ 183%, P 2 O 2 >. Furthermore, H 2 O 2 inhibited phosphorylation of the phosphatase and tensin homologue (PTEN; peak activity at 10 min; Δ −32%, P 2 O 2 on IR phosphorylation by about 40% (from 2.07 ± 0.28 to 1.28 ± 0.12, P 2 O 2 increased glucose uptake in podocytes (from 0.88 ± 0.04 to 1.29 ± 0.12 nmol/min/mg protein, P 2 O 2 activated the insulin signaling pathway and glucose uptake via AMPK in cultured rat podocytes. This signaling may play a potential role in the prevention of insulin resistance under conditions associated with oxidative stress.

  5. Reconstruction and signal propagation analysis of the Syk signaling network in breast cancer cells.

    Directory of Open Access Journals (Sweden)

    Aurélien Naldi

    2017-03-01

    Full Text Available The ability to build in-depth cell signaling networks from vast experimental data is a key objective of computational biology. The spleen tyrosine kinase (Syk protein, a well-characterized key player in immune cell signaling, was surprisingly first shown by our group to exhibit an onco-suppressive function in mammary epithelial cells and corroborated by many other studies, but the molecular mechanisms of this function remain largely unsolved. Based on existing proteomic data, we report here the generation of an interaction-based network of signaling pathways controlled by Syk in breast cancer cells. Pathway enrichment of the Syk targets previously identified by quantitative phospho-proteomics indicated that Syk is engaged in cell adhesion, motility, growth and death. Using the components and interactions of these pathways, we bootstrapped the reconstruction of a comprehensive network covering Syk signaling in breast cancer cells. To generate in silico hypotheses on Syk signaling propagation, we developed a method allowing to rank paths between Syk and its targets. We first annotated the network according to experimental datasets. We then combined shortest path computation with random walk processes to estimate the importance of individual interactions and selected biologically relevant pathways in the network. Molecular and cell biology experiments allowed to distinguish candidate mechanisms that underlie the impact of Syk on the regulation of cortactin and ezrin, both involved in actin-mediated cell adhesion and motility. The Syk network was further completed with the results of our biological validation experiments. The resulting Syk signaling sub-networks can be explored via an online visualization platform.

  6. Involvement of intracellular Zn2+ signaling in LTP at perforant pathway-CA1 pyramidal cell synapse.

    Science.gov (United States)

    Tamano, Haruna; Nishio, Ryusuke; Takeda, Atsushi

    2017-07-01

    Physiological significance of synaptic Zn 2+ signaling was examined at perforant pathway-CA1 pyramidal cell synapses. In vivo long-term potentiation (LTP) at perforant pathway-CA1 pyramidal cell synapses was induced using a recording electrode attached to a microdialysis probe and the recording region was locally perfused with artificial cerebrospinal fluid (ACSF) via the microdialysis probe. Perforant pathway LTP was not attenuated under perfusion with CaEDTA (10 mM), an extracellular Zn 2+ chelator, but attenuated under perfusion with ZnAF-2DA (50 μM), an intracellular Zn 2+ chelator, suggesting that intracellular Zn 2+ signaling is required for perforant pathway LTP. Even in rat brain slices bathed in CaEDTA in ACSF, intracellular Zn 2+ level, which was measured with intracellular ZnAF-2, was increased in the stratum lacunosum-moleculare where perforant pathway-CA1 pyramidal cell synapses were contained after tetanic stimulation. These results suggest that intracellular Zn 2+ signaling, which originates in internal stores/proteins, is involved in LTP at perforant pathway-CA1 pyramidal cell synapses. Because the influx of extracellular Zn 2+ , which originates in presynaptic Zn 2+ release, is involved in LTP at Schaffer collateral-CA1 pyramidal cell synapses, synapse-dependent Zn 2+ dynamics may be involved in plasticity of postsynaptic CA1 pyramidal cells. © 2017 Wiley Periodicals, Inc.

  7. Proinflammatory Cytokine IL-6 and JAK-STAT Signaling Pathway in Myeloproliferative Neoplasms

    Directory of Open Access Journals (Sweden)

    Vladan P. Čokić

    2015-01-01

    Full Text Available The recent JAK1/2 inhibitor trial in myeloproliferative neoplasms (MPNs showed that reducing inflammation can be more beneficial than targeting gene mutants. We evaluated the proinflammatory IL-6 cytokine and JAK-STAT signaling pathway related genes in circulating CD34+ cells of MPNs. Regarding laboratory data, leukocytosis has been observed in polycythemia vera (PV and JAK2V617F mutation positive versus negative primary myelofibrosis (PMF patients. Moreover, thrombocytosis was reduced by JAK2V617F allele burden in essential thrombocythemia (ET and PMF. 261 significantly changed genes have been detected in PV, 82 in ET, and 94 genes in PMF. The following JAK-STAT signaling pathway related genes had augmented expression in CD34+ cells of MPNs: CCND3 and IL23A regardless of JAK2V617F allele burden; CSF3R, IL6ST, and STAT1/2 in ET and PV with JAK2V617F mutation; and AKT2, IFNGR2, PIM1, PTPN11, and STAT3 only in PV. STAT5A gene expression was generally reduced in MPNs. IL-6 cytokine levels were increased in plasma, as well as IL-6 protein levels in bone marrow stroma of MPNs, dependent on JAK2V617F mutation presence in ET and PMF patients. Therefore, the JAK2V617F mutant allele burden participated in inflammation biomarkers induction and related signaling pathways activation in MPNs.

  8. Large scale statistical inference of signaling pathways from RNAi and microarray data

    Directory of Open Access Journals (Sweden)

    Poustka Annemarie

    2007-10-01

    Full Text Available Abstract Background The advent of RNA interference techniques enables the selective silencing of biologically interesting genes in an efficient way. In combination with DNA microarray technology this enables researchers to gain insights into signaling pathways by observing downstream effects of individual knock-downs on gene expression. These secondary effects can be used to computationally reverse engineer features of the upstream signaling pathway. Results In this paper we address this challenging problem by extending previous work by Markowetz et al., who proposed a statistical framework to score networks hypotheses in a Bayesian manner. Our extensions go in three directions: First, we introduce a way to omit the data discretization step needed in the original framework via a calculation based on p-values instead. Second, we show how prior assumptions on the network structure can be incorporated into the scoring scheme using regularization techniques. Third and most important, we propose methods to scale up the original approach, which is limited to around 5 genes, to large scale networks. Conclusion Comparisons of these methods on artificial data are conducted. Our proposed module network is employed to infer the signaling network between 13 genes in the ER-α pathway in human MCF-7 breast cancer cells. Using a bootstrapping approach this reconstruction can be found with good statistical stability. The code for the module network inference method is available in the latest version of the R-package nem, which can be obtained from the Bioconductor homepage.

  9. Salicylic acid induces vanillin synthesis through the phospholipid signaling pathway in Capsicum chinense cell cultures.

    Science.gov (United States)

    Rodas-Junco, Beatriz A; Cab-Guillén, Yahaira; Muñoz-Sánchez, J Armando; Vázquez-Flota, Felipe; Monforte-González, Miriam; Hernández-Sotomayor, S M Teresa

    2013-10-01

    Signal transduction via phospholipids is mediated by phospholipases such as phospholipase C (PLC) and D (PLD), which catalyze hydrolysis of plasma membrane structural phospholipids. Phospholipid signaling is also involved in plant responses to phytohormones such as salicylic acid (SA). The relationships between phospholipid signaling, SA, and secondary metabolism are not fully understood. Using a Capsicum chinense cell suspension as a model, we evaluated whether phospholipid signaling modulates SA-induced vanillin production through the activation of phenylalanine ammonia lyase (PAL), a key enzyme in the biosynthetic pathway. Salicylic acid was found to elicit PAL activity and consequently vanillin production, which was diminished or reversed upon exposure to the phosphoinositide-phospholipase C (PI-PLC) signaling inhibitors neomycin and U73122. Exposure to the phosphatidic acid inhibitor 1-butanol altered PLD activity and prevented SA-induced vanillin production. Our results suggest that PLC and PLD-generated secondary messengers may be modulating SA-induced vanillin production through the activation of key biosynthetic pathway enzymes.

  10. Transmembrane signaling in Saccharomyces cerevisiae as a model for signaling in metazoans: state of the art after 25 years.

    Science.gov (United States)

    Engelberg, David; Perlman, Riki; Levitzki, Alexander

    2014-12-01

    In the very first article that appeared in Cellular Signalling, published in its inaugural issue in October 1989, we reviewed signal transduction pathways in Saccharomyces cerevisiae. Although this yeast was already a powerful model organism for the study of cellular processes, it was not yet a valuable instrument for the investigation of signaling cascades. In 1989, therefore, we discussed only two pathways, the Ras/cAMP and the mating (Fus3) signaling cascades. The pivotal findings concerning those pathways undoubtedly contributed to the realization that yeast is a relevant model for understanding signal transduction in higher eukaryotes. Consequently, the last 25 years have witnessed the discovery of many signal transduction pathways in S. cerevisiae, including the high osmotic glycerol (Hog1), Stl2/Mpk1 and Smk1 mitogen-activated protein (MAP) kinase pathways, the TOR, AMPK/Snf1, SPS, PLC1 and Pkr/Gcn2 cascades, and systems that sense and respond to various types of stress. For many cascades, orthologous pathways were identified in mammals following their discovery in yeast. Here we review advances in the understanding of signaling in S. cerevisiae over the last 25 years. When all pathways are analyzed together, some prominent themes emerge. First, wiring of signaling cascades may not be identical in all S. cerevisiae strains, but is probably specific to each genetic background. This situation complicates attempts to decipher and generalize these webs of reactions. Secondly, the Ras/cAMP and the TOR cascades are pivotal pathways that affect all processes of the life of the yeast cell, whereas the yeast MAP kinase pathways are not essential. Yeast cells deficient in all MAP kinases proliferate normally. Another theme is the existence of central molecular hubs, either as single proteins (e.g., Msn2/4, Flo11) or as multisubunit complexes (e.g., TORC1/2), which are controlled by numerous pathways and in turn determine the fate of the cell. It is also apparent that

  11. Desert dust induces TLR signaling to trigger Th2-dominant lung allergic inflammation via a MyD88-dependent signaling pathway

    International Nuclear Information System (INIS)

    He, Miao; Ichinose, Takamichi; Song, Yuan; Yoshida, Yasuhiro; Bekki, Kanae; Arashidani, Keiichi; Yoshida, Seiichi; Nishikawa, Masataka; Takano, Hirohisa; Shibamoto, Takayuki; Sun, Guifan

    2016-01-01

    Asian sand dust (ASD) is known to exacerbate asthma, although its mechanism is not yet well understood. In this study, when the effects on inflammatory response by LPS present in ASD was investigated by measuring the gene expression of cytokines and chemokines in RAW264.7 cells treated with ASD and/or polymyxin B (PMB), the ASD effects were attenuated by PMB, but not completely. When an in vitro study was performed using bone marrow-derived macrophages (BMDMs) from WT, TLR2 −/− , TLR4 −/− , and MyD88 −/− BALB/c mice and BMDMs from WT, TLR2 −/− , TLR4 −/− , TLR2/4 −/− , TLR7/9 −/− , and MyD88 −/− C57BL/6J mice, cytokine (IL-6, IL-12) production in BMDMs was higher in ASD-stimulated TLR2 −/− cells than in TLR4 −/− cells, whereas it was lower or undetectable in TLR2/4 −/− and MyD88 −/− cells. These results suggest that ASD causes cytokine production predominantly in a TLR4/MyD88-dependent pathway. When WT and TLRs 2 −/− , 4 −/− , and MyD88 −/− BALB/c mice were intratracheally challenged with OVA and/or ASD, ASD caused exacerbation of lung eosinophilia along with Th2 cytokine and eosinophil-relevant chemokine production. Serum OVA-specific IgE and IgG1 similar to WT was observed in TLRs 2 −/− , 4 −/− mice, but not in MyD88 −/− mice. The Th2 responses in TLR2 −/− mice were attenuated remarkably by PMB. These results indicate that ASD exacerbates lung eosinophilia in a MyD88-dependent pathway. TLRs 2 and 4 signaling may be important in the increase in lung eosinophilia. Also, the TLR4 ligand LPS and TLR2 ligand like β-glucan may be strong candidates for exacerbation of lung eosinophilia. - Highlights: • ASD enhanced Th2 response in TLR2 −/− , TLR4 −/− and WT mice, but not in MyD88 −/− . • Th2 responses in TLR2 −/− mice were attenuated by LPS inhibitor polymyxin B. • TLR2 and TLR4 signaling is important in allergic lung disease aggravation by ASD. • MyD88 is the key

  12. Overexpression of protein O-fucosyltransferase 1 accelerates hepatocellular carcinoma progression via the Notch signaling pathway

    International Nuclear Information System (INIS)

    Ma, Lijie; Dong, Pingping; Liu, Longzi; Gao, Qiang; Duan, Meng; Zhang, Si; Chen, She; Xue, Ruyi; Wang, Xiaoying

    2016-01-01

    Aberrant activation of Notch signaling frequently occurs in liver cancer, and is associated with liver malignancies. However, the mechanisms regulating pathologic Notch activation in hepatocellular carcinoma (HCC) remain unclear. Protein O-fucosyltransferase 1 (Pofut1) catalyzes the addition of O-linked fucose to the epidermal growth factor-like repeats of Notch. In the present study, we detected the expression of Pofut1 in 8 HCC cell lines and 253 human HCC tissues. We reported that Pofut1 was overexpressed in HCC cell lines and clinical HCC tissues, and Pofut1 overexpression clinically correlated with the unfavorable survival and high disease recurrence in HCC. The in vitro assay demonstrated that Pofut1 overexpression accelerated the cell proliferation and migration in HCC cells. Furthermore, Pofut1 overexpression promoted the binding of Notch ligand Dll1 to Notch receptor, and hence activated Notch signaling pathway in HCC cells, indicating that Pofut1 overexpression could be a reason for the aberrant activation of Notch signaling in HCC. Taken together, our findings indicated that an aberrant activated Pofut1-Notch pathway was involved in HCC progression, and blockage of this pathway could be a promising strategy for the therapy of HCC. - Highlights: • Pofut1 overexpression in HCC was correlated with aggressive tumor behaviors. • Pofut1 overexpression in HCC was associated with poor prognosis. • Pofut1 promoted cell proliferation, migration and invasion in hepatoma cells. • Pofut1 activated Notch signaling pathway in hepatoma cells.

  13. Overexpression of protein O-fucosyltransferase 1 accelerates hepatocellular carcinoma progression via the Notch signaling pathway

    Energy Technology Data Exchange (ETDEWEB)

    Ma, Lijie [Liver Surgery Department, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Shanghai (China); Dong, Pingping [Department of Gastroenterology and Hepatology, Shanghai Institute of Liver Diseases, Zhongshan Hospital of Fudan University, Shanghai (China); Liu, Longzi; Gao, Qiang; Duan, Meng [Liver Surgery Department, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Shanghai (China); Zhang, Si; Chen, She [Key Laboratory of Glycoconjugate Research Ministry of Public Health, Department of Biochemistry and Molecular Biology, Shanghai Medical College, Fudan University, Shanghai (China); Xue, Ruyi, E-mail: xue.ruyi@zs-hospital.sh.cn [Department of Gastroenterology and Hepatology, Shanghai Institute of Liver Diseases, Zhongshan Hospital of Fudan University, Shanghai (China); Wang, Xiaoying, E-mail: xiaoyingwang@fudan.edu.cn [Liver Surgery Department, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Shanghai (China)

    2016-04-29

    Aberrant activation of Notch signaling frequently occurs in liver cancer, and is associated with liver malignancies. However, the mechanisms regulating pathologic Notch activation in hepatocellular carcinoma (HCC) remain unclear. Protein O-fucosyltransferase 1 (Pofut1) catalyzes the addition of O-linked fucose to the epidermal growth factor-like repeats of Notch. In the present study, we detected the expression of Pofut1 in 8 HCC cell lines and 253 human HCC tissues. We reported that Pofut1 was overexpressed in HCC cell lines and clinical HCC tissues, and Pofut1 overexpression clinically correlated with the unfavorable survival and high disease recurrence in HCC. The in vitro assay demonstrated that Pofut1 overexpression accelerated the cell proliferation and migration in HCC cells. Furthermore, Pofut1 overexpression promoted the binding of Notch ligand Dll1 to Notch receptor, and hence activated Notch signaling pathway in HCC cells, indicating that Pofut1 overexpression could be a reason for the aberrant activation of Notch signaling in HCC. Taken together, our findings indicated that an aberrant activated Pofut1-Notch pathway was involved in HCC progression, and blockage of this pathway could be a promising strategy for the therapy of HCC. - Highlights: • Pofut1 overexpression in HCC was correlated with aggressive tumor behaviors. • Pofut1 overexpression in HCC was associated with poor prognosis. • Pofut1 promoted cell proliferation, migration and invasion in hepatoma cells. • Pofut1 activated Notch signaling pathway in hepatoma cells.

  14. New advances of TMEM88 in cancer initiation and progression, with special emphasis on Wnt signaling pathway.

    Science.gov (United States)

    Ge, Yun-Xuan; Wang, Chang-Hui; Hu, Fu-Yong; Pan, Lin-Xin; Min, Jie; Niu, Kai-Yuan; Zhang, Lei; Li, Jun; Xu, Tao

    2018-01-01

    Transmembrane protein 88 (TMEM88), a newly discovered protein localized on the cell membrane. Recent studies showed that TMEM88 was involved in the regulation of several types of cancer. TMEM88 was expressed at significantly higher levels in breast cancer (BC) cell line than in normal breast cell line with co-localized with Dishevelled (DVL) in the cytoplasm of BC cell line. TMEM88 silencing in the ovarian cancer cell line CP70 resulted in significant upregulation of Wnt downstream genes (c-Myc, cyclin-D1) and other Wnt target genes including JUN, PTIX2, CTNNB1 (β-catenin), further supporting that TMEM88 inhibits canonical Wnt signaling pathway. Wnt signaling pathway has been known to play important roles in many diseases, especially in cancer. For instance, hepatocellular carcinoma (HCC) has become one of the most common tumors harboring mutations in the Wnt signaling pathway. As the inhibitor of Wnt signaling, TMEM88 has been considered to act as an oncogene or a tumor suppressor. Up-regulated TMEM88 or gene therapy approaches could be an effective therapeutic approach against tumor as TMEM88 inhibits Wnt signaling through direct interaction with DVL. Here, we review the current knowledge on the functional role and potential clinical application of TMEM88 in the control of various cancers. Highlights Wnt signaling displays an important role in several pathogenesis of cancer. Wnt signaling pathway is activated during cancer development. TMEM88 has an impact on cancer by inhibiting canonical Wnt signaling. We discuss the importance and new applications of TMEM88 in cancer therapy. © 2017 Wiley Periodicals, Inc.

  15. Effects of Qingshen Granules on the Oxidative Stress-NF/kB Signal Pathway in Unilateral Ureteral Obstruction Rats.

    Science.gov (United States)

    Jin, Hua; Wang, Yiping; Wang, Dong; Zhang, Lei

    2018-01-01

    Background . The activation of NF-kappa B (NF/kB) signaling pathway plays an important role in the process of epithelial-mesenchymal transition (EMT) and renal interstitial fibrosis (RIF) in renal tubules. The process of oxidative stress reaction in kidney is via excessive reactive oxygen species (ROS) production to activate NF/kB signaling pathway. Qingshen Granule (QSG) is an effective Chinese formula utilized to treat chronic renal failure. Previous studies confirmed that QSG could inhibit RIF in unilateral ureteral obstruction (UUO) rats. In this study, we used UUO rats to investigate the effects of QSG on oxidative stress and the activation of NF/kB signaling. Seventy male Sprague-Dawley (SD) rats were randomly divided into a sham group, UUO model group, Qingshen Granules (QSG) high-dose, medium-dose, and low-dose groups, PDTC group, and candesartan group (10 rats in each group). Our study demonstrated that oxidative stress-NF/kB signal pathway contributed to the formation of UUO renal interstitial fibrosis. QSG may protect against RIF by inhibiting the oxidative stress-NF/kB signal pathway, reducing inflammation, and improving renal tubular EMT.

  16. FREQUENT SUBGRAPH MINING OF PERSONALIZED SIGNALING PATHWAY NETWORKS GROUPS PATIENTS WITH FREQUENTLY DYSREGULATED DISEASE PATHWAYS AND PREDICTS PROGNOSIS.

    Science.gov (United States)

    Durmaz, Arda; Henderson, Tim A D; Brubaker, Douglas; Bebek, Gurkan

    2017-01-01

    Large scale genomics studies have generated comprehensive molecular characterization of numerous cancer types. Subtypes for many tumor types have been established; however, these classifications are based on molecular characteristics of a small gene sets with limited power to detect dysregulation at the patient level. We hypothesize that frequent graph mining of pathways to gather pathways functionally relevant to tumors can characterize tumor types and provide opportunities for personalized therapies. In this study we present an integrative omics approach to group patients based on their altered pathway characteristics and show prognostic differences within breast cancer (p network-based classifier algorithms and showed that our unsupervised approach generates more robust and biologically relevant clustering whereas previous approaches failed to report specific functions for similar patient groups or classify patients into prognostic groups. These results could serve as a means to improve prognosis for future cancer patients, and to provide opportunities for improved treatment options and personalized interventions. The proposed novel graph mining approach is able to integrate PPI networks with gene expression in a biologically sound approach and cluster patients in to clinically distinct groups. We have utilized breast cancer and glioblastoma multiforme datasets from microarray and RNA-Seq platforms and identified disease mechanisms differentiating samples. Supplementary methods, figures, tables and code are available at https://github.com/bebeklab/dysprog.

  17. Primary cilia and coordination of signaling pathways in heart development and tissue Homeostasis

    DEFF Research Database (Denmark)

    Clement, Christian Alexandro

    of primary cilia in coordinating Hh signaling in human pancreatic development and postnatal tissue homeostasis. In cultures of human pancreatic duct adenocarcinoma cell lines PANC-1 and CFPAC-1, Ptc in addition to Gli2 and Smo localize to primary cilia. These findings are consistent with the idea...... that the primary cilium continues to coordinate Hh signaling in cells derived from the mature pancreas. The fact that the Hh signaling pathway is active in the CFPAC-1 and PANC-1 cell lines without Hh stimulation suggests that ciliary Hh signaling plays a potential role in tumorigenesis. In conclusion, this thesis...

  18. Curcumin mediates anticancer effects by modulating multiple cell signaling pathways.

    Science.gov (United States)

    Kunnumakkara, Ajaikumar B; Bordoloi, Devivasha; Harsha, Choudhary; Banik, Kishore; Gupta, Subash C; Aggarwal, Bharat B

    2017-08-01

    Curcumin, a component of a spice native to India, was first isolated in 1815 by Vogel and Pelletier from the rhizomes of Curcuma longa (turmeric) and, subsequently, the chemical structure of curcumin as diferuloylmethane was reported by Milobedzka et al. [(1910) 43., 2163-2170]. Since then, this polyphenol has been shown to exhibit antioxidant, anti-inflammatory, anticancer, antiviral, antibacterial, and antifungal activities. The current review primarily focuses on the anticancer potential of curcumin through the modulation of multiple cell signaling pathways. Curcumin modulates diverse transcription factors, inflammatory cytokines, enzymes, kinases, growth factors, receptors, and various other proteins with an affinity ranging from the pM to the mM range. Furthermore, curcumin effectively regulates tumor cell growth via modulation of numerous cell signaling pathways and potentiates the effect of chemotherapeutic agents and radiation against cancer. Curcumin can interact with most of the targets that are modulated by FDA-approved drugs for cancer therapy. The focus of this review is to discuss the molecular basis for the anticancer activities of curcumin based on preclinical and clinical findings. © 2017 The Author(s). Published by Portland Press Limited on behalf of the Biochemical Society.

  19. β2-Adrenergic receptor activation mobilizes intracellular calcium via a non-canonical cAMP-independent signaling pathway.

    Science.gov (United States)

    Galaz-Montoya, Monica; Wright, Sara J; Rodriguez, Gustavo J; Lichtarge, Olivier; Wensel, Theodore G

    2017-06-16

    Beta adrenergic receptors (βARs) are G-protein-coupled receptors essential for physiological responses to the hormones/neurotransmitters epinephrine and norepinephrine which are found in the nervous system and throughout the body. They are the targets of numerous widely used drugs, especially in the case of the most extensively studied βAR, β 2 AR, whose ligands are used for asthma and cardiovascular disease. βARs signal through Gα s G-proteins and via activation of adenylyl cyclase and cAMP-dependent protein kinase, but some alternative downstream pathways have also been proposed that could be important for understanding normal physiological functioning of βAR signaling and its disruption in disease. Using fluorescence-based Ca 2+ flux assays combined with pharmacology and gene knock-out methods, we discovered a previously unrecognized endogenous pathway in HEK-293 cells whereby β 2 AR activation leads to robust Ca 2+ mobilization from intracellular stores via activation of phospholipase C and opening of inositol trisphosphate (InsP 3 ) receptors. This pathway did not involve cAMP, Gα s , or Gα i or the participation of the other members of the canonical β 2 AR signaling cascade and, therefore, constitutes a novel signaling mechanism for this receptor. This newly uncovered mechanism for Ca 2+ mobilization by β 2 AR has broad implications for adrenergic signaling, cross-talk with other signaling pathways, and the effects of βAR-directed drugs. © 2017 by The American Society for Biochemistry and Molecular Biology, Inc.

  20. Can Co-Activation of Nrf2 and Neurotrophic Signaling Pathway Slow Alzheimer’s Disease?

    Directory of Open Access Journals (Sweden)

    Kelsey E. Murphy

    2017-05-01

    Full Text Available Alzheimer’s disease (AD is a multifaceted disease that is hard to treat by single-modal treatment. AD starts with amyloid peptides, mitochondrial dysfunction, and oxidative stress and later is accompanied with chronic endoplasmic reticulum (ER stress and autophagy dysfunction, resulting in more complicated pathogenesis. Currently, few treatments can modify the complicated pathogenic progress of AD. Compared to the treatment with exogenous antioxidants, the activation of global antioxidant defense system via Nrf2 looks more promising in attenuating oxidative stress in AD brains. Accompanying the activation of the Nrf2-mediated antioxidant defense system that reduce the AD-causative factor, oxidative stress, it is also necessary to activate the neurotrophic signaling pathway that replaces damaged organelles and molecules with new ones. Thus, the dual actions to activate both the Nrf2 antioxidant system and neurotrophic signaling pathway are expected to provide a better strategy to modify AD pathogenesis. Here, we review the current understanding of AD pathogenesis and neuronal defense systems and discuss a possible way to co-activate the Nrf2 antioxidant system and neurotrophic signaling pathway with the hope of helping to find a better strategy to slow AD.

  1. Decoding resistant hypertension signalling pathways.

    Science.gov (United States)

    Parreira, Ricardo Cambraia; Lacerda, Leandro Heleno Guimarães; Vasconcellos, Rebecca; Lima, Swiany Silveira; Santos, Anderson Kenedy; Fontana, Vanessa; Sandrim, Valéria Cristina; Resende, Rodrigo Ribeiro

    2017-12-01

    Resistant hypertension (RH) is a clinical condition in which the hypertensive patient has become resistant to drug therapy and is often associated with increased cardiovascular morbidity and mortality. Several signalling pathways have been studied and related to the development and progression of RH: modulation of sympathetic activity by leptin and aldosterone, primary aldosteronism, arterial stiffness, endothelial dysfunction and variations in the renin-angiotensin-aldosterone system (RAAS). miRNAs comprise a family of small non-coding RNAs that participate in the regulation of gene expression at post-transcriptional level. miRNAs are involved in the development of both cardiovascular damage and hypertension. Little is known of the molecular mechanisms that lead to development and progression of this condition. This review aims to cover the potential roles of miRNAs in the mechanisms associated with the development and consequences of RH, and explore the current state of the art of diagnostic and therapeutic tools based on miRNA approaches. © 2017 The Author(s). Published by Portland Press Limited on behalf of the Biochemical Society.

  2. Nitric Oxide Synthase and Cyclooxygenase Pathways: A Complex Interplay in Cellular Signaling.

    Science.gov (United States)

    Sorokin, Andrey

    2016-01-01

    The cellular reaction to external challenges is a tightly regulated process consisting of integrated processes mediated by a variety of signaling molecules, generated as a result of modulation of corresponding biosynthetic systems. Both, nitric oxide synthase (NOS) and cyclooxygenase (COX) systems, consist of constitutive forms (NOS1, NOS3 and COX-1), which are mostly involved in housekeeping tasks, and inducible forms (NOS2 and COX-2), which shape the cellular response to stress and variety of bioactive agents. The complex interplay between NOS and COX pathways can be observed at least at three levels. Firstly, products of NOS and Cox systems can mediate the regulation and the expression of inducible forms (NOS2 and COX-2) in response of similar and dissimilar stimulus. Secondly, the reciprocal modulation of cyclooxygenase activity by nitric oxide and NOS activity by prostaglandins at the posttranslational level has been shown to occur. Mechanisms by which nitric oxide can modulate prostaglandin synthesis include direct S-nitrosylation of COX and inactivation of prostaglandin I synthase by peroxynitrite, product of superoxide reaction with nitric oxide. Prostaglandins, conversely, can promote an increased association of dynein light chain (DLC) (also known as protein inhibitor of neuronal nitric oxide synthase) with NOS1, thereby reducing its activity. The third level of interplay is provided by intracellular crosstalk of signaling pathways stimulated by products of NOS and COX which contributes significantly to the complexity of cellular signaling. Since modulation of COX and NOS pathways was shown to be principally involved in a variety of pathological conditions, the dissection of their complex relationship is needed for better understanding of possible therapeutic strategies. This review focuses on implications of interplay between NOS and COX for cellular function and signal integration.

  3. Downregulation of toll-like receptor-mediated signalling pathways in oral lichen planus.

    Science.gov (United States)

    Sinon, Suraya H; Rich, Alison M; Parachuru, Venkata P B; Firth, Fiona A; Milne, Trudy; Seymour, Gregory J

    2016-01-01

    The objective of this study was to investigate the expression of Toll-like receptors (TLR) and TLR-associated signalling pathway genes in oral lichen planus (OLP). Initially, immunohistochemistry was used to determine TLR expression in 12 formalin-fixed archival OLP tissues with 12 non-specifically inflamed oral tissues as controls. RNA was isolated from further fresh samples of OLP and non-specifically inflamed oral tissue controls (n = 6 for both groups) and used in qRT(2)-PCR focused arrays to determine the expression of TLRs and associated signalling pathway genes. Genes with a statistical significance of ±two-fold regulation (FR) and a P-value < 0.05 were considered as significantly regulated. Significantly more TLR4(+) cells were present in the inflammatory infiltrate in OLP compared with the control tissues (P < 0.05). There was no statistically significant difference in the numbers of TLR2(+) and TLR8(+) cells between the groups. TLR3 was significantly downregulated in OLP (P < 0.01). TLR8 was upregulated in OLP, but the difference between the groups was not statistically significant. The TLR-mediated signalling-associated protein genes MyD88 and TIRAP were significantly downregulated (P < 0.01 and P < 0.05), as were IRAK1 (P < 0.05), MAPK8 (P < 0.01), MAP3K1 (P < 0.05), MAP4K4 (P < 0.05), REL (P < 0.01) and RELA (P < 0.01). Stress proteins HMGB1 and the heat shock protein D1 were significantly downregulated in OLP (P < 0.01). These findings suggest a downregulation of TLR-mediated signalling pathways in OLP lesions. © 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  4. Advances in cell proliferation and apoptosis signal pathway and therapies of polycystic kidney disease

    Directory of Open Access Journals (Sweden)

    Xiao-ying LIAN

    2016-12-01

    Full Text Available Polycystic kidney disease (PKD is one of the monogenic inherited diseases. In PKD, excessive cell proliferation and fluid secretion, and disruption of the mechanisms controlling tubular diameter may all lead to cyst formation. Current evidence has demonstrated that intracellular calcium ion and cAMP imbalance drive both abnormal cell proliferation and apoptosis signal pathway. The present paper summarized the evidence implicating calcium ion and cAMP as central players in the signaling pathway of cell proliferation and apoptosis in PKD, and considered the potential therapeutic approaches targeted to slow cyst growth in PKD. DOI: 10.11855/j.issn.0577-7402.2016.11.13

  5. Computation of restoration of ligand response in the random kinetics of a prostate cancer cell signaling pathway.

    Science.gov (United States)

    Dana, Saswati; Nakakuki, Takashi; Hatakeyama, Mariko; Kimura, Shuhei; Raha, Soumyendu

    2011-01-01

    Mutation and/or dysfunction of signaling proteins in the mitogen activated protein kinase (MAPK) signal transduction pathway are frequently observed in various kinds of human cancer. Consistent with this fact, in the present study, we experimentally observe that the epidermal growth factor (EGF) induced activation profile of MAP kinase signaling is not straightforward dose-dependent in the PC3 prostate cancer cells. To find out what parameters and reactions in the pathway are involved in this departure from the normal dose-dependency, a model-based pathway analysis is performed. The pathway is mathematically modeled with 28 rate equations yielding those many ordinary differential equations (ODE) with kinetic rate constants that have been reported to take random values in the existing literature. This has led to us treating the ODE model of the pathways kinetics as a random differential equations (RDE) system in which the parameters are random variables. We show that our RDE model captures the uncertainty in the kinetic rate constants as seen in the behavior of the experimental data and more importantly, upon simulation, exhibits the abnormal EGF dose-dependency of the activation profile of MAP kinase signaling in PC3 prostate cancer cells. The most likely set of values of the kinetic rate constants obtained from fitting the RDE model into the experimental data is then used in a direct transcription based dynamic optimization method for computing the changes needed in these kinetic rate constant values for the restoration of the normal EGF dose response. The last computation identifies the parameters, i.e., the kinetic rate constants in the RDE model, that are the most sensitive to the change in the EGF dose response behavior in the PC3 prostate cancer cells. The reactions in which these most sensitive parameters participate emerge as candidate drug targets on the signaling pathway. 2011 Elsevier Ireland Ltd. All rights reserved.

  6. The potential signalling pathways which regulate surface changes induced by phytohormones in the potato cyst nematode (Globodera rostochiensis).

    Science.gov (United States)

    Akhkha, A; Curtis, R; Kennedy, M; Kusel, J

    2004-05-01

    It has been demonstrated that the surface lipophilicity of the plant-parasitic nematode Globodera rostochiensis decreases when infective larvae are exposed to the phytohormones indole-3-acetic acid (auxin) or kinetin (cytokinin). In the present study, it was shown that inhibition of phospholipase C (PLC) or phosphatidylinositol 3 kinase (PI3-kinase) reversed the effect of phytohormones on surface lipophilicity. The signalling pathway(s) involved in surface modification were investigated using 'caged' signalling molecules and stimulators or inhibitors of different signalling enzymes. Photolysis of the 'caged' signalling molecules, NPE-caged Ins 1,4,5-P3, NITR-5/AM or caged-cAMP to liberate IP3, Ca2+ or cAMP respectively, decreased the surface lipophilicity. Activation of adenylate cyclase also decreased the surface lipophilicity. In contrast, inhibition of PI3-kinase using Wortmannin, LY-294002 or Quercetin, and inhibition of PLC using U-73122 all increased the surface lipophilicity. Two possible signalling pathways involved in phytohormone-induced surface modification are proposed.

  7. LPA, HGF, and EGF utilize distinct combinations of signaling pathways to promote migration and invasion of MDA-MB-231 breast carcinoma cells

    International Nuclear Information System (INIS)

    Harrison, Susan MW; Knifley, Teresa; Chen, Min; O’Connor, Kathleen L

    2013-01-01

    Various pathways impinge on the actin-myosin pathway to facilitate cell migration and invasion including members of the Rho family of small GTPases and MAPK. However, the signaling components that are considered important for these processes vary substantially within the literature with certain pathways being favored. These distinctions in signaling pathways utilized are often attributed to differences in cell type or physiological conditions; however, these attributes have not been systematically assessed. To address this question, we analyzed the migration and invasion of MDA-MB-231 breast carcinoma cell line in response to various stimuli including lysophosphatidic acid (LPA), hepatocyte growth factor (HGF) and epidermal growth factor (EGF) and determined the involvement of select signaling pathways that impact myosin light chain phosphorylation. LPA, a potent stimulator of the Rho-ROCK pathway, surprisingly did not require the Rho-ROCK pathway to stimulate migration but instead utilized Rac and MAPK. In contrast, LPA-stimulated invasion required Rho, Rac, and MAPK. Of these three major pathways, EGF-stimulated MDA-MB-231 migration and invasion required Rho; however, Rac was essential only for invasion and MAPK was dispensable for migration. HGF signaling, interestingly, utilized the same pathways for migration and invasion, requiring Rho but not Rac signaling. Notably, the dependency of HGF-stimulated migration and invasion as well as EGF-stimulated invasion on MAPK was subject to the inhibitors used. As expected, myosin light chain kinase (MLCK), a convergence point for MAPK and Rho family GTPase signaling, was required for all six conditions. These observations suggest that, while multiple signaling pathways contribute to cancer cell motility, not all pathways operate under all conditions. Thus, our study highlights the plasticity of cancer cells to adapt to multiple migratory cues

  8. Suppression of the auxin response pathway enhances susceptibility to Phytophthora cinnamomi while phosphite-mediated resistance stimulates the auxin signalling pathway

    Science.gov (United States)

    2014-01-01

    Background Phytophthora cinnamomi is a devastating pathogen worldwide and phosphite (Phi), an analogue of phosphate (Pi) is highly effective in the control of this pathogen. Phi also interferes with Pi starvation responses (PSR), of which auxin signalling is an integral component. In the current study, the involvement of Pi and the auxin signalling pathways in host and Phi-mediated resistance to P. cinnamomi was investigated by screening the Arabidopsis thaliana ecotype Col-0 and several mutants defective in PSR and the auxin response pathway for their susceptibility to this pathogen. The response to Phi treatment was also studied by monitoring its effect on Pi- and the auxin response pathways. Results Here we demonstrate that phr1-1 (phosphate starvation response 1), a mutant defective in response to Pi starvation was highly susceptible to P. cinnamomi compared to the parental background Col-0. Furthermore, the analysis of the Arabidopsis tir1-1 (transport inhibitor response 1) mutant, deficient in the auxin-stimulated SCF (Skp1 − Cullin − F-Box) ubiquitination pathway was also highly susceptible to P. cinnamomi and the susceptibility of the mutants rpn10 and pbe1 further supported a role for the 26S proteasome in resistance to P. cinnamomi. The role of auxin was also supported by a significant (P < 0.001) increase in susceptibility of blue lupin (Lupinus angustifolius) to P. cinnamomi following treatment with the inhibitor of auxin transport, TIBA (2,3,5-triiodobenzoic acid). Given the apparent involvement of auxin and PSR signalling in the resistance to P. cinnamomi, the possible involvement of these pathways in Phi mediated resistance was also investigated. Phi (especially at high concentrations) attenuates the response of some Pi starvation inducible genes such as AT4, AtACP5 and AtPT2 in Pi starved plants. However, Phi enhanced the transcript levels of PHR1 and the auxin responsive genes (AUX1, AXR1and AXR2), suppressed the primary root

  9. RhoA/ROCK Signaling Pathway Mediates Shuanghuanglian Injection-Induced Pseudo-allergic Reactions.

    Science.gov (United States)

    Han, Jiayin; Zhao, Yong; Zhang, Yushi; Li, Chunying; Yi, Yan; Pan, Chen; Tian, Jingzhuo; Yang, Yifei; Cui, Hongyu; Wang, Lianmei; Liu, Suyan; Liu, Jing; Deng, Nuo; Liang, Aihua

    2018-01-01

    Background: Shuanghuanglian injection (SHLI) is a famous Chinese medicine used as an intravenous preparation for the treatment of acute respiratory tract infections. In the recent years, the immediate hypersensitivity reactions induced by SHLI have attracted broad attention. However, the mechanism involved in these reactions has not yet been elucidated. The present study aims to explore the characteristics of the immediate hypersensitivity reactions induced by SHLI and deciphers the role of the RhoA/ROCK signaling pathway in these reactions. Methods: SHLI-immunized mice or naive mice were intravenously injected (i.v.) with SHLI (600 mg/kg) once, and vascular leakage in the ears was evaluated. Passive cutaneous anaphylaxis test was conducted using sera collected from SHLI-immunized mice. Naive mice were administered (i.v.) with a single dose of 150, 300, or 600 mg/kg of SHLI, and vascular leakage, histamine release, and histopathological alterations in the ears, lungs, and intestines were tested. In vitro , human umbilical vein endothelial cell (HUVEC) monolayer was incubated with SHLI (0.05, 0.1, or 0.15 mg/mL), and the changes in endothelial permeability and cytoskeleton were observed. Western blot analysis was performed and ROCK inhibitor was employed to investigate the contribution of the RhoA/ROCK signaling pathway in SHLI-induced hypersensitivity reactions, both in HUVECs and in mice. Results: Our results indicate that SHLI was able to cause immediate dose-dependent vascular leakage, edema, and exudates in the ears, lungs, and intestines, and histamine release in mice. These were pseudo-allergic reactions, as SHLI-specific IgE was not elicited during sensitization. In addition, SHLI induced reorganization of actin cytoskeleton and disrupted the endothelial barrier. The administration of SHLI directly activated the RhoA/ROCK signaling pathway both in HUVECs and in the ears, lungs, and intestines of mice. Fasudil hydrochloride, a ROCK inhibitor, ameliorated the

  10. Mucin 4 Gene Silencing Reduces Oxidative Stress and Calcium Oxalate Crystal Formation in Renal Tubular Epithelial Cells Through the Extracellular Signal-Regulated Kinase Signaling Pathway in Nephrolithiasis Rat Model

    Directory of Open Access Journals (Sweden)

    Ling Sun

    2018-05-01

    Full Text Available Background/Aims: Nephrolithiasis plagues a great number of patients all over the world. Increasing evidence shows that the extracellular signal-regulated kinase (ERK signaling pathway and renal tubular epithelial cell (RTEC dysfunction and attrition are central to the pathogenesis of kidney diseases. Mucin 4 (MUC4 is reported as an activator of ERK signaling pathway in epithelial cells. In this study, using rat models of calcium oxalate (CaOx nephrolithiasis, the present study aims to define the roles of MUC4 and ERK signaling pathway as contributors to oxidative stress and CaOx crystal formation in RTEC. Methods: Data sets of nephrolithiasis were searched using GEO database and a heat flow map was drawn. Then MUC4 function was predicted. Wistar rats were prepared for the purpose of model establishment of ethylene glycol and ammonium chloride induced CaOx nephrolithiasis. In order to assess the detailed regulatory mechanism of MUC4 silencing on the ERK signaling pathway and RTEC, we used recombinant plasmid to downregulate MUC4 expression in Wistar rat-based models. Samples from rat urine, serum and kidney tissues were reviewed to identify oxalic acid and calcium contents, BUN, Cr, Ca2+ and P3+ levels, calcium crystal formation in renal tubules and MUC4 positive expression rate. Finally, RT-qPCR, Western blot analysis, and ELISA were employed to access oxidative stress state and CaOx crystal formation in RTEC. Results: Initially, MUC4 was found to have an influence on the process of nephrolithiasis. MUC4 was upregulated in the CaOx nephrolithiasis model rats. We proved that the silencing of MUC4 triggered the inactivation of ERK signaling pathway. Following the silencing of MUC4 or the inhibition of ERK signaling pathway, the oxalic acid and calcium contents in rat urine, BUN, Cr, Ca2+ and P3+ levels in rat serum, p-ERK1/2, MCP-1 and OPN expressions in RTEC and H2O2 and MDA levels in the cultured supernatant were downregulated, but the GSH

  11. Opposing roles of Toll-like receptor and cytosolic DNA-STING signaling pathways for Staphylococcus aureus cutaneous host defense.

    Directory of Open Access Journals (Sweden)

    Philip O Scumpia

    2017-07-01

    Full Text Available Successful host defense against pathogens requires innate immune recognition of the correct pathogen associated molecular patterns (PAMPs by pathogen recognition receptors (PRRs to trigger the appropriate gene program tailored to the pathogen. While many PRR pathways contribute to the innate immune response to specific pathogens, the relative importance of each pathway for the complete transcriptional program elicited has not been examined in detail. Herein, we used RNA-sequencing with wildtype and mutant macrophages to delineate the innate immune pathways contributing to the early transcriptional response to Staphylococcus aureus, a ubiquitous microorganism that can activate a wide variety of PRRs. Unexpectedly, two PRR pathways-the Toll-like receptor (TLR and Stimulator of Interferon Gene (STING pathways-were identified as dominant regulators of approximately 95% of the genes that were potently induced within the first four hours of macrophage infection with live S. aureus. TLR signaling predominantly activated a pro-inflammatory program while STING signaling activated an antiviral/type I interferon response with live but not killed S. aureus. This STING response was largely dependent on the cytosolic DNA sensor cyclic guanosine-adenosine synthase (cGAS. Using a cutaneous infection model, we found that the TLR and STING pathways played opposite roles in host defense to S. aureus. TLR signaling was required for host defense, with its absence reducing interleukin (IL-1β production and neutrophil recruitment, resulting in increased bacterial growth. In contrast, absence of STING signaling had the opposite effect, enhancing the ability to restrict the infection. These results provide novel insights into the complex interplay of innate immune signaling pathways triggered by S. aureus and uncover opposing roles of TLR and STING in cutaneous host defense to S. aureus.

  12. Endogenous ribosomal frameshift signals operate as mRNA destabilizing elements through at least two molecular pathways in yeast.

    Science.gov (United States)

    Belew, Ashton T; Advani, Vivek M; Dinman, Jonathan D

    2011-04-01

    Although first discovered in viruses, previous studies have identified operational -1 ribosomal frameshifting (-1 RF) signals in eukaryotic genomic sequences, and suggested a role in mRNA stability. Here, four yeast -1 RF signals are shown to promote significant mRNA destabilization through the nonsense mediated mRNA decay pathway (NMD), and genetic evidence is presented suggesting that they may also operate through the no-go decay pathway (NGD) as well. Yeast EST2 mRNA is highly unstable and contains up to five -1 RF signals. Ablation of the -1 RF signals or of NMD stabilizes this mRNA, and changes in -1 RF efficiency have opposing effects on the steady-state abundance of the EST2 mRNA. These results demonstrate that endogenous -1 RF signals function as mRNA destabilizing elements through at least two molecular pathways in yeast. Consistent with current evolutionary theory, phylogenetic analyses suggest that -1 RF signals are rapidly evolving cis-acting regulatory elements. Identification of high confidence -1 RF signals in ∼10% of genes in all eukaryotic genomes surveyed suggests that -1 RF is a broadly used post-transcriptional regulator of gene expression.

  13. Chitosan oligosaccharide induces resistance to Tobacco mosaic virus in Arabidopsis via the salicylic acid-mediated signalling pathway.

    Science.gov (United States)

    Jia, Xiaochen; Meng, Qingshan; Zeng, Haihong; Wang, Wenxia; Yin, Heng

    2016-05-18

    Chitosan is one of the most abundant carbohydrate biopolymers in the world, and chitosan oligosaccharide (COS), which is prepared from chitosan, is a plant immunity regulator. The present study aimed to validate the effect of COS on inducing resistance to tobacco mosaic virus (TMV) in Arabidopsis and to investigate the potential defence-related signalling pathways involved. Optimal conditions for the induction of TMV resistance in Arabidopsis were COS pretreatment at 50 mg/L for 1 day prior to inoculation with TMV. Multilevel indices, including phenotype data, and TMV coat protein expression, revealed that COS induced TMV resistance in wild-type and jasmonic acid pathway- deficient (jar1) Arabidopsis plants, but not in salicylic acid pathway deficient (NahG) Arabidopsis plants. Quantitative-PCR and analysis of phytohormone levels confirmed that COS pretreatment enhanced the expression of the defence-related gene PR1, which is a marker of salicylic acid signalling pathway, and increased the amount of salicylic acid in WT and jar1, but not in NahG plants. Taken together, these results confirm that COS induces TMV resistance in Arabidopsis via activation of the salicylic acid signalling pathway.

  14. Curcumol suppresses RANKL-induced osteoclast formation by attenuating the JNK signaling pathway

    International Nuclear Information System (INIS)

    Yu, Mingxiang; Chen, Xianying; Lv, Chaoyang; Yi, Xilu; Zhang, Yao; Xue, Mengjuan; He, Shunmei; Zhu, Guoying; Wang, Hongfu

    2014-01-01

    Highlights: • Curcumol suppresses osteoclasts differentiation in vitro. • Curcumol impairs JNK/AP-1 signaling pathway. • Curcumol may be used for treating osteoclast related diseases. - Abstract: Osteoclasts, derived from hemopoietic progenitors of the monocyte/macrophage lineage, have a unique role in bone resorption, and are considered a potential therapeutic target in the treatment of such pathologic bone diseases as osteoporosis, rheumatoid arthritis, and periodontitis. In the present study, we demonstrate that curcumol, one of the major components of the essential oil of Rhizoma Curcumae, exhibits an inhibitory effect on receptor activator of nuclear factor kappaB ligand (RANKL)-induced osteoclast differentiation with both bone marrow-derived macrophages and RAW264.7 cells in a dose-dependent manner. In addition, RANKL-induced mRNA expression of osteoclast-specific genes, such as tartrate-resistant acid phosphatase, calcitonin receptor, and cathepsin K, is prominently reduced in the presence of curcumol. Furthermore, the molecular mechanism of action was investigated, and curcumol inhibited osteoclastogenesis by specifically impairing RANKL-induced c-Jun N-terminal kinase (JNK)/activator protein-1 (AP-1) signaling, which was further identified in rescue studies by means of anisomycin, a JNK signaling-specific activator. Taken together, these findings suggest that curcumol suppresses RANKL-induced osteoclast differentiation through the JNK/AP-1 signaling pathway, and may be useful as a therapeutic treatment for bone resorption-associated diseases

  15. Curcumol suppresses RANKL-induced osteoclast formation by attenuating the JNK signaling pathway

    Energy Technology Data Exchange (ETDEWEB)

    Yu, Mingxiang, E-mail: yu.mingxiang@zs-hospital.sh.cn [Department of Endocrinology and Metabolism, Zhongshan Hospital, Fudan University, Shanghai (China); Chen, Xianying [Department of Endocrinology and Metabolism, Hainan Provincial Nong Ken Hospital, Hainan (China); Lv, Chaoyang [Department of Endocrinology and Metabolism, Zhongshan Hospital, Fudan University, Shanghai (China); Yi, Xilu [Department of Endocrinology and Metabolism, Shanghai Songjiang District Central Hospital, Shanghai (China); Zhang, Yao; Xue, Mengjuan; He, Shunmei [Department of Endocrinology and Metabolism, Zhongshan Hospital, Fudan University, Shanghai (China); Zhu, Guoying [Institute of Radiation Medicine, Fudan University, Shanghai (China); Wang, Hongfu, E-mail: hfwang@shmu.edu.cn [Institute of Radiation Medicine, Fudan University, Shanghai (China)

    2014-05-02

    Highlights: • Curcumol suppresses osteoclasts differentiation in vitro. • Curcumol impairs JNK/AP-1 signaling pathway. • Curcumol may be used for treating osteoclast related diseases. - Abstract: Osteoclasts, derived from hemopoietic progenitors of the monocyte/macrophage lineage, have a unique role in bone resorption, and are considered a potential therapeutic target in the treatment of such pathologic bone diseases as osteoporosis, rheumatoid arthritis, and periodontitis. In the present study, we demonstrate that curcumol, one of the major components of the essential oil of Rhizoma Curcumae, exhibits an inhibitory effect on receptor activator of nuclear factor kappaB ligand (RANKL)-induced osteoclast differentiation with both bone marrow-derived macrophages and RAW264.7 cells in a dose-dependent manner. In addition, RANKL-induced mRNA expression of osteoclast-specific genes, such as tartrate-resistant acid phosphatase, calcitonin receptor, and cathepsin K, is prominently reduced in the presence of curcumol. Furthermore, the molecular mechanism of action was investigated, and curcumol inhibited osteoclastogenesis by specifically impairing RANKL-induced c-Jun N-terminal kinase (JNK)/activator protein-1 (AP-1) signaling, which was further identified in rescue studies by means of anisomycin, a JNK signaling-specific activator. Taken together, these findings suggest that curcumol suppresses RANKL-induced osteoclast differentiation through the JNK/AP-1 signaling pathway, and may be useful as a therapeutic treatment for bone resorption-associated diseases.

  16. Diet-induced obesity mediated by the JNK/DIO2 signal transduction pathway

    Science.gov (United States)

    Vernia, Santiago; Cavanagh-Kyros, Julie; Barrett, Tamera; Jung, Dae Young; Kim, Jason K.; Davis, Roger J.

    2013-01-01

    The cJun N-terminal kinase (JNK) signaling pathway is a key mediator of metabolic stress responses caused by consuming a high-fat diet, including the development of obesity. To test the role of JNK, we examined diet-induced obesity in mice with targeted ablation of Jnk genes in the anterior pituitary gland. These mice exhibited an increase in the pituitary expression of thyroid-stimulating hormone (TSH), an increase in the blood concentration of thyroid hormone (T4), increased energy expenditure, and markedly reduced obesity compared with control mice. The increased amount of pituitary TSH was caused by reduced expression of type 2 iodothyronine deiodinase (Dio2), a gene that is required for T4-mediated negative feedback regulation of TSH expression. These data establish a molecular mechanism that accounts for the regulation of energy expenditure and the development of obesity by the JNK signaling pathway. PMID:24186979

  17. Molecular Pathways for Immune Recognition of Preproinsulin Signal Peptide in Type 1 Diabetes.

    Science.gov (United States)

    Kronenberg-Versteeg, Deborah; Eichmann, Martin; Russell, Mark A; de Ru, Arnoud; Hehn, Beate; Yusuf, Norkhairin; van Veelen, Peter A; Richardson, Sarah J; Morgan, Noel G; Lemberg, Marius K; Peakman, Mark

    2018-04-01

    The signal peptide region of preproinsulin (PPI) contains epitopes targeted by HLA-A-restricted (HLA-A0201, A2402) cytotoxic T cells as part of the pathogenesis of β-cell destruction in type 1 diabetes. We extended the discovery of the PPI epitope to disease-associated HLA-B*1801 and HLA-B*3906 (risk) and HLA-A*1101 and HLA-B*3801 (protective) alleles, revealing that four of six alleles present epitopes derived from the signal peptide region. During cotranslational translocation of PPI, its signal peptide is cleaved and retained within the endoplasmic reticulum (ER) membrane, implying it is processed for immune recognition outside of the canonical proteasome-directed pathway. Using in vitro translocation assays with specific inhibitors and gene knockout in PPI-expressing target cells, we show that PPI signal peptide antigen processing requires signal peptide peptidase (SPP). The intramembrane protease SPP generates cytoplasm-proximal epitopes, which are transporter associated with antigen processing (TAP), ER-luminal epitopes, which are TAP independent, each presented by different HLA class I molecules and N-terminal trimmed by ER aminopeptidase 1 for optimal presentation. In vivo, TAP expression is significantly upregulated and correlated with HLA class I hyperexpression in insulin-containing islets of patients with type 1 diabetes. Thus, PPI signal peptide epitopes are processed by SPP and loaded for HLA-guided immune recognition via pathways that are enhanced during disease pathogenesis. © 2018 by the American Diabetes Association.

  18. Activation of the TOR Signalling Pathway by Glutamine Regulates Insect Fecundity.

    Science.gov (United States)

    Zhai, Yifan; Sun, Zhongxiang; Zhang, Jianqing; Kang, Kui; Chen, Jie; Zhang, Wenqing

    2015-05-29

    The target of rapamycin (TOR) positively controls cell growth in response to nutrients such as amino acids. However, research on the specific nutrients sensed by TOR is limited. Glutamine (Gln), a particularly important amino acid involved in metabolism in organisms, is synthesised and catalysed exclusively by glutamine synthetase (GS), and our previous studies have shown that Gln may regulate fecundity in vivo levels of the brown planthopper (BPH) Nilaparvata lugens. Until now, it has remained unclear whether Gln activates or inhibits the TOR signalling pathway. Here, we performed the combined analyses of iTRAQ (isobaric tags for relative and absolute quantification) and DGE (tag-based digital gene expression) data in N. lugens at the protein and transcript levels after GS RNAi, and we found that 52 pathways overlap, including the TOR pathway. We further experimentally demonstrate that Gln activates the TOR pathway by promoting the serine/threonine protein kinase AKT and inhibiting the 5'AMP-activated protein kinase AMPK phosphorylation activity in the pest. Furthermore, TOR regulates the fecundity of N. lugens probably by mediating vitellogenin (Vg) expression. This work is the first report that Gln activates the TOR pathway in vivo.

  19. Ethanol negatively regulates hepatic differentiation of hESC by inhibition of the MAPK/ERK signaling pathway in vitro.

    Directory of Open Access Journals (Sweden)

    Wei Gao

    Full Text Available Alcohol insult triggers complex events in the liver, promoting fibrogenic/inflammatory signals and in more advanced cases, aberrant matrix deposition. It is well accepted that the regenerative capacity of the adult liver is impaired during alcohol injury. The liver progenitor/stem cells have been shown to play an important role in liver regeneration -in response to various chronic injuries; however, the effects of alcohol on stem cell differentiation in the liver are not well understood.We employed hepatic progenitor cells derived from hESCs to study the impact of ethanol on hepatocyte differentiation by exposure of these progenitor cells to ethanol during hepatocyte differentiation.We found that ethanol negatively regulated hepatic differentiation of hESC-derived hepatic progenitor cells in a dose-dependent manner. There was also a moderate cell cycle arrest at G1/S checkpoint in the ethanol treated cells, which is associated with a reduced level of cyclin D1 in these cells. Ethanol treatment specifically inhibited the activation of the ERK but not JNK nor the p38 MAP signaling pathway. At the same time, the WNT signaling pathway was also reduced in the cells exposed to ethanol. Upon evaluating the effects of the inhibitors of these two signaling pathways, we determined that the Erk inhibitor replicated the effects of ethanol on the hepatocyte differentiation and attenuated the WNT/β-catenin signaling, however, inhibitors of WNT only partially replicated the effects of ethanol on the hepatocyte differentiation.Our results demonstrated that ethanol negatively regulated hepatic differentiation of hESC-derived hepatic progenitors through inhibiting the MAPK/ERK signaling pathway, and subsequently attenuating the WNT signaling pathway. Thus, our finding provides a novel insight into the mechanism by which alcohol regulates cell fate selection of hESC-derived hepatic progenitor cells, and the identified pathways may provide therapeutic targets

  20. Kinetic studies of the yeast His-Asp phosphorelay signaling pathway

    Science.gov (United States)

    Kaserer, Alla O.; Andi, Babak; Cook, Paul F.; West, Ann H.

    2010-01-01

    For both prokaryotic and eukaryotic His-Asp phosphorelay signaling pathways, the rates of protein phosphorylation and dephosphorylation determine the stimulus-to-response time frame. Thus, kinetic studies of phosphoryl group transfer between signaling partners are important for gaining a full understanding of how the system is regulated. In many cases, the phosphotransfer reactions are too fast for rates to be determined by manual experimentation. Rapid quench flow techniques thus provide a powerful method for studying rapid reactions that occur in the millisecond time frame. In this chapter, we describe experimental design and procedures for kinetic characterization of the yeast SLN1-YPD1-SSK1 osmoregulatory phosphorelay system using a rapid quench flow kinetic instrument. PMID:20946842

  1. Differential gene expressions of the MAPK signaling pathway in enterovirus 71-infected rhabdomyosarcoma cells

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    Weifeng Shi

    Full Text Available BACKGROUND: Mitogen-activated protein kinase (MAPK signaling pathway plays an important role in response to viral infection. The aim of this study was to explore the function and mechanism of MAPK signaling pathway in enterovirus 71 (EV71 infection of human rhabdomyosarcoma (RD cells. METHODS: Apoptosis of RD cells was observed using annexin V-FITC/PI binding assay under a fluorescence microscope. Cellular RNA was extracted and transcribed to cDNA. The expressions of 56 genes of MAPK signaling pathway in EV71-infected RD cells at 8 h and 20 h after infection were analyzed by PCR array. The levels of IL-2, IL-4, IL-10, and TNF-α in the supernatant of RD cells infected with EV71 at different time points were measured by ELISA. RESULTS: The viability of RD cells decreased obviously within 48 h after EV71 infection. Compared with the control group, EV71 infection resulted in the significantly enhanced releases of IL-2, IL-4, IL-10 and TNF-α from infected RD cells (p < 0.05. At 8 h after infection, the expressions of c-Jun, c-Fos, IFN-i, MEKK1, MLK3 and NIK genes in EV71-infected RD cells were up-regulated by 2.08-6.12-fold, whereas other 19 genes (e.g. AKT1, AKT2, E2F1, IKK and NF-κB1 exhibited down-regulation. However, at 20 h after infection, those MAPK signaling molecules including MEKK1, ASK1, MLK2, MLK3, NIK, MEK1, MEK2, MEK4, MEK7, ERK1, JNK1 and JNK2 were up-regulated. In addition, the expressions of AKT2, ELK1, c-Jun, c-Fos, NF-κB p65, PI3K and STAT1 were also increased. CONCLUSION: EV71 infection induces the differential gene expressions of MAPK signaling pathway such as ERK, JNK and PI3K/AKT in RD cells, which may be associated with the secretions of inflammatory cytokines and host cell apoptosis.

  2. A pivotal role of the jasmonic acid signal pathway in mediating radiation-induced bystander effects in Arabidopsis thaliana.

    Science.gov (United States)

    Wang, Ting; Xu, Wei; Deng, Chenguang; Xu, Shaoxin; Li, Fanghua; Wu, Yuejin; Wu, Lijun; Bian, Po

    Although radiation-induced bystander effects (RIBE) in Arabidopsis thaliana have been well demonstrated in vivo, little is known about their underlying mechanisms, particularly with regard to the participating signaling molecules and signaling pathways. In higher plants, jasmonic acid (JA) and its bioactive derivatives are well accepted as systemic signal transducers that are produced in response to various environmental stresses. It is therefore speculated that the JA signal pathway might play a potential role in mediating radiation-induced bystander signaling of root-to-shoot. In the present study, pretreatment of seedlings with Salicylhydroxamic acid, an inhibitor of lipoxigenase (LOX) in JA biosynthesis, significantly suppressed RIBE-mediated expression of the AtRAD54 gene. After root irradiation, the aerial parts of A. thaliana mutants deficient in JA biosynthesis (aos) and signaling cascades (jar1-1) showed suppressed induction of the AtRAD54 and AtRAD51 genes and TSI and 180-bp repeats, which have been extensively used as endpoints of bystander genetic and epigenetic effects in plants. These results suggest an involvement of the JA signal pathway in the RIBE of plants. Using the root micro-grafting technique, the JA signal pathway was shown to participate in both the generation of bystander signals in irradiated root cells and radiation responses in the bystander aerial parts of plants. The over-accumulation of endogenous JA in mutant fatty acid oxygenation up-regulated 2 (fou2), in which mutation of the Two Pore Channel 1 (TPC1) gene up-regulates expression of the LOX and allene oxide synthase (AOS) genes, inhibited RIBE-mediated expression of the AtRAD54 gene, but up-regulated expression of the AtKU70 and AtLIG4 genes in the non-homologous end joining (NHEJ) pathway. Considering that NHEJ is employed by plants with increased DNA damage, the switch from HR to NHEJ suggests that over-accumulation of endogenous JA might enhance the radiosensitivity of plants

  3. Unstable Modes and Order Parameters of Bistable Signaling Pathways at Saddle-Node Bifurcations: A Theoretical Study Based on Synergetics

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    Till D. Frank

    2016-01-01

    Full Text Available Mathematical modeling has become an indispensable part of systems biology which is a discipline that has become increasingly popular in recent years. In this context, our understanding of bistable signaling pathways in terms of mathematical modeling is of particular importance because such bistable components perform crucial functions in living cells. Bistable signaling pathways can act as switches or memory functions and can determine cell fate. In the present study, properties of mathematical models of bistable signaling pathways are examined from the perspective of synergetics, a theory of self-organization and pattern formation founded by Hermann Haken. At the heart of synergetics is the concept of so-called unstable modes or order parameters that determine the behavior of systems as a whole close to bifurcation points. How to determine these order parameters for bistable signaling pathways at saddle-node bifurcation points is shown. The procedure is outlined in general and an explicit example is worked out in detail.

  4. Rare genomic variants link bipolar disorder to CREB regulated intracellular signaling pathways

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    Berit eKerner

    2013-11-01

    Full Text Available Bipolar disorder is a common, complex, and severe psychiatric disorder with cyclical disturbances of mood and a high suicide rate. Here, we describe a family with four siblings, three affected females and one unaffected male. The disease course was characterized by early-onset bipolar disorder and co-morbid anxiety spectrum disorders that followed the onset of bipolar disorder. Genetic risk factors were suggested by the early onset of the disease, the severe disease course, including multiple suicide attempts, and lack of adverse prenatal or early life events. In particular, drug and alcohol abuse did not contribute to the disease onset. Exome sequencing identified very rare, heterozygous, and likely protein-damaging variants in eight brain-expressed genes: IQUB, JMJD1C, GADD45A, GOLGB1, PLSCR5, VRK2, MESDC2, and FGGY. The variants were shared among all three affected family members but absent in the unaffected sibling and in more than 200 controls. The genes encode proteins with significant regulatory roles in the ERK/MAPK and CREB-regulated intracellular signaling pathways. These pathways are central to neuronal and synaptic plasticity, cognition, affect regulation and response to chronic stress. In addition, proteins in these pathways are the target of commonly used mood stabilizing drugs, such as tricyclic antidepressants, lithium and valproic acid. The combination of multiple rare, damaging mutations in these central pathways could lead to reduced resilience and increased vulnerability to stressful life events. Our results support a new model for psychiatric disorders, in which multiple rare, damaging mutations in genes functionally related to a common signaling pathway contribute to the manifestation of bipolar disorder.

  5. Targeting embryonic signaling pathways in cancer therapy.

    Science.gov (United States)

    Harris, Pamela Jo; Speranza, Giovanna; Dansky Ullmann, Claudio

    2012-01-01

    The embryonic signaling pathways (ESP), Hedgehog, Notch and Wnt, are critical for the regulation of normal stem cells and cellular development processes. They are also activated in the majority of cancers. ESP are operational in putative cancer stem cells (CSC), which drive initial tumorigenesis and sustain cancer progression and recurrence in non-CSC bulk subpopulations. ESP represent novel therapeutic targets. A variety of inhibitors and targeting strategies are being developed. This review discusses the rationale for targeting ESP for cancer treatment, as well as specific inhibitors under development; mainly focusing on those approaching clinical use and the challenges that lie ahead. The data sources utilized are several database search engines (PubMed, Google, Clinicaltrials.gov), and the authors' involvement in the field. CSC research is rapidly evolving. Expectations regarding their therapeutic targeting are rising quickly. Further definition of what constitutes a true CSC, proper validation of CSC markers, a better understanding of cross-talk among ESP and other pathways, and interactions with tumor non-CSC and the tumor microenvironment are needed. The appropriate patient population, the right clinical setting and combination strategies to test these therapies, as well as the proper pharmacodynamic markers to measure, need to be further established.

  6. NLRC5 promotes cell proliferation via regulating the AKT/VEGF-A signaling pathway in hepatocellular carcinoma

    International Nuclear Information System (INIS)

    He, Ying-hua; Li, Ming-fang; Zhang, Xing-yan; Meng, Xiao-ming; Huang, Cheng; Li, Jun

    2016-01-01

    NLRC5, a newly found member of the NLR family and the largest member of nucleotide-binding, has been reported to regulate immune responses and is associated with hepatocellular carcinoma (HCC). We investigated the mechanisms and signaling pathways of NLRC5 in HCC progression. Increased expression of NLRC5, vascular endothelial growth factor-A (VEGF-A) were found in human HCC tissue. There was a positive correlation between NLRC5 and VEGF-A expression and cell proliferation were enhanced in NLRC5-overexpressing HepG2 cells, but inhibited in cells with NLRC5 silencing treatment. Interestingly, we found that up-regulation of NLRC5 also coordinated the activation of PI3K/AKT signaling pathway. An AKT inhibitor LY294002 blocked VEGF-A expression and AKT phosphorylation in HepG2 cells and NLRC5-overexpressing HepG2 cells. These results demonstrate that NLRC5 promotes HCC progression via the AKT/VEGF-A signaling pathway.

  7. Disorders of dysregulated signal traffic through the RAS-MAPK pathway: phenotypic spectrum and molecular mechanisms.

    Science.gov (United States)

    Tartaglia, Marco; Gelb, Bruce D

    2010-12-01

    RAS GTPases control a major signaling network implicated in several cellular functions, including cell fate determination, proliferation, survival, differentiation, migration, and senescence. Within this network, signal flow through the RAF-MEK-ERK pathway-the first identified mitogen-associated protein kinase (MAPK) cascade-mediates early and late developmental processes controlling morphology determination, organogenesis, synaptic plasticity, and growth. Signaling through the RAS-MAPK cascade is tightly controlled; and its enhanced activation represents a well-known event in oncogenesis. Unexpectedly, in the past few years, inherited dysregulation of this pathway has been recognized as the cause underlying a group of clinically related disorders sharing facial dysmorphism, cardiac defects, reduced postnatal growth, ectodermal anomalies, variable cognitive deficits, and susceptibility to certain malignancies as major features. These disorders are caused by heterozygosity for mutations in genes encoding RAS proteins, regulators of RAS function, modulators of RAS interaction with effectors, or downstream signal transducers. Here, we provide an overview of the phenotypic spectrum associated with germline mutations perturbing RAS-MAPK signaling, the unpredicted molecular mechanisms converging toward the dysregulation of this signaling cascade, and major genotype-phenotype correlations. © 2010 New York Academy of Sciences.

  8. Bioreactors to influence stem cell fate: augmentation of mesenchymal stem cell signaling pathways via dynamic culture systems.

    Science.gov (United States)

    Yeatts, Andrew B; Choquette, Daniel T; Fisher, John P

    2013-02-01

    Mesenchymal stem cells (MSCs) are a promising cell source for bone and cartilage tissue engineering as they can be easily isolated from the body and differentiated into osteoblasts and chondrocytes. A cell based tissue engineering strategy using MSCs often involves the culture of these cells on three-dimensional scaffolds; however the size of these scaffolds and the cell population they can support can be restricted in traditional static culture. Thus dynamic culture in bioreactor systems provides a promising means to culture and differentiate MSCs in vitro. This review seeks to characterize key MSC differentiation signaling pathways and provides evidence as to how dynamic culture is augmenting these pathways. Following an overview of dynamic culture systems, discussion will be provided on how these systems can effectively modify and maintain important culture parameters including oxygen content and shear stress. Literature is reviewed for both a highlight of key signaling pathways and evidence for regulation of these signaling pathways via dynamic culture systems. The ability to understand how these culture systems are affecting MSC signaling pathways could lead to a shear or oxygen regime to direct stem cell differentiation. In this way the efficacy of in vitro culture and differentiation of MSCs on three-dimensional scaffolds could be greatly increased. Bioreactor systems have the ability to control many key differentiation stimuli including mechanical stress and oxygen content. The further integration of cell signaling investigations within dynamic culture systems will lead to a quicker realization of the promise of tissue engineering and regenerative medicine. This article is part of a Special Issue entitled Biochemistry of Stem Cells. Copyright © 2012 Elsevier B.V. All rights reserved.

  9. Outer Membrane Protein 25 of Brucella Activates Mitogen-Activated Protein Kinase Signal Pathway in Human Trophoblast Cells

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    Jing Zhang

    2017-12-01

    Full Text Available Outer membrane protein 25 (OMP25, a virulence factor from Brucella, plays an important role in maintaining the structural stability of Brucella. Mitogen-activated protein kinase (MAPK signal pathway widely exists in eukaryotic cells. In this study, human trophoblast cell line HPT-8 and BALB/c mice were infected with Brucella abortus 2308 strain (S2308 and 2308ΔOmp25 mutant strain. The expression of cytokines and activation of MAPK signal pathway were detected. We found that the expressions of tumor necrosis factor-α, interleukin-1, and interleukin-10 (IL-10 were increased in HPT-8 cells infected with S2308 and 2308ΔOmp25 mutant. S2308 also activated p38 phosphorylation protein, extracellular-regulated protein kinases (ERK, and Jun-N-terminal kinase (JNK from MAPK signal pathway. 2308ΔOmp25 could not activate p38, ERK, and JNK branches. Immunohistochemistry experiments showed that S2308 was able to activate phosphorylation of p38 and ERK in BABL/c mice. However, 2308ΔOmp25 could weakly activate phosphorylation of p38 and ERK. These results suggest that Omp25 played an important role in the process of Brucella activation of the MAPK signal pathway.

  10. Biphasic effects of FGF2 on odontoblast differentiation involve changes in the BMP and Wnt signaling pathways.

    Science.gov (United States)

    Sagomonyants, Karen; Mina, Mina

    2014-08-01

    Odontoblast differentiation during physiological and reparative dentinogenesis is dependent upon multiple signaling molecules, including fibroblast growth factors (FGFs), bone morphogenetic proteins (BMPs) and Wingless/Integrated (Wnt) ligands. Recent studies in our laboratory showed that continuous exposure of primary dental pulp cultures to FGF2 exerted biphasic effects on the expression of markers of dentinogenesis. In the present study, we examined the possible involvement of the BMP and Wnt signaling pathways in mediating the effects of FGF2 on dental pulp cells. Our results showed that stimulatory effects of FGF2 on dentinogenesis during the proliferation phase of growth were associated with increased expression of the components of the BMP (Bmp2, Dlx5, Msx2, Osx) and Wnt (Wnt10a, Wisp2) pathways, and decreased expression of an inhibitor of the Wnt signaling, Nkd2. Further addition of FGF2 during the differentiation/mineralization phase of growth resulted in decreased expression of components of the BMP signaling (Bmp2, Runx2, Osx) and increased expression of inhibitors of the Wnt signaling (Nkd2, Dkk3). This suggests that both BMP and Wnt pathways may be involved in mediating the effects of FGF2 on dental pulp cells.

  11. The EBI2 signalling pathway plays a role in cellular crosstalk between astrocytes and macrophages.

    Science.gov (United States)

    Rutkowska, Aleksandra; O'Sullivan, Sinead A; Christen, Isabelle; Zhang, Juan; Sailer, Andreas W; Dev, Kumlesh K

    2016-05-11

    EBI2 is a G protein-coupled receptor activated by oxysterol 7α, 25-dihydroxycholesterol (7α25HC) and regulates T cell-dependant antibody response and B cell migration. We recently found EBI2 is expressed in human astrocytes, regulates intracellular signalling and modulates astrocyte migration. Here, we report that LPS treatment of mouse astrocytes alters mRNA levels of EBI2 and oxysterols suggesting that the EBI2 signalling pathway is sensitive to LPS-mediated immune challenge. We also find that conditioned media obtained from LPS-stimulated mouse astrocytes induces macrophage migration, which is inhibited by the EBI2 antagonist NIBR189. These results demonstrate a role for the EBI2 signalling pathway in astrocytes as a sensor for immune challenge and for communication with innate immune cells such as macrophages.

  12. Diabetes alters activation and repression of pro- and anti- inflammatory signalling pathways in the vasculature

    Directory of Open Access Journals (Sweden)

    Elyse eDi Marco

    2013-06-01

    Full Text Available A central mechanism driving vascular disease in diabetes is immune cell-mediated inflammation. In diabetes, enhanced oxidation and glycation of macromolecules, such as lipoproteins, insults the endothelium and activates both innate and adaptive arms of the immune system by generating new antigens for presentation to adaptive immune cells. Chronic inflammation of the endothelium in diabetes leads to continuous infiltration and accumulation of leukocytes at sites of endothelial cell injury. We will describe the central role of the macrophage as a source of signalling molecules and damaging by-products which activate infiltrating lymphocytes in the tissue and contribute to the pro-oxidant and pro-inflammatory micro-environment. An important aspect to be considered is the diabetes- associated defects in the immune system, such as fewer or dysfunctional athero-protective leukocyte subsets in the diabetic lesion compared to non-diabetic lesions. This review will discuss the key pro-inflammatory signalling pathways responsible for leukocyte recruitment and activation in the injured vessel, with particular focus on pro- and anti-inflammatory pathways aberrantly activated or repressed in diabetes. We aim to describe the interaction between advanced glycation end products (AGEs and their principle receptor RAGE, Angiotensin II (Ang II and the Ang II type 1 receptor (AT1R, in addition to reactive oxygen species (ROS production by NADPH oxidase (Nox enzymes that are relevant to vascular and immune cell function in the context of diabetic vasculopathy. Furthermore, we will touch on recent advances in epigenetic medicine that have revealed high glucose-mediated changes in the transcription of genes with known pro-inflammatory downstream targets. Finally, novel anti-atherosclerosis strategies that target the vascular immune interface will be explored; such as vaccination against modified LDL and pharmacological inhibition of ROS producing enzymes.

  13. Clinical and prognostic value of the C-Met/HGF signaling pathway in cervical cancer.

    Science.gov (United States)

    Boromand, Nadia; Hasanzadeh, Malihe; ShahidSales, Soodabeh; Farazestanian, Marjaneh; Gharib, Masoumeh; Fiuji, Hamid; Behboodi, Negin; Ghobadi, Niloofar; Hassanian, Seyed Mahdi; Ferns, Gordon A; Avan, Amir

    2018-06-01

    Aberrant activation of the HGF/c-Met signalling pathway is reported to be associated with cell proliferation, progression, and metastasis features of several tumor types, including cervical cancer, suggesting that it may be of potential value as a novel therapeutic target. Furthermore, HPV-positive patients had a higher serum level of HGF or c-Met protein, compared with HPV-negative patients. c-Met or HGF overexpression in lesions of cervical cancer is reported to be related to a poorer prognosis, and hence this may be of value as a prognostic and predictive biomarker. Several approaches have been developed for targeting HGF and/or c-Met. One of these is crizotinib (a dual c-Met/ALK inhibitor). This has been approved by FDA for the treatment of lung-cancer. Further investigations are required to evaluate and optimize the use of c-Met inhibitors in cervical cancer or parallel targeting signalling pathway associated/activated via MET/HGF pathway. The main aim of current review was to give an overview of the potential of the c-Met/HGF pathway as a prognostic, or predictive biomarker in cervical cancer. © 2017 Wiley Periodicals, Inc.

  14. Emergence, development and diversification of the TGF-beta signalling pathway within the animal kingdom.

    Science.gov (United States)

    Huminiecki, Lukasz; Goldovsky, Leon; Freilich, Shiri; Moustakas, Aristidis; Ouzounis, Christos; Heldin, Carl-Henrik

    2009-02-03

    The question of how genomic processes, such as gene duplication, give rise to co-ordinated organismal properties, such as emergence of new body plans, organs and lifestyles, is of importance in developmental and evolutionary biology. Herein, we focus on the diversification of the transforming growth factor-beta (TGF-beta) pathway -- one of the fundamental and versatile metazoan signal transduction engines. After an investigation of 33 genomes, we show that the emergence of the TGF-beta pathway coincided with appearance of the first known animal species. The primordial pathway repertoire consisted of four Smads and four receptors, similar to those observed in the extant genome of the early diverging tablet animal (Trichoplax adhaerens). We subsequently retrace duplications in ancestral genomes on the lineage leading to humans, as well as lineage-specific duplications, such as those which gave rise to novel Smads and receptors in teleost fishes. We conclude that the diversification of the TGF-beta pathway can be parsimoniously explained according to the 2R model, with additional rounds of duplications in teleost fishes. Finally, we investigate duplications followed by accelerated evolution which gave rise to an atypical TGF-beta pathway in free-living bacterial feeding nematodes of the genus Rhabditis. Our results challenge the view of well-conserved developmental pathways. The TGF-beta signal transduction engine has expanded through gene duplication, continually adopting new functions, as animals grew in anatomical complexity, colonized new environments, and developed an active immune system.

  15. Suppression of NF-κB signal pathway by NLRC3-like protein in stony coral Acropora aculeus under heat stress.

    Science.gov (United States)

    Zhou, Zhi; Wu, Yibo; Zhang, Chengkai; Li, Can; Chen, Guangmei; Yu, Xiaopeng; Shi, Xiaowei; Xu, Yanlai; Wang, Lingui; Huang, Bo

    2017-08-01

    Heat stress is the most common factor for coral bleaching, which has increased both in frequency and severity due to global warming. In the present study, the stony coral Acropora aculeus was subjected to acute heat stress and entire transcriptomes were sequenced via the next generation sequencing platform. Four paired-end libraries were constructed and sequenced in two groups, including a control and a heat stress group. A total of 120,319,751 paired-end reads with lengths of 2 × 100 bp were assembled and 55,021 coral-derived genes were obtained. After read mapping and abundance estimation, 9110 differentially expressed genes were obtained in the comparison between the control and heat stress group, including 4465 significantly upregulated and 4645 significantly downregulated genes. Twenty-three GO terms in the Biological Process category were overrepresented for significantly upregulated genes, and divided into six groups according to their relationship. These three groups were related to the NF-κB signal pathway, and the remaining three groups were relevant for pathogen response, immunocyte activation and protein ubiquitination. Forty-three common genes were found in four GO terms, which were directly related to the NF-κB signal pathway. These included 2 NACHT, LRR, PYD domains-containing protein, 5 nucleotide-binding oligomerization domain-containing protein, 29 NLRC3-like protein, 4 NLRC5-like protein, and 3 uncharacterized protein. For significantly downregulated genes, 27 overrepresented GO terms were found in the Biological Process category, which were relevant to protein ubiquitination and ATP metabolism. Our results indicate that heat stress suppressed the immune response level via the NLRC3-like protein, the fine-tuning of protein turnover activity, and ATP metabolism. This might disrupt the balance of coral-zooxanthellae symbiosis and result in the bleaching of the coral A. aculeus. Copyright © 2017 Elsevier Ltd. All rights reserved.

  16. Data on quantification of signaling pathways activated by KIT and PDGFRA mutants

    Directory of Open Access Journals (Sweden)

    Christelle Bahlawane

    2016-12-01

    Full Text Available The present data are related to the article entitled “Insights into ligand stimulation effects on gastro-intestinal stromal tumors signaling” (C. Bahlawane, M. Schmitz, E. Letellier, K. Arumugam, N. Nicot, P.V. Nazarov, S. Haan, 2016 [1]. Constitutive and ligand-derived signaling pathways mediated by KIT and PDGFRA mutated proteins found in gastrointestinal stromal tumors (GIST were compared. Expression of mutant proteins was induced by doxycycline in an isogenic background (Hek293 cells. Kit was identified by FACS at the cell surface and found to be quickly degraded or internalized upon SCF stimulation for both Kit Wild type and Kit mutant counterparts. Investigation of the main activated pathways in GIST unraveled a new feature specific for oncogenic KIT mutants, namely their ability to be further activated by Kit ligand, the stem cell factor (scf. We were also able to identify the MAPK pathway as the most prominent target for a common inhibition of PDGFRA and KIT oncogenic signaling. Western blotting and micro-array analysis were applied to analyze the capacities of the mutant to induce an effective STATs response. Among all Kit mutants, only Kit Ex11 deletion mutant was able to elicit an effective STATs response whereas all PDGFRA were able to do so.

  17. Cartography of Pathway Signal Perturbations Identifies Distinct Molecular Pathomechanisms in Malignant and Chronic Lung Diseases

    Science.gov (United States)

    Arakelyan, Arsen; Nersisyan, Lilit; Petrek, Martin; Löffler-Wirth, Henry; Binder, Hans

    2016-01-01

    Lung diseases are described by a wide variety of developmental mechanisms and clinical manifestations. Accurate classification and diagnosis of lung diseases are the bases for development of effective treatments. While extensive studies are conducted toward characterization of various lung diseases at molecular level, no systematic approach has been developed so far. Here we have applied a methodology for pathway-centered mining of high throughput gene expression data to describe a wide range of lung diseases in the light of shared and specific pathway activity profiles. We have applied an algorithm combining a Pathway Signal Flow (PSF) algorithm for estimation of pathway activity deregulation states in lung diseases and malignancies, and a Self Organizing Maps algorithm for classification and clustering of the pathway activity profiles. The analysis results allowed clearly distinguish between cancer and non-cancer lung diseases. Lung cancers were characterized by pathways implicated in cell proliferation, metabolism, while non-malignant lung diseases were characterized by deregulations in pathways involved in immune/inflammatory response and fibrotic tissue remodeling. In contrast to lung malignancies, chronic lung diseases had relatively heterogeneous pathway deregulation profiles. We identified three groups of interstitial lung diseases and showed that the development of characteristic pathological processes, such as fibrosis, can be initiated by deregulations in different signaling pathways. In conclusion, this paper describes the pathobiology of lung diseases from systems viewpoint using pathway centered high-dimensional data mining approach. Our results contribute largely to current understanding of pathological events in lung cancers and non-malignant lung diseases. Moreover, this paper provides new insight into molecular mechanisms of a number of interstitial lung diseases that have been studied to a lesser extent. PMID:27200087

  18. Distinct UV-B and UV-A/blue light signal transduction pathways induce chalcone synthase gene expression in Arabidopsis cells

    International Nuclear Information System (INIS)

    Christie, J.M.; Jenkins, G.I.

    1996-01-01

    UV and blue light control the expression of flavonoid biosynthesis genes in a range of higher plants. To investigate the signal transduction processes involved in the induction of chalcone synthase (CHS) gene expression by UV-B and UV-A/blue light, we examined the, effects of specific agonists and inhibitors of known signaling components in mammalian systems in a photomixotrophic Arabidopsis cell suspension culture. CHS expression is induced specifically by these wavelengths in the cell culture, in a manner similar to that in mature Arabidopsis leaf tissue. Both the UV-B and UV-A/blue phototransduction processes involve calcium, although the elevation of cytosolic calcium is insufficient on its own to stimulate CHS expression. The UV-A/blue light induction of CHS expression does not appear to involve calmodulin, whereas the UV-B response does; this difference indicates that the signal transduction pathways are, at least in part, distinct. We provide evidence that both pathways involve reversible protein phosphorylation and require protein synthesis. The UV-B and UV-A/blue light signaling pathways are therefore different from the phytochrome signal transduction pathway regulating CHS expression in other species

  19. Systems Biology Model of Interactions Between Tissue Growth Factors and DNA Damage Pathways: Low Dose Response and Cross-Talk in TGFbeta and ATM Signaling

    Energy Technology Data Exchange (ETDEWEB)

    O' Neill, Peter [University of Oxford; Anderson, Jennifer [University of Oxford

    2014-10-02

    The etiology of radiation carcinogenesis has been described in terms of aberrant changes that span several levels of biological organization. Growth factors regulate many important cellular and tissue functions including apoptosis, differentiation and proliferation. A variety of genetic and epigenetic changes of growth factors have been shown to contribute to cancer initiation and progression. It is known that cellular and tissue damage to ionizing radiation is in part initiated by the production of reactive oxygen species, which can activate cytokine signaling, and the DNA damage response pathways, most notably the ATM signaling pathway. Recently the transforming growth factor β (TGFβ) pathway has been shown to regulate or directly interact with the ATM pathway in the response to radiation. The relevance of this interaction with the ATM pathway is not known although p53 becomes phosphorylated and DNA damage responses are involved. However, growth factor interactions with DNA damage responses have not been elucidated particularly at low doses and further characterization of their relationship to cancer processes is warranted. Our goal will be to use a systems biology approach to mathematically and experimentally describe the low dose responses and cross-talk between the ATM and TGFβ pathways initiated by low and high LET radiation. We will characterize ATM and TGFβ signaling in epithelial and fibroblast cells using 2D models and ultimately extending to 3D organotypic cell culture models to begin to elucidate possible differences that may occur for different cell types and/or inter-cellular communication. We will investigate the roles of the Smad and Activating transcription factor 2 (ATF2) proteins as the potential major contributors to cross- talk between the TGFβ and ATM pathways, and links to cell cycle control and/or the DNA damage response, and potential differences in their responses at low and high doses. We have developed various experimental

  20. Systems Biology Model of Interactions between Tissue Growth Factors and DNA Damage Pathways: Low Dose Response and Cross-Talk in TGFβ and ATM Signaling

    International Nuclear Information System (INIS)

    Cucinotta, Francis A

    2016-01-01

    The etiology of radiation carcinogenesis has been described in terms of aberrant changes that span several levels of biological organization. Growth factors regulate many important cellular and tissue functions including apoptosis, differentiation and proliferation. A variety of genetic and epigenetic changes of growth factors have been shown to contribute to cancer initiation and progression. It is known that cellular and tissue damage to ionizing radiation is in part initiated by the production of reactive oxygen species, which can activate cytokine signaling, and the DNA damage response pathways, most notably the ATM signaling pathway. Recently, the transforming growth factor β (TGFβ) pathway has been shown to regulate or directly interact with the ATM pathway in the response to radiation. The relevance of this interaction with the ATM pathway is not known although p53 becomes phosphorylated and DNA damage responses are involved. However, growth factor interactions with DNA damage responses have not been elucidated particularly at low doses, and further characterization of their relationship to cancer processes is warranted. Our goal will be to use a systems biology approach to mathematically and experimentally describe the low-dose responses and cross-talk between the ATM and TGFβ pathways initiated by low- and high-LET radiation. We will characterize ATM and TGFβ signaling in epithelial and fibroblast cells using 2D models and ultimately extending to 3D organotypic cell culture models to begin to elucidate possible differences that may occur for different cell types and/or inter-cellular communication. We will investigate the roles of the Smad and Activating transcription factor 2 (ATF2) proteins as the potential major contributors to crosstalk between the TGFβ and ATM pathways, and links to cell cycle control and/or the DNA damage response, and potential differences in their responses at low and high doses. We have developed various experimental

  1. Systems Biology Model of Interactions between Tissue Growth Factors and DNA Damage Pathways: Low Dose Response and Cross-Talk in TGFβ and ATM Signaling

    Energy Technology Data Exchange (ETDEWEB)

    Cucinotta, Francis A [Univ. of Nevada, Las Vegas, NV (United States)

    2016-09-01

    The etiology of radiation carcinogenesis has been described in terms of aberrant changes that span several levels of biological organization. Growth factors regulate many important cellular and tissue functions including apoptosis, differentiation and proliferation. A variety of genetic and epigenetic changes of growth factors have been shown to contribute to cancer initiation and progression. It is known that cellular and tissue damage to ionizing radiation is in part initiated by the production of reactive oxygen species, which can activate cytokine signaling, and the DNA damage response pathways, most notably the ATM signaling pathway. Recently, the transforming growth factor β (TGFβ) pathway has been shown to regulate or directly interact with the ATM pathway in the response to radiation. The relevance of this interaction with the ATM pathway is not known although p53 becomes phosphorylated and DNA damage responses are involved. However, growth factor interactions with DNA damage responses have not been elucidated particularly at low doses, and further characterization of their relationship to cancer processes is warranted. Our goal will be to use a systems biology approach to mathematically and experimentally describe the low-dose responses and cross-talk between the ATM and TGFβ pathways initiated by low- and high-LET radiation. We will characterize ATM and TGFβ signaling in epithelial and fibroblast cells using 2D models and ultimately extending to 3D organotypic cell culture models to begin to elucidate possible differences that may occur for different cell types and/or inter-cellular communication. We will investigate the roles of the Smad and Activating transcription factor 2 (ATF2) proteins as the potential major contributors to crosstalk between the TGFβ and ATM pathways, and links to cell cycle control and/or the DNA damage response, and potential differences in their responses at low and high doses. We have developed various experimental

  2. Understanding Resolvin Signaling Pathways to Improve Oral Health

    Directory of Open Access Journals (Sweden)

    Laura De Oleo

    2013-03-01

    Full Text Available The discovery of resolvins has been a major breakthrough for understanding the processes involved in resolution of inflammation. Resolvins belong to a family of novel lipid mediators that possess dual anti-inflammatory and pro-resolution actions. Specifically, they protect healthy tissue during immune-inflammatory responses to infection or injury, thereby aiding inflammation resolution and promoting tissue healing. One of the major concerns in modern medicine is the management and treatment of oral diseases, as they are related to systemic outcomes impacting the quality of life of many patients. This review summarizes known signaling pathways utilized by resolvins to regulate inflammatory responses associated with the oral cavity.

  3. The Arabidopsis mutant cev1 has constitutively active jasmonate and ethylene signal pathways and enhanced resistance to pathogens.

    Science.gov (United States)

    Ellis, C; Turner, J G

    2001-05-01

    Jasmonates (JAs) inhibit plant growth and induce plant defense responses. To define genes in the Arabidopsis JA signal pathway, we screened for mutants with constitutive expression of a luciferase reporter for the JA-responsive promoter from the vegetative storage protein gene VSP1. One mutant, named constitutive expression of VSP1 (cev1), produced plants that were smaller than wild type, had stunted roots with long root hairs, accumulated anthocyanin, had constitutive expression of the defense-related genes VSP1, VSP2, Thi2.1, PDF1.2, and CHI-B, and had enhanced resistance to powdery mildew diseases. Genetic evidence indicated that the cev1 phenotype required both COI1, an essential component of the JA signal pathway, and ETR1, which encodes the ethylene receptor. We conclude that cev1 stimulates both the JA and the ethylene signal pathways and that CEV1 regulates an early step in an Arabidopsis defense pathway.

  4. Neuroprotective capabilities of TSA against cerebral ischemia/reperfusion injury via PI3K/Akt signaling pathway in rats.

    Science.gov (United States)

    Ma, Xiao-Hui; Gao, Qiang; Jia, Zhen; Zhang, Ze-Wei

    2015-02-01

    Hundreds of previous studies demonstrated the cytoprotective effect of trichostatin-A (TSA), a kind of histone deacetylases inhibitors (HDACIs), against cerebral ischemia/reperfusion insult. Meanwhile, phosphatidylinositol-3 kinase/Akt (PI3K/Akt) is a well-known, important signaling pathway that mediates neuroprotection. However, it should be remains unclear whether the neuroprotective capabilities of TSA against cerebral ischemia/reperfusion is mediated by activation of the PI3K/Akt signaling pathway. Five groups rats (n = 12 each), with middle cerebral artery occlusion (MCAO) except sham group, were used to investigate the neuroprotective effect of certain concentration (0.05 mg/kg) of TSA, and whether the neuroprotective effect of TSA is associated with activation of the PI3K/Akt signaling pathway through using of wortmannin (0.25 mg/kg). TSA significantly increased the expression of p-Akt protein, reduced infarct volume, and attenuated neurological deficit in rats with transient MCAO, wortmannin weakened such effect of TSA dramatically. TSA could significantly decrease the neurological deficit scores and reduce the cerebral infarct volume during cerebral ischemia/reperfusion injury, which was achieved partly by activation of the PI3K/Akt signaling pathway via upgrading of p-Akt protein.

  5. The chromatin remodeler SPLAYED regulates specific stress signaling pathways.

    Directory of Open Access Journals (Sweden)

    Justin W Walley

    2008-12-01

    Full Text Available Organisms are continuously exposed to a myriad of environmental stresses. Central to an organism's survival is the ability to mount a robust transcriptional response to the imposed stress. An emerging mechanism of transcriptional control involves dynamic changes in chromatin structure. Alterations in chromatin structure are brought about by a number of different mechanisms, including chromatin modifications, which covalently modify histone proteins; incorporation of histone variants; and chromatin remodeling, which utilizes ATP hydrolysis to alter histone-DNA contacts. While considerable insight into the mechanisms of chromatin remodeling has been gained, the biological role of chromatin remodeling complexes beyond their function as regulators of cellular differentiation and development has remained poorly understood. Here, we provide genetic, biochemical, and biological evidence for the critical role of chromatin remodeling in mediating plant defense against specific biotic stresses. We found that the Arabidopsis SWI/SNF class chromatin remodeling ATPase SPLAYED (SYD is required for the expression of selected genes downstream of the jasmonate (JA and ethylene (ET signaling pathways. SYD is also directly recruited to the promoters of several of these genes. Furthermore, we show that SYD is required for resistance against the necrotrophic pathogen Botrytis cinerea but not the biotrophic pathogen Pseudomonas syringae. These findings demonstrate not only that chromatin remodeling is required for selective pathogen resistance, but also that chromatin remodelers such as SYD can regulate specific pathways within biotic stress signaling networks.

  6. Downstream divergence of the ethylene signaling pathway for harpin-stimulated Arabidopsis growth and insect defense.

    Science.gov (United States)

    Dong, Hong-Ping; Peng, Jianling; Bao, Zhilong; Meng, Xiangdong; Bonasera, Jean M; Chen, Guangyong; Beer, Steven V; Dong, Hansong

    2004-11-01

    Ethylene (ET) signal transduction may regulate plant growth and defense, depending on which components are recruited into the pathway in response to different stimuli. We report here that the ET pathway controls both insect resistance (IR) and plant growth enhancement (PGE) in Arabidopsis (Arabidopsis thaliana) plants responding to harpin, a protein produced by a plant pathogenic bacterium. PGE may result from spraying plant tops with harpin or by soaking seeds in harpin solution; the latter especially enhances root growth. Plants treated similarly develop resistance to the green peach aphid (Myzus persicae). The salicylic acid pathway, although activated by harpin, does not lead to PGE and IR. By contrast, PGE and IR are induced in both wild-type plants and genotypes that have defects in salicylic acid signaling. In response to harpin, levels of jasmonic acid (JA) decrease, and the COI1 gene, which is indispensable for JA signal transduction, is not expressed in wild-type plants. However, PGE and IR are stimulated in the JA-resistant mutant jar1-1. In the wild type, PGE and IR develop coincidently with increases in ET levels and the expression of several genes essential for ET signaling. The ET receptor gene ETR1 is required because both phenotypes are arrested in the etr1-1 mutant. Consistently, inhibition of ET perception nullifies the induction of both PGE and IR. The signal transducer EIN2 is required for IR, and EIN5 is required for PGE because IR and PGE are impaired correspondingly in the ein2-1 and ein5-1 mutants. Therefore, harpin activates ET signaling while conscribing EIN2 and EIN5 to confer IR and PGE, respectively.

  7. Effects of PM2.5 exposure on the Notch signaling pathway and immune imbalance in chronic obstructive pulmonary disease

    International Nuclear Information System (INIS)

    Gu, Xing-yu; Chu, Xu; Zeng, Xiao-Li; Bao, Hai-Rong; Liu, Xiao-Ju

    2017-01-01

    Chronic Obstructive Pulmonary Disease (COPD) is associated with T lymphocytes subset (Th1/Th2, Th17/Treg) imbalance. Notch signaling pathway plays a key role in the development of the adaptive immunity. The immune disorder induced by fine particulate matter (PM2.5) is related to COPD. The aim of this study was to investigate the mechanism by which PM2.5 influences the Notch signaling pathway leading to worsening immune disorder and accelerating COPD development. A COPD mouse model was established by cigarette smoke exposure. PM2.5 exposure was performed by aerosol inhalation. γ-secretase inhibitor (GSI) was given using intraperitoneal injection. Splenic T lymphocytes were purified using a density gradient centrifugation method. CD4 + T lymphocyte subsets (Th1/Th2, Th17/Treg) were detected using flow cytometry. mRNA and proteins of Notch1/2/3/4, Hes1/5, and Hey1 were detected using RT-PCR and Western blot. Serum INF-γ, IL-4, IL-17 and IL-10 concentrations were measured using ELISA. The results showed that in COPD mice Th1% and Th17%, Th1/Th2 and Th17/Treg were increased, and the levels of mRNA and protein in Notch1/2/3/4, Hes1/5, and Hey1 and serum INF-γ and IL-17 concentrations were significantly increased, and Th2%, Treg%, and serum IL-4 and IL-10 concentrations were significantly decreased. COPD Mice have Th1- and Th17-mediated immune disorder, and the Notch signaling pathway is in an overactivated state. PM2.5 promotes the overactivation of the Notch signaling pathway and aggravates the immune disorder of COPD. GSI can partially inhibit the activation of the Notch signaling pathway and alleviate the immune disorder under basal state and the immune disorder of COPD caused by PM2.5. This result suggests that PM2.5 is involved in the immune disorder of mice with COPD by affecting the Notch signaling pathway and that PM2.5 aggravates COPD. - Highlights: • The COPD mice demonstrated Th1 and Th17 dominant immune imbalance. • PM2.5 aggravates the Th1/Th2 and Th

  8. Is autoinducer-2 a universal signal for interspecies communication: a comparative genomic and phylogenetic analysis of the synthesis and signal transduction pathways

    Directory of Open Access Journals (Sweden)

    Wagner-Döbler Irene

    2004-09-01

    Full Text Available Abstract Background Quorum sensing is a process of bacterial cell-to-cell communication involving the production and detection of extracellular signaling molecules called autoinducers. Recently, it has been proposed that autoinducer-2 (AI-2, a furanosyl borate diester derived from the recycling of S-adenosyl-homocysteine (SAH to homocysteine, serves as a universal signal for interspecies communication. Results In this study, 138 completed genomes were examined for the genes involved in the synthesis and detection of AI-2. Except for some symbionts and parasites, all organisms have a pathway to recycle SAH, either using a two-step enzymatic conversion by the Pfs and LuxS enzymes or a one-step conversion using SAH-hydrolase (SahH. 51 organisms including most Gamma-, Beta-, and Epsilonproteobacteria, and Firmicutes possess the Pfs-LuxS pathway, while Archaea, Eukarya, Alphaproteobacteria, Actinobacteria and Cyanobacteria prefer the SahH pathway. In all 138 organisms, only the three Vibrio strains had strong, bidirectional matches to the periplasmic AI-2 binding protein LuxP and the central signal relay protein LuxU. The initial two-component sensor kinase protein LuxQ, and the terminal response regulator luxO are found in most Proteobacteria, as well as in some Firmicutes, often in several copies. Conclusions The genomic analysis indicates that the LuxS enzyme required for AI-2 synthesis is widespread in bacteria, while the periplasmic binding protein LuxP is only present in Vibrio strains. Thus, other organisms may either use components different from the AI-2 signal transduction system of Vibrio strains to sense the signal of AI-2, or they do not have such a quorum sensing system at all.

  9. Identification of Pathways in Liver Repair Potentially Targeted by Secretory Proteins from Human Mesenchymal Stem Cells

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    Sandra Winkler

    2016-07-01

    Full Text Available Background: The beneficial impact of mesenchymal stem cells (MSC on both acute and chronic liver diseases has been confirmed, although the molecular mechanisms behind it remain elusive. We aim to identify factors secreted by undifferentiated and hepatocytic differentiated MSC in vitro in order to delineate liver repair pathways potentially targeted by MSC. Methods: Secreted factors were determined by protein arrays and related pathways identified by biomathematical analyses. Results: MSC from adipose tissue and bone marrow expressed a similar pattern of surface markers. After hepatocytic differentiation, CD54 (intercellular adhesion molecule 1, ICAM-1 increased and CD166 (activated leukocyte cell adhesion molecule, ALCAM decreased. MSC secreted different factors before and after differentiation. These comprised cytokines involved in innate immunity and growth factors regulating liver regeneration. Pathway analysis revealed cytokine-cytokine receptor interactions, chemokine signalling pathways, the complement and coagulation cascades as well as the Januskinase-signal transducers and activators of transcription (JAK-STAT and nucleotide-binding oligomerization domain-like receptor (NOD-like receptor signalling pathways as relevant networks. Relationships to transforming growth factor β (TGF-β and hypoxia-inducible factor 1-α (HIF1-α signalling seemed also relevant. Conclusion: MSC secreted proteins, which differed depending on cell source and degree of differentiation. The factors might address inflammatory and growth factor pathways as well as chemo-attraction and innate immunity. Since these are prone to dysregulation in most liver diseases, MSC release hepatotropic factors, potentially supporting liver regeneration.

  10. The Wnt signalling pathway is upregulated in an in vitro model of acquired tamoxifen resistant breast cancer

    International Nuclear Information System (INIS)

    Loh, Yan Ni; Hedditch, Ellen L; Baker, Laura A; Jary, Eve; Ward, Robyn L; Ford, Caroline E

    2013-01-01

    Acquired resistance to Tamoxifen remains a critical problem in breast cancer patient treatment, yet the underlying causes of resistance have not been fully elucidated. Abberations in the Wnt signalling pathway have been linked to many human cancers, including breast cancer, and appear to be associated with more metastatic and aggressive types of cancer. Here, our aim was to investigate if this key pathway was involved in acquired Tamoxifen resistance, and could be targeted therapeutically. An in vitro model of acquired Tamoxifen resistance (named TamR) was generated by growing the estrogen receptor alpha (ER) positive MCF7 breast cancer cell line in increasing concentrations of Tamoxifen (up to 5 uM). Alterations in the Wnt signalling pathway and epithelial to mesenchymal transition (EMT) in response to Tamoxifen and treatment with the Wnt inhibitor, IWP-2 were measured via quantitative RT-PCR (qPCR) and TOP/FOP Wnt reporter assays. Resistance to Tamoxifen, and effects of IWP-2 treatment were determined by MTT proliferation assays. TamR cells exhibited increased Wnt signalling as measured via the TOP/FOP Wnt luciferase reporter assays. Genes associated with both the β-catenin dependent (AXIN2, MYC, CSNK1A1) and independent arms (ROR2, JUN), as well as general Wnt secretion (PORCN) of the Wnt signalling pathway were upregulated in the TamR cells compared to the parental MCF7 cell line. Treatment of the TamR cell line with human recombinant Wnt3a (rWnt3a) further increased the resistance of both MCF7 and TamR cells to the anti-proliferative effects of Tamoxifen treatment. TamR cells demonstrated increased expression of EMT markers (VIM, TWIST1, SNAI2) and decreased CDH1, which may contribute to their resistance to Tamoxifen. Treatment with the Wnt inhibitor, IWP-2 inhibited cell proliferation and markers of EMT. These data support the role of the Wnt signalling pathway in acquired resistance to Tamoxifen. Further research into the mechanism by which activated Wnt

  11. Inflammation Activates the Interferon Signaling Pathways in Taste Bud Cells

    OpenAIRE

    Wang, Hong; Zhou, Minliang; Brand, Joseph; Huang, Liquan

    2007-01-01

    Patients with viral and bacterial infections or other inflammatory illnesses often experience taste dysfunctions. The agents responsible for these taste disorders are thought to be related to infection-induced inflammation, but the mechanisms are not known. As a first step in characterizing the possible role of inflammation in taste disorders, we report here evidence for the presence of interferon (IFN)-mediated signaling pathways in taste bud cells. IFN receptors, particularly the IFN-γ rece...

  12. The NOD-like receptor signalling pathway in Helicobacter pylori infection and related gastric cancer: a case-control study and gene expression analyses.

    Directory of Open Access Journals (Sweden)

    Natalia Castaño-Rodríguez

    , NLRP3, NLRP12, NLRX1, and CASP1 and GC were identified in Chinese individuals. Our genetic polymorphisms and gene expression results highlight the relevance of the NLR signalling pathway in gastric carcinogenesis and its close interaction with NF-κB.

  13. Reconstruction of the High-Osmolarity Glycerol (HOG) Signaling Pathway from the Halophilic Fungus Wallemia ichthyophaga in Saccharomyces cerevisiae.

    Science.gov (United States)

    Konte, Tilen; Terpitz, Ulrich; Plemenitaš, Ana

    2016-01-01

    The basidiomycetous fungus Wallemia ichthyophaga grows between 1.7 and 5.1 M NaCl and is the most halophilic eukaryote described to date. Like other fungi, W. ichthyophaga detects changes in environmental salinity mainly by the evolutionarily conserved high-osmolarity glycerol (HOG) signaling pathway. In Saccharomyces cerevisiae, the HOG pathway has been extensively studied in connection to osmotic regulation, with a valuable knock-out strain collection established. In the present study, we reconstructed the architecture of the HOG pathway of W. ichthyophaga in suitable S. cerevisiae knock-out strains, through heterologous expression of the W. ichthyophaga HOG pathway proteins. Compared to S. cerevisiae, where the Pbs2 (ScPbs2) kinase of the HOG pathway is activated via the SHO1 and SLN1 branches, the interactions between the W. ichthyophaga Pbs2 (WiPbs2) kinase and the W. ichthyophaga SHO1 branch orthologs are not conserved: as well as evidence of poor interactions between the WiSho1 Src-homology 3 (SH3) domain and the WiPbs2 proline-rich motif, the absence of a considerable part of the osmosensing apparatus in the genome of W. ichthyophaga suggests that the SHO1 branch components are not involved in HOG signaling in this halophilic fungus. In contrast, the conserved activation of WiPbs2 by the S. cerevisiae ScSsk2/ScSsk22 kinase and the sensitivity of W. ichthyophaga cells to fludioxonil, emphasize the significance of two-component (SLN1-like) signaling via Group III histidine kinase. Combined with protein modeling data, our study reveals conserved and non-conserved protein interactions in the HOG signaling pathway of W. ichthyophaga and therefore significantly improves the knowledge of hyperosmotic signal processing in this halophilic fungus.

  14. The Spectrin cytoskeleton regulates the Hippo signalling pathway.

    Science.gov (United States)

    Fletcher, Georgina C; Elbediwy, Ahmed; Khanal, Ichha; Ribeiro, Paulo S; Tapon, Nic; Thompson, Barry J

    2015-04-01

    The Spectrin cytoskeleton is known to be polarised in epithelial cells, yet its role remains poorly understood. Here, we show that the Spectrin cytoskeleton controls Hippo signalling. In the developing Drosophila wing and eye, loss of apical Spectrins (alpha/beta-heavy dimers) produces tissue overgrowth and mis-regulation of Hippo target genes, similar to loss of Crumbs (Crb) or the FERM-domain protein Expanded (Ex). Apical beta-heavy Spectrin binds to Ex and co-localises with it at the apical membrane to antagonise Yki activity. Interestingly, in both the ovarian follicular epithelium and intestinal epithelium of Drosophila, apical Spectrins and Crb are dispensable for repression of Yki, while basolateral Spectrins (alpha/beta dimers) are essential. Finally, the Spectrin cytoskeleton is required to regulate the localisation of the Hippo pathway effector YAP in response to cell density human epithelial cells. Our findings identify both apical and basolateral Spectrins as regulators of Hippo signalling and suggest Spectrins as potential mechanosensors. © 2015 The Authors. Published under the terms of the CC BY 4.0 license.

  15. Multiple interactions between maternally-activated signalling pathways control Xenopus nodal-related genes.

    Science.gov (United States)

    Rex, Maria; Hilton, Emma; Old, Robert

    2002-03-01

    We have investigated the induction of the six Xenopus nodal-related genes, Xnr1-Xnr6, by maternal determinants. The beta-catenin pathway was modelled by stimulation using Xwnt8, activin-like signalling was modelled by activin, and VegT action was studied by overexpression in animal cap explants. Combinations of factors were examined, and previously unrecognised interactions were revealed in animal caps and whole embryos. For the induction of Xnr5 and Xnr6 in whole embryos, using a beta-catenin antisense morpholino oligonucleotide or a dominant negative XTcf3, we have demonstrated an absolute permissive requirement for the beta-catenin/Tcf pathway, in addition to the requirement for VegT action. In animal caps Xnr5 and Xnr6 are induced in response to VegT overexpression, and this induction is dependent upon the concomitant activation of the beta-catenin pathway that VegT initiates in animal caps. For the induction of Xnr3, VegT interacts negatively so as to inhibit the induction otherwise observed with wnt-signalling alone. The negative effect of VegT is not the result of a general inhibition of wnt-signalling, and does not result from an inhibition of wnt-induced siamois expression. A 294 bp proximal promoter fragment of the Xnr3 gene is sufficient to mediate the negative effect of VegT. Further experiments, employing cycloheximide to examine the dependence of Xnr gene expression upon proteins translated after the mid-blastula stage, demonstrated that Xnrs 4, 5 and 6 are 'primary' Xnr genes whose expression in the late blastula is solely dependent upon factors present before the mid-blastula stage.

  16. Radiation-induced adaptive response and intracellular signal transduction pathways

    International Nuclear Information System (INIS)

    Tachibana, Akira

    2009-01-01

    As an essential biological function, cells can sense the radiation even at low dose and respond to it, and which is one of bases of the radiation-induced adaptive response (AR) where effects caused by high dose radiation are reduced by prior exposure to low dose radiation (LDR). Here described are studies of AR in well established m5S cells on the intracellular signal transduction that involves sensing of LDR and transmitting of its signal within the cell network. The first signal for AR yielded by LDR on the cell membrane is exactly unknown though hydrogen peroxide and phorbol ester (PMA) can reportedly cause AR. As PMA activates protein kinase C (PKC) and its inhibitors suppress AR, participation of PKC in AR has been suggested and supported by studies showing PKCα activation by LDR. In addition, p38 mitogen-activated protein kinase (MAPK) is shown to participate in AR by those facts that the enzyme is activated by LDR, a p38 MAPK inhibitor suppresses AR, and PKC inhibitors suppress the enzyme activation, which also suggesting that the signaling from PKC to p38 MAPK can become operative by LDR. However, the possible reverse signaling is also suggested, and thus the activation of positive feedback mechanism is postulated in PKC/p38 MAPK/phospholipase δ1/ PKC pathway. Cells introduced with siRNA against Prkca gene (coding PKCs) produce reduced amount of the enzyme, particularly, of PKCα. In those cells, AR by 5 Gy X-ray is not observed and thereby PKCα is involved in AR. The signaling in AR is only partly elucidated at present as above, and more detailed studies including identification of more PKC subtypes and signaling to DNA repair system are considered necessary. (K.T.)

  17. Desert dust induces TLR signaling to trigger Th2-dominant lung allergic inflammation via a MyD88-dependent signaling pathway

    Energy Technology Data Exchange (ETDEWEB)

    He, Miao, E-mail: hemiao@mail.cmu.edu.cn [Environment and Non-communicable Disease Research Center, School of Public Health, China Medical University, Shenyang 110122 (China); Ichinose, Takamichi, E-mail: ichinose@oita-nhs.ac.jp [Department of Health Sciences, Oita University of Nursing and Health Sciences, Oita 870-1201 (Japan); Song, Yuan; Yoshida, Yasuhiro [Department of Immunology and Parasitology, School of Medicine, University of Occupational and Environmental Health, Fukuoka 807-8555 (Japan); Bekki, Kanae [Department of Environmental Health, National Institute of Public Health, Saitama 351-0197 (Japan); Arashidani, Keiichi [Department of Immunology and Parasitology, School of Medicine, University of Occupational and Environmental Health, Fukuoka 807-8555 (Japan); Yoshida, Seiichi [Department of Health Sciences, Oita University of Nursing and Health Sciences, Oita 870-1201 (Japan); Nishikawa, Masataka [Environmental Chemistry Division, National Institute for Environmental Studies, Ibaraki 305-8506 (Japan); Takano, Hirohisa [Environmental Health Division, Department of Environmental Engineering, Graduate School of Engineering, Kyoto University, Kyoto 615-8530 (Japan); Shibamoto, Takayuki [Department of Environmental Toxicology, University of California, Davis, CA 95616, USA. (United States); Sun, Guifan [Environment and Non-communicable Disease Research Center, School of Public Health, China Medical University, Shenyang 110122 (China)

    2016-04-01

    Asian sand dust (ASD) is known to exacerbate asthma, although its mechanism is not yet well understood. In this study, when the effects on inflammatory response by LPS present in ASD was investigated by measuring the gene expression of cytokines and chemokines in RAW264.7 cells treated with ASD and/or polymyxin B (PMB), the ASD effects were attenuated by PMB, but not completely. When an in vitro study was performed using bone marrow-derived macrophages (BMDMs) from WT, TLR2{sup −/−}, TLR4{sup −/−}, and MyD88{sup −/−} BALB/c mice and BMDMs from WT, TLR2{sup −/−}, TLR4{sup −/−}, TLR2/4{sup −/−}, TLR7/9{sup −/−}, and MyD88{sup −/−} C57BL/6J mice, cytokine (IL-6, IL-12) production in BMDMs was higher in ASD-stimulated TLR2{sup −/−} cells than in TLR4{sup −/−} cells, whereas it was lower or undetectable in TLR2/4{sup −/−} and MyD88{sup −/−} cells. These results suggest that ASD causes cytokine production predominantly in a TLR4/MyD88-dependent pathway. When WT and TLRs 2{sup −/−}, 4{sup −/−}, and MyD88{sup −/−} BALB/c mice were intratracheally challenged with OVA and/or ASD, ASD caused exacerbation of lung eosinophilia along with Th2 cytokine and eosinophil-relevant chemokine production. Serum OVA-specific IgE and IgG1 similar to WT was observed in TLRs 2{sup −/−}, 4{sup −/−} mice, but not in MyD88{sup −/−} mice. The Th2 responses in TLR2{sup −/−} mice were attenuated remarkably by PMB. These results indicate that ASD exacerbates lung eosinophilia in a MyD88-dependent pathway. TLRs 2 and 4 signaling may be important in the increase in lung eosinophilia. Also, the TLR4 ligand LPS and TLR2 ligand like β-glucan may be strong candidates for exacerbation of lung eosinophilia. - Highlights: • ASD enhanced Th2 response in TLR2{sup −/−}, TLR4{sup −/−} and WT mice, but not in MyD88{sup −/−}. • Th2 responses in TLR2{sup −/−} mice were attenuated by LPS inhibitor polymyxin B. • TLR2

  18. CD25 and CD69 induction by α4β1 outside-in signalling requires TCR early signalling complex proteins

    Science.gov (United States)

    Cimo, Ann-Marie; Ahmed, Zamal; McIntyre, Bradley W.; Lewis, Dorothy E.; Ladbury, John E.

    2013-01-01

    Distinct signalling pathways producing diverse cellular outcomes can utilize similar subsets of proteins. For example, proteins from the TCR (T-cell receptor) ESC (early signalling complex) are also involved in interferon-α receptor signalling. Defining the mechanism for how these proteins function within a given pathway is important in understanding the integration and communication of signalling networks with one another. We investigated the contributions of the TCR ESC proteins Lck (lymphocyte-specific kinase), ZAP-70 (ζ-chain-associated protein of 70 kDa), Vav1, SLP-76 [SH2 (Src homology 2)-domain-containing leukocyte protein of 76 kDa] and LAT (linker for activation of T-cells) to integrin outside-in signalling in human T-cells. Lck, ZAP-70, SLP-76, Vav1 and LAT were activated by α4β1 outside-in signalling, but in a manner different from TCR signalling. TCR stimulation recruits ESC proteins to activate the mitogen-activated protein kinase ERK (extracellular-signal-regulated kinase). α4β1 outside-in-mediated ERK activation did not require TCR ESC proteins. However, α4β1 outside-in signalling induced CD25 and co-stimulated CD69 and this was dependent on TCR ESC proteins. TCR and α4β1 outside-in signalling are integrated through the common use of TCR ESC proteins; however, these proteins display functionally distinct roles in these pathways. These novel insights into the cross-talk between integrin outside-in and TCR signalling pathways are highly relevant to the development of therapeutic strategies to overcome disease associated with T-cell deregulation. PMID:23758320

  19. New Insights into Glomerular Parietal Epithelial Cell Activation and Its Signaling Pathways in Glomerular Diseases

    Directory of Open Access Journals (Sweden)

    Hua Su

    2015-01-01

    Full Text Available The glomerular parietal epithelial cells (PECs have aroused an increasing attention recently. The proliferation of PECs is the main feature of crescentic glomerulonephritis; besides that, in the past decade, PEC activation has been identified in several types of noninflammatory glomerulonephropathies, such as focal segmental glomerulosclerosis, diabetic glomerulopathy, and membranous nephropathy. The pathogenesis of PEC activation is poorly understood; however, a few studies delicately elucidate the potential mechanisms and signaling pathways implicated in these processes. In this review we will focus on the latest observations and concepts about PEC activation in glomerular diseases and the newest identified signaling pathways in PEC activation.

  20. Rapamycin targeting mTOR and hedgehog signaling pathways blocks human rhabdomyosarcoma growth in xenograft murine model

    Energy Technology Data Exchange (ETDEWEB)

    Kaylani, Samer Z. [Division of Hematology and Oncology, Department of Pediatrics, University of Alabama at Birmingham, 1600 7th Avenue South, ACC 414, Birmingham, AL 35233 (United States); Xu, Jianmin; Srivastava, Ritesh K. [Department of Dermatology and Skin Diseases Research Center, University of Alabama at Birmingham, 1530 3rd Avenue South, VH 509, Birmingham, AL 35294-0019 (United States); Kopelovich, Levy [Division of Cancer Prevention, National Cancer Institute, Bethesda (United States); Pressey, Joseph G. [Division of Hematology and Oncology, Department of Pediatrics, University of Alabama at Birmingham, 1600 7th Avenue South, ACC 414, Birmingham, AL 35233 (United States); Athar, Mohammad, E-mail: mathar@uab.edu [Department of Dermatology and Skin Diseases Research Center, University of Alabama at Birmingham, 1530 3rd Avenue South, VH 509, Birmingham, AL 35294-0019 (United States)

    2013-06-14

    Graphical abstract: Intervention of poorly differentiated RMS by rapamycin: In poorly differentiated RMS, rapamycin blocks mTOR and Hh signaling pathways concomitantly. This leads to dampening in cell cycle regulation and induction of apoptosis. This study provides a rationale for the therapeutic intervention of poorly differentiated RMS by treating patients with rapamycin alone or in combination with other chemotherapeutic agents. -- Highlights: •Rapamycin abrogates RMS tumor growth by modulating proliferation and apoptosis. •Co-targeting mTOR/Hh pathways underlie the molecular basis of effectiveness. •Reduction in mTOR/Hh pathways diminish EMT leading to reduced invasiveness. -- Abstract: Rhabdomyosarcomas (RMS) represent the most common childhood soft-tissue sarcoma. Over the past few decades outcomes for low and intermediate risk RMS patients have slowly improved while patients with metastatic or relapsed RMS still face a grim prognosis. New chemotherapeutic agents or combinations of chemotherapies have largely failed to improve the outcome. Based on the identification of novel molecular targets, potential therapeutic approaches in RMS may offer a decreased reliance on conventional chemotherapy. Thus, identification of effective therapeutic agents that specifically target relevant pathways may be particularly beneficial for patients with metastatic and refractory RMS. The PI3K/AKT/mTOR pathway has been found to be a potentially attractive target in RMS therapy. In this study, we provide evidence that rapamycin (sirolimus) abrogates growth of RMS development in a RMS xenograft mouse model. As compared to a vehicle-treated control group, more than 95% inhibition in tumor growth was observed in mice receiving parenteral administration of rapamycin. The residual tumors in rapamycin-treated group showed significant reduction in the expression of biomarkers indicative of proliferation and tumor invasiveness. These tumors also showed enhanced apoptosis

  1. Amorphous Silica Particles Relevant in Food Industry Influence Cellular Growth and Associated Signaling Pathways in Human Gastric Carcinoma Cells.

    Science.gov (United States)

    Wittig, Anja; Gehrke, Helge; Del Favero, Giorgia; Fritz, Eva-Maria; Al-Rawi, Marco; Diabaté, Silvia; Weiss, Carsten; Sami, Haider; Ogris, Manfred; Marko, Doris

    2017-01-13

    Nanostructured silica particles are commonly used in biomedical and biotechnical fields, as well as, in cosmetics and food industry. Thus, their environmental and health impacts are of great interest and effects after oral uptake are only rarely investigated. In the present study, the toxicological effects of commercially available nano-scaled silica with a nominal primary diameter of 12 nm were investigated on the human gastric carcinoma cell line GXF251L. Besides the analysis of cytotoxic and proliferative effects and the comparison with effects of particles with a nominal primary diameter of 200 nm, emphasis was also given to their influence on the cellular epidermal growth factor receptor (EGFR) and mitogen-activated protein kinases (MAPK) signaling pathways-both of them deeply involved in the regulation of cellular processes like cell cycle progression, differentiation or proliferation. The investigated silica nanoparticles (NPs) were found to stimulate cell proliferation as measured by microscopy and the sulforhodamine B assay. In accordance, the nuclear level of the proliferation marker Ki-67 was enhanced in a concentration-dependent manner. At high particle concentrations also necrosis was induced. Finally, silica NPs affected the EGFR and MAPK pathways at various levels dependent on concentration and time. However, classical activation of the EGFR, to be reflected by enhanced levels of phosphorylation, could be excluded as major trigger of the proliferative stimulus. After 45 min of incubation the level of phosphorylated EGFR did not increase, whereas enhanced levels of total EGFR protein were observed. These results indicate interference with the complex homeostasis of the EGFR protein, whereby up to 24 h no impact on the transcription level was detected. In addition, downstream on the level of the MAP kinases ERK1/2 short term incubation appeared to affect total protein levels without clear increase in phosphorylation. Depending on the concentration

  2. Dual TORK/DNA-PK inhibition blocks critical signaling pathways in chronic lymphocytic leukemia

    NARCIS (Netherlands)

    Thijssen, Rachel; ter Burg, Johanna; Garrick, Brett; van Bochove, Gregor G. W.; Brown, Jennifer R.; Fernandes, Stacey M.; Rodríguez, María Solé; Michot, Jean-Marie; Hallek, Michael; Eichhorst, Barbara; Reinhardt, Hans Christian; Bendell, Johanna; Derks, Ingrid A. M.; van Kampen, Roel J. W.; Hege, Kristen; Kersten, Marie José; Trowe, Torsten; Filvaroff, Ellen H.; Eldering, Eric; Kater, Arnon P.

    2016-01-01

    Inhibition of B-cell receptor (BCR) signaling pathways in chronic lymphocytic leukemia (CLL) provides significant clinical benefit to patients, mainly by blocking adhesion of CLL cells in the lymph node microenvironment. The currently applied inhibitors ibrutinib and idelalisib have limited capacity

  3. Emergence, development and diversification of the TGF-β signalling pathway within the animal kingdom

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    Moustakas Aristidis

    2009-02-01

    Full Text Available Abstract Background The question of how genomic processes, such as gene duplication, give rise to co-ordinated organismal properties, such as emergence of new body plans, organs and lifestyles, is of importance in developmental and evolutionary biology. Herein, we focus on the diversification of the transforming growth factor-β (TGF-β pathway – one of the fundamental and versatile metazoan signal transduction engines. Results After an investigation of 33 genomes, we show that the emergence of the TGF-β pathway coincided with appearance of the first known animal species. The primordial pathway repertoire consisted of four Smads and four receptors, similar to those observed in the extant genome of the early diverging tablet animal (Trichoplax adhaerens. We subsequently retrace duplications in ancestral genomes on the lineage leading to humans, as well as lineage-specific duplications, such as those which gave rise to novel Smads and receptors in teleost fishes. We conclude that the diversification of the TGF-β pathway can be parsimoniously explained according to the 2R model, with additional rounds of duplications in teleost fishes. Finally, we investigate duplications followed by accelerated evolution which gave rise to an atypical TGF-β pathway in free-living bacterial feeding nematodes of the genus Rhabditis. Conclusion Our results challenge the view of well-conserved developmental pathways. The TGF-β signal transduction engine has expanded through gene duplication, continually adopting new functions, as animals grew in anatomical complexity, colonized new environments, and developed an active immune system.

  4. Tyrosine Phosphorylation in Toll-Like Receptor Signaling

    Science.gov (United States)

    Chattopadhyay, Saurabh; Sen, Ganes C.

    2014-01-01

    There is a wealth of knowledge about how different Ser/Thr protein kinases participate in Toll-like receptor (TLR) signaling. In many cases, we know the identities of the Ser/Thr residues of various components of the TLR-signaling pathways that are phosphorylated, the functional consequences of the phosphorylation and the responsible protein kinases. In contrast, the analysis of Tyr-phosphorylation of TLRs and their signaling proteins is currently incomplete, because several existing analyses are not systematic or they do not rely on robust experimental data. Nevertheless, it is clear that many TLRs require, for signaling, ligand-dependent phosphorylation of specific Tyr residues in their cytoplasmic domains; the list includes TLR2, TLR3, TLR4, TLR5, TLR8 and TLR9. In this article, we discuss the current status of knowledge on the effect of Tyr-phosphorylation of TLRs and their signaling proteins on their biochemical and biological functions, the possible identities of the relevant protein tyrosine kinases (PTKs) and the nature of regulations of PTK-mediated activation of TLR signaling pathways. PMID:25022196

  5. Single-cell analysis reveals a link between CD3- and CD59-mediated signaling pathways in Jurkat T cells

    International Nuclear Information System (INIS)

    Lipp, A. M.

    2012-01-01

    Elevation of intracellular free calcium concentration ([Ca2+]i) is a key signal during T cell activation and is commonly used as a read-out parameter for stimulation of T cell signaling. Upon T cell stimulation a variety of calcium signals is produced by individual cells of the T cell population and the type of calcium signal strongly influences cell fate decisions. The heterogeneous nature of T cells is masked in ensemble measurements, which highlights the need for single-cell measurements. In this study we used single-cell calcium measurements in Jurkat cells to investigate signaling pathways, which are triggered by different proteins, namely CD3 and CD59. By application of an automated cluster algorithm the presented assay provides unbiased analysis of a large data set of individual calcium time traces generated by the whole cell population. By using this method we could demonstrate that the Jurkat population generates heterogeneous calcium signals in a stimulus-dependent manner. Furthermore, our data revealed the existence of a link between CD3- and CD59-mediated signaling pathways. Single-cell calcium measurements in Jurkat cells expressing different levels of the T cell receptor (TCR) complex indicated that CD59-mediated calcium signaling is critically dependent on TCR surface expression levels. In addition, triggering CD59-mediated calcium signaling resulted in down-regulation of TCR surface expression levels, which is known to happen upon direct TCR triggering too. Moreover, by using siRNA-mediated protein knock-downs and protein knock-out Jurkat mutants we could show that CD3- and CD59-mediated calcium signaling require identical key proteins. We therefore explored by which mechanism CD59-mediated signaling couples into TCR-mediated signaling. Fluorescence recovery after photobleaching (FRAP) experiments and live-cell protein-protein interaction assays provided no evidence of a direct physical interaction between CD3- and CD59-mediated signaling pathways

  6. Mechanisms of amino acid sensing in mTOR signaling pathway

    OpenAIRE

    Kim, Eunjung

    2009-01-01

    Amino acids are fundamental nutrients for protein synthesis and cell growth (increase in cell size). Recently, many compelling evidences have shown that the level of amino acids is sensed by extra- or intra-cellular amino acids sensor(s) and regulates protein synthesis/degradation. Mammalian target of rapamycin complex 1 (mTORC1) is placed in a central position in cell growth regulation and dysregulation of mTOR signaling pathway has been implicated in many serious human diseases including ca...

  7. Regulator of calcineurin 1 differentially regulates TLR-dependent MyD88 and TRIF signaling pathways.

    Directory of Open Access Journals (Sweden)

    Zheng Pang

    Full Text Available Toll-like receptors (TLRs recognize the conserved molecular patterns in microorganisms and trigger myeloid differentiation primary response 88 (MyD88 and/or TIR-domain-containing adapter-inducing interferon-β (TRIF pathways that are critical for host defense against microbial infection. However, the molecular mechanisms that govern TLR signaling remain incompletely understood. Regulator of calcineurin-1 (RCAN1, a small evolutionarily conserved protein that inhibits calcineurin phosphatase activity, suppresses inflammation during Pseudomonas aeruginosa infection. Here, we define the roles for RCAN1 in P. aeruginosa lipopolysaccharide (LPS-activated TLR4 signaling. We compared the effects of P. aeruginosa LPS challenge on bone marrow-derived macrophages from both wild-type and RCAN1-deficient mice and found that RCAN1 deficiency increased the MyD88-NF-κB-mediated cytokine production (IL-6, TNF and MIP-2, whereas TRIF-interferon-stimulated response elements (ISRE-mediated cytokine production (IFNβ, RANTES and IP-10 was suppressed. RCAN1 deficiency caused increased IκBα phosphorylation and NF-κB activity in the MyD88-dependent pathway, but impaired ISRE activation and reduced IRF7 expression in the TRIF-dependent pathway. Complementary studies of a mouse model of P. aeruginosa LPS-induced acute pneumonia confirmed that RCAN1-deficient mice displayed greatly enhanced NF-κB activity and MyD88-NF-κB-mediated cytokine production, which correlated with enhanced pulmonary infiltration of neutrophils. By contrast, RCAN1 deficiency had little effect on the TRIF pathway in vivo. These findings demonstrate a novel regulatory role of RCAN1 in TLR signaling, which differentially regulates MyD88 and TRIF pathways.

  8. Regulation of PGE2 signaling pathways and TNF-alpha signaling pathways on the function of bone marrow-derived dendritic cells and the effects of CP-25.

    Science.gov (United States)

    Li, Ying; Sheng, Kangliang; Chen, Jingyu; Wu, Yujing; Zhang, Feng; Chang, Yan; Wu, Huaxun; Fu, Jingjing; Zhang, Lingling; Wei, Wei

    2015-12-15

    This study was to investigate PGE2 and TNF-alpha signaling pathway involving in the maturation and activation of bone marrow dendritic cells (DCs) and the effect of CP-25. Bone marrow DCs were isolated and stimulated by PGE2 and TNF-alpha respectively. The markers of maturation and activation expressed on DCs, such as CD40, CD80, CD83, CD86, MHC-II, and the ability of antigen uptake of DCs were analyzed by flow cytometry. The proliferation of T cells co-cultured with DCs, the signaling pathways of PGE2-EP4-cAMP and TNF-alpha-TRADD-TRAF2-NF-κB in DCs were analyzed. The results showed that both PGE2 and TNF-alpha up-regulated the expressions of CD40, CD80, CD83, CD86, and MHC-II, decreased the antigen uptake of DCs, and DCs stimulated by PGE2 or TNF-alpha could increase T cell proliferation. CP-25 (10(-5), 10(-6), and 10(-7)mol/l) decreased significantly the expressions of CD40, CD80, CD83, CD86 and MHC-II, increased the antigen uptake of DCs, and suppressed T cell proliferation induced by DCs. PGE2 increased the expressions of EP4, NF-κB and down-regulated cAMP level of DCs. TNF-alpha could also up-regulate TNFR1, TRADD, TRAF2, and NF-κB expression of DCs. CP-25 (10(-5), 10(-6), and 10(-7)mol/l) decreased the expressions of EP4 and NF-κB, increased cAMP level in DCs stimulated by PGE2. CP-25 (10(-5), 10(-6), and 10(-7)mol/l) also could down-regulate significantly TNFR1, TRADD, TRAF2, and NF-κB expression in DCs stimulated by TNF-alpha. These results demonstrate that PGE2 and TNF-alpha could enhance DCs functions by mediating PGE2-EP4-cAMP pathway, TNF-alpha-TNFR1-TRADD-TRAF2-NF-κB pathway respectively. CP-25 might inhibit the function of DCs through regulating PGE2-EP4-cAMP and TNF-alpha-TNFR1-TRADD-TRAF2-NF-κB pathways. Copyright © 2015 Elsevier B.V. All rights reserved.

  9. APC Inhibits Ligand-Independent Wnt Signaling by the Clathrin Endocytic Pathway.

    Science.gov (United States)

    Saito-Diaz, Kenyi; Benchabane, Hassina; Tiwari, Ajit; Tian, Ai; Li, Bin; Thompson, Joshua J; Hyde, Annastasia S; Sawyer, Leah M; Jodoin, Jeanne N; Santos, Eduardo; Lee, Laura A; Coffey, Robert J; Beauchamp, R Daniel; Williams, Christopher S; Kenworthy, Anne K; Robbins, David J; Ahmed, Yashi; Lee, Ethan

    2018-03-12

    Adenomatous polyposis coli (APC) mutations cause Wnt pathway activation in human cancers. Current models for APC action emphasize its role in promoting β-catenin degradation downstream of Wnt receptors. Unexpectedly, we find that blocking Wnt receptor activity in APC-deficient cells inhibits Wnt signaling independently of Wnt ligand. We also show that inducible loss of APC is rapidly followed by Wnt receptor activation and increased β-catenin levels. In contrast, APC2 loss does not promote receptor activation. We show that APC exists in a complex with clathrin and that Wnt pathway activation in APC-deficient cells requires clathrin-mediated endocytosis. Finally, we demonstrate conservation of this mechanism in Drosophila intestinal stem cells. We propose a model in which APC and APC2 function to promote β-catenin degradation, and APC also acts as a molecular "gatekeeper" to block receptor activation via the clathrin pathway. Copyright © 2018 Elsevier Inc. All rights reserved.

  10. AKTivation of the PI3K/AKT/mTOR signaling pathway by KSHV

    Directory of Open Access Journals (Sweden)

    Aadra P Bhatt

    2013-01-01

    Full Text Available As an obligate intracellular parasite, the Kaposi sarcoma-associated herpesvirus (KSHV relies on host cell machinery to meet its needs for survival, viral replication, production, and dissemination of progeny virions. KSHV is a ɣ-herpesvirus that is associated with three different malignancies: Kaposi sarcoma (KS, and two B cell lymphoproliferative disorders, primary effusion lymphoma (PEL and multicentric Castleman disease (MCD. KSHV viral proteins modulate cellular phosphatidylinositol-3-kinase (PI3K/AKT/mammalian target of rapamycin (mTOR signaling pathway, which is a ubiquitous pathway that also controls B lymphocyte proliferation and development. We review the mechanisms by which KSHV manipulates the PI3K/AKT/mTOR pathway, with a specific focus on B cells.

  11. Molecular pathway profiling of T lymphocyte signal transduction pathways; Th1 and Th2 genomic fingerprints are defined by TCR and CD28-mediated signaling

    Directory of Open Access Journals (Sweden)

    Smeets Ruben L

    2012-03-01

    Full Text Available Abstract Background T lymphocytes are orchestrators of adaptive immunity. Naïve T cells may differentiate into Th1, Th2, Th17 or iTreg phenotypes, depending on environmental co-stimulatory signals. To identify genes and pathways involved in differentiation of Jurkat T cells towards Th1 and Th2 subtypes we performed comprehensive transcriptome analyses of Jurkat T cells stimulated with various stimuli and pathway inhibitors. Results from these experiments were validated in a human experimental setting using whole blood and purified CD4+ Tcells. Results Calcium-dependent activation of T cells using CD3/CD28 and PMA/CD3 stimulation induced a Th1 expression profile reflected by increased expression of T-bet, RUNX3, IL-2, and IFNγ, whereas calcium-independent activation via PMA/CD28 induced a Th2 expression profile which included GATA3, RXRA, CCL1 and Itk. Knock down with siRNA and gene expression profiling in the presence of selective kinase inhibitors showed that proximal kinases Lck and PKCθ are crucial signaling hubs during T helper cell activation, revealing a clear role for Lck in Th1 development and for PKCθ in both Th1 and Th2 development. Medial signaling via MAPkinases appeared to be less important in these pathways, since specific inhibitors of these kinases displayed a minor effect on gene expression. Translation towards a primary, whole blood setting and purified human CD4+ T cells revealed that PMA/CD3 stimulation induced a more pronounced Th1 specific, Lck and PKCθ dependent IFNγ production, whereas PMA/CD28 induced Th2 specific IL-5 and IL-13 production, independent of Lck activation. PMA/CD3-mediated skewing towards a Th1 phenotype was also reflected in mRNA expression of the master transcription factor Tbet, whereas PMA/CD28-mediated stimulation enhanced GATA3 mRNA expression in primary human CD4+ Tcells. Conclusions This study identifies stimulatory pathways and gene expression profiles for in vitro skewing of T helper cell

  12. Neuronal apoptotic signaling pathways probed and intervened by synthetically and modularly modified (SMM) chemokines.

    Science.gov (United States)

    Choi, Won-Tak; Kaul, Marcus; Kumar, Santosh; Wang, Jun; Kumar, I M Krishna; Dong, Chang-Zhi; An, Jing; Lipton, Stuart A; Huang, Ziwei

    2007-03-09

    As the main coreceptors for human immunodeficiency virus type 1 (HIV-1) entry, CXCR4 and CCR5 play important roles in HIV-associated dementia (HAD). HIV-1 glycoprotein gp120 contributes to HAD by causing neuronal damage and death, either directly by triggering apoptotic pathways or indirectly by stimulating glial cells to release neurotoxins. Here, to understand the mechanism of CXCR4 or CCR5 signaling in neuronal apoptosis associated with HAD, we have applied synthetically and modularly modified (SMM)-chemokine analogs derived from natural stromal cell-derived factor-1alpha or viral macrophage inflammatory protein-II as chemical probes of the mechanism(s) whereby these SMM-chemokines prevent or promote neuronal apoptosis. We show that inherently neurotoxic natural ligands of CXCR4, such as stromal cell-derived factor-1alpha or viral macrophage inflammatory protein-II, can be modified to protect neurons from apoptosis induced by CXCR4-preferring gp120(IIIB), and that the inhibition of CCR5 by antagonist SMM-chemokines, unlike neuroprotective CCR5 natural ligands, leads to neurotoxicity by activating a p38 mitogen-activated protein kinase (MAPK)-dependent pathway. Furthermore, we discover distinct signaling pathways activated by different chemokine ligands that are either natural agonists or synthetic antagonists, thus demonstrating a chemical biology strategy of using chemically engineered inhibitors of chemokine receptors to study the signaling mechanism of neuronal apoptosis and survival.

  13. Matrine pretreatment improves cardiac function in rats with diabetic cardiomyopathy via suppressing ROS/TLR-4 signaling pathway.

    Science.gov (United States)

    Liu, Zhong-wei; Wang, Jun-kui; Qiu, Chuan; Guan, Gong-chang; Liu, Xin-hong; Li, Shang-jian; Deng, Zheng-rong

    2015-03-01

    Matrine is an alkaloid from Sophora alopecuroides L, which has shown a variety of pharmacological activities and potential therapeutic value in cardiovascular diseases. In this study we examined the protective effects of matrine against diabetic cardiomyopathy (DCM) in rats. Male SD rats were injected with streptozotocin (STZ) to induce DCM. One group of DCM rats was pretreated with matrine (200 mg·kg(-1)·d(-1), po) for 10 consecutive days before STZ injection. Left ventricular function was evaluated using invasive hemodynamic examination, and myocardiac apoptosis was assessed. Primary rat myocytes were used for in vitro experiments. Intracellular ROS generation, MDA content and GPx activity were determined. Real-time PCR and Western blotting were performed to detect the expression of relevant mRNAs and proteins. DCM rats exhibited abnormally elevated non-fasting blood glucose levels at 4 weeks after STZ injection, and LV function impairment at 16 weeks. The cardiac tissues of DCM rats showed markedly increased apoptosis, excessive ROS production, and activation of TLR-4/MyD-88/caspase-8/caspase-3 signaling. Pretreatment with matrine significantly decreased non-fasting blood glucose levels and improved LV function in DCM rats, which were associated with reducing apoptosis and ROS production, and suppressing TLR-4/MyD-88/caspase-8/caspase-3 signaling in cardiac tissues. Incubation in a high-glucose medium induced oxidative stress and activation of TLR-4/MyD-88 signaling in cultured myocytes in vitro, which were significantly attenuated by pretreatment with N-acetylcysteine. Excessive ROS production in DCM activates the TLR-4/MyD-88 signaling, resulting in cardiomyocyte apoptosis, whereas pretreatment with matrine improves cardiac function via suppressing ROS/TLR-4 signaling pathway.

  14. Hepatitis C virus E2 protein promotes human hepatoma cell proliferation through the MAPK/ERK signaling pathway via cellular receptors

    International Nuclear Information System (INIS)

    Zhao Lanjuan; Wang Lu; Ren Hao; Cao Jie; Li Li; Ke Jinshan; Qi Zhongtian

    2005-01-01

    Dysregulation of mitogen-activated protein kinase (MAPK) signaling pathways by various viruses has been shown to be responsible for viral pathogenicity. The molecular mechanism by which hepatitis C virus (HCV) infection caused human liver diseases has been investigated on the basis of abnormal intracellular signal events. Current data are very limited involved in transmembrane signal transduction triggered by HCV E2 protein. Here we explored regulation of the MAPK/extracellular signal-regulated kinase (MAPK/ERK) signaling pathway by E2 expressed in Chinese hamster oval cells. In human hepatoma Huh-7 cells, E2 specifically activated the MAPK/ERK pathway including downstream transcription factor ATF-2 and greatly promoted cell proliferation. CD81 and low density lipoprotein receptor (LDLR) on the cell surface mediated binding of E2 to Huh-7 cells. The MAPK/ERK activation and cell proliferation driven by E2 were suppressed by blockage of CD81 as well as LDLR. Furthermore, pretreatment with an upstream kinase MEK1/2 inhibitor U0126 also impaired the MAPK/ERK activation and cell proliferation induced by E2. Our results suggest that the MAPK/ERK signaling pathway triggered by HCV E2 via its receptors maintains survival and growth of target cells

  15. Exosomes Derived from Human Bone Marrow Mesenchymal Stem Cells Promote Tumor Growth Through Hedgehog Signaling Pathway

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    Jin Qi

    2017-08-01

    Full Text Available Background/Aims: Mesenchymal stem/stromal cells (MSCs are known to home to sites of tumor microenvironments where they participate in the formation of the tumor microenvironment and to interplay with tumor cells. However, the potential functional effects of MSCs on tumor cell growth are controversial. Here, we, from the view of bone marrow MSC-derived exosomes, study the molecular mechanism of MSCs on the growth of human osteosarcoma and human gastric cancer cells. Methods: MSCs derived from human bone marrow (hBMSCs were isolated and cultured in complete DMEM/F12 supplemented with 10% exosome-depleted fetal bovine serum and 1% penicillin-streptomycin, cell culture supernatants containing exosomes were harvested and exosome purification was performed by ultracentrifugation. Osteosarcoma (MG63 and gastric cancer (SGC7901 cells, respectively, were treated with hBMSC-derived exosomes in the presence or absence of a small molecule inhibitor of Hedgehog pathway. Cell viability was measured by transwell invasion assay, scratch migration assay and CCK-8 test. The expression of the signaling molecules Smoothened, Patched-1, Gli1 and the ligand Shh were tested by western blot and RT-PCR. Results: In this study, we found that hBMSC-derived exosomes promoted MG63 and SGC7901 cell growth through the activation of Hedgehog signaling pathway. Inhibition of Hedgehog signaling pathway significantly suppressed the process of hBMSC-derived exosomes on tumor growth. Conclusion: Our findings demonstrated the new roles of hedgehog signaling pathway in the hBMSCs-derived exosomes induced tumor progression.

  16. Cardioprotection against Heart Failure by Shenfu Injection via TGF-β/Smads Signaling Pathway

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    Jingyu Ni

    2017-01-01

    Full Text Available Objective. To explore the potential cardioprotective mechanism of Shenfu injection (SFI against heart failure (HF by attenuating myocardial fibrosis and cardiac remodeling. Methods and Results. Four weeks after myocardial infarction (MI, adult male Sprague Dawley rats were randomized for 4-week treatment with Valsartan, SFI, or vehicle. Echocardiography and hemodynamics were applied to evaluate cardiac functions. Myocardia of coronary artery ligated (CAD rats were observed to investigate changes in cardiac structure and function. Our findings suggest that treatment with SFI could inhibit progression of myocardial fibrosis and attenuate cardiac remodeling. In addition, SFI decreased expression of Smad2 and Smad3, while increasing the expression of Smad7 through regulation of TGF-β/Smads signaling pathway. Conclusion. Treatment with SFI in Sprague Dawley rats improves ventricular structure and function and reduces cardiac fibrosis by ameliorating TGF-β/Smads signaling pathway after ventricular remodeling.

  17. Modeling the Intra- and Extracellular Cytokine Signaling Pathway under Heat Stroke in the Liver

    Science.gov (United States)

    2013-09-05

    to be construed as official or as reflecting the views of the Army or the Department of Defense. Citations of commercial organizations and trade names...commercial organizations and trade names in this report do not constitute an official Department of the Army endorsement or approval of the products or...pathway. Nature Medicine 6: 422–428. 93. Murray PJ (2007) The jak-stat signaling pathway: Input and output intergration . Journal of Immunology 178

  18. A SNP uncoupling Mina expression from the TGFβ signaling pathway.

    Science.gov (United States)

    Lian, Shang L; Mihi, Belgacem; Koyanagi, Madoka; Nakayama, Toshinori; Bix, Mark

    2018-03-01

    Mina is a JmjC family 2-oxoglutarate oxygenase with pleiotropic roles in cell proliferation, cancer, T cell differentiation, pulmonary inflammation, and intestinal parasite expulsion. Although Mina expression varies according to cell-type, developmental stage and activation state, its transcriptional regulation is poorly understood. Across inbred mouse strains, Mina protein level exhibits a bimodal distribution, correlating with inheritance of a biallelic haplotype block comprising 21 promoter/intron 1-region SNPs. We previously showed that heritable differences in Mina protein level are transcriptionally regulated. Accordingly, we decided to test the hypothesis that at least one of the promoter/intron 1-region SNPs perturbs a Mina cis-regulatory element (CRE). Here, we have comprehensively scanned for CREs across a Mina locus-spanning 26-kilobase genomic interval. We discovered 8 potential CREs and functionally validated 4 of these, the strongest of which (E2), residing in intron 1, contained a SNP whose BALB/c-but not C57Bl/6 allele-abolished both Smad3 binding and transforming growth factor beta (TGFβ) responsiveness. Our results demonstrate the TGFβ signaling pathway plays a critical role in regulating Mina expression and SNP rs4191790 controls heritable variation in Mina expression level, raising important questions regarding the evolution of an allele that uncouples Mina expression from the TGFβ signaling pathway. © 2017 The Authors. Immunity, Inflammation and Disease Published by John Wiley & Sons Ltd.

  19. Association between PI3K/Akt/mTOR/p70S6K signaling pathway and hepatic fibrosis

    Directory of Open Access Journals (Sweden)

    WU Changhui

    2015-11-01

    Full Text Available Phosphoinositide 3-kinase (PI3K/protein kinase-B (AkT/mammalian target of rapamycin (mTOR/70-kDa ribosomal protein S6 kinase (p70S6K, PI3K/Akt/mTOR/p70S6K, is an important signaling pathway in the life activities of cells, and it plays an important role in promoting the growth, proliferation, invasion, and anti-apoptosis of cells and promoting angiogenesis. It was clarified that the PI3K/Akt/mTOR/p70S6K signaling pathway is involved in regulating the activities of hepatic stellate cell(HSC, thus influencing the development and progression of hepatic fibrosis. Analysis demonstrated that blocking any target of the PI3K/Akt/mTOR/p70S6K signaling pathway can inhibit the activation and proliferation of HSC, promote the apoptosis of HSC, inhibit the extracellular matrix secretion from HSC, and delay the progression of hepatic fibrosis. Blocking the pathway is expected to be a treatment strategy for hepatic fibrosis.

  20. Atypical Diabetic Foot Ulcer Keratinocyte Protein Signaling Correlates with Impaired Wound Healing

    Science.gov (United States)

    Hoke, Glenn D.; Ramos, Corrine; Hoke, Nicholas N.; Crossland, Mary C.; Shawler, Lisa G.

    2016-01-01

    Diabetes mellitus is associated with chronic diabetic foot ulcers (DFUs) and wound infections often resulting in lower extremity amputations. The protein signaling architecture of the mechanisms responsible for impaired DFU healing has not been characterized. In this preliminary clinical study, the intracellular levels of proteins involved in signal transduction networks relevant to wound healing were non-biasedly measured using reverse-phase protein arrays (RPPA) in keratinocytes isolated from DFU wound biopsies. RPPA allows for the simultaneous documentation and assessment of the signaling pathways active in each DFU. Thus, RPPA provides for the accurate mapping of wound healing pathways associated with apoptosis, proliferation, senescence, survival, and angiogenesis. From the study data, we have identified potential diagnostic, or predictive, biomarkers for DFU wound healing derived from the ratios of quantified signaling protein expressions within interconnected pathways. These biomarkers may allow physicians to personalize therapeutic strategies for DFU management on an individual basis based upon the signaling architecture present in each wound. Additionally, we have identified altered, interconnected signaling pathways within DFU keratinocytes that may help guide the development of therapeutics to modulate these dysregulated pathways, many of which parallel the therapeutic targets which are the hallmarks of molecular therapies for treating cancer. PMID:27840833

  1. Atypical Diabetic Foot Ulcer Keratinocyte Protein Signaling Correlates with Impaired Wound Healing.

    Science.gov (United States)

    Hoke, Glenn D; Ramos, Corrine; Hoke, Nicholas N; Crossland, Mary C; Shawler, Lisa G; Boykin, Joseph V

    2016-01-01

    Diabetes mellitus is associated with chronic diabetic foot ulcers (DFUs) and wound infections often resulting in lower extremity amputations. The protein signaling architecture of the mechanisms responsible for impaired DFU healing has not been characterized. In this preliminary clinical study, the intracellular levels of proteins involved in signal transduction networks relevant to wound healing were non-biasedly measured using reverse-phase protein arrays (RPPA) in keratinocytes isolated from DFU wound biopsies. RPPA allows for the simultaneous documentation and assessment of the signaling pathways active in each DFU. Thus, RPPA provides for the accurate mapping of wound healing pathways associated with apoptosis, proliferation, senescence, survival, and angiogenesis. From the study data, we have identified potential diagnostic, or predictive, biomarkers for DFU wound healing derived from the ratios of quantified signaling protein expressions within interconnected pathways. These biomarkers may allow physicians to personalize therapeutic strategies for DFU management on an individual basis based upon the signaling architecture present in each wound. Additionally, we have identified altered, interconnected signaling pathways within DFU keratinocytes that may help guide the development of therapeutics to modulate these dysregulated pathways, many of which parallel the therapeutic targets which are the hallmarks of molecular therapies for treating cancer.

  2. Blocking Ihh signaling pathway inhibits the proliferation and promotes the apoptosis of PSCs.

    Science.gov (United States)

    Xu, Kai; Guo, Fengjing; Zhang, Shuwei; Liu, Cheng; Wang, Feixiong; Zhou, Zhiguo; Chen, Anmin

    2009-02-01

    The roles of Indian hedgehog (Ihh) signaling pathway in the proliferation and apoptosis of precartilaginous stem cells (PSCs) were investigated. PSCs, labeled with fibroblast growth factor receptor 3 (FGFR-3), were isolated from neonatal rats by immunomagnetic separation. After identification with FGFR-3 and Col II, the cells were incubated with different concentrations of cyclopamine (cyclo), the specific inhibitor of Ihh signaling pathway. The morphologic changes of the cells were observed under the inverted phase contrast microscope. The mRNA expression levels of Ihh, parathyroid hormonerelated peptide (PTHrP), protein Patched (Ptch), Bcl-2 and p21 were detected by RT-PCR. The protein expression levels of Ihh and Ptch were measured by Western blot. MTT assay was used to examine the effects of cyclo on proliferation of PSCs. Apoptosis rate of PSCs was examined by Annexin V/PI assay of flow cytometric analyses. After PSCs were incubated with cyclo, obvious morphologic changes were observed as compared with the control group. The mRNA expression levels of PTHrP, Ptch and Bcl-2 were decreased to varying degrees in a cyclo dose-dependent manner. However, the expression levels of Ihh and p21 mRNA were increased. The protein expression of Ptch and Ihh had the same change as the mRNA expression. Meanwhile, cyclo could obviously inhibit the proliferation and promote the apoptosis of PSCs. The results indicated that Ihh signaling pathway plays an important role in regulating the proliferation and apoptosis of PSCs, which is probably mediated by Bcl-2 and p21.

  3. The crosstalk between α-irradiated Beas-2B cells and its bystander U937 cells through MAPK and NF-κB signaling pathways.

    Science.gov (United States)

    Fu, Jiamei; Yuan, Dexiao; Xiao, Linlin; Tu, Wenzhi; Dong, Chen; Liu, Weili; Shao, Chunlin

    2016-01-01

    Although accumulated evidence suggests that α-particle irradiation induced bystander effect may relevant to lung injury and cancer risk assessment, the exact mechanisms are not yet elucidated. In the present study, a cell co-culture system was used to investigate the interaction between α-particle irradiated human bronchial epithelial cells (Beas-2B) and its bystander macrophage U937 cells. It was found that the cell co-culture amplified the detrimental effects of α-irradiation including cell viability decrease and apoptosis promotion on both irradiated cells and bystander cells in a feedback loop which was closely relevant to the activation of MAPK and NF-κB pathways in the bystander U937 cells. When these two pathways in U937 cells were disturbed by special pharmacological inhibitors before cell co-culture, it was found that a NF-κB inhibitor of BAY 11-7082 further enhanced the proliferation inhibition and apoptosis induction in bystander U937 cells, but MAPK inhibitors of SP600125 and SB203580 protected cells from viability loss and apoptosis and U0126 presented more beneficial effect on cell protection. For α-irradiated epithelial cells, the activation of NF-κB and MAPK pathways in U937 cells participated in detrimental cellular responses since the above inhibitors could largely attenuate cell viability loss and apoptosis of irradiated cells. Our results demonstrated that there are bilateral bystander responses between irradiated lung epithelial cells and macrophages through MAPK and NF-κB signaling pathways, which accounts for the enhancement of α-irradiation induced damage. Copyright © 2015 Elsevier B.V. All rights reserved.

  4. Targeting Signaling Pathways in Epithelial Ovarian Cancer

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    Johannes Haybaeck

    2013-05-01

    Full Text Available Ovarian carcinoma (OC is the most lethal gynecological malignancy. Response to platinum-based chemotherapy is poor in some patients and, thus, current research is focusing on new therapy options. The various histological types of OC are characterized by distinctive molecular genetic alterations that are relevant for ovarian tumorigenesis. The understanding of these molecular pathways is essential for the development of novel therapeutic strategies. Purpose: We want to give an overview on the molecular genetic changes of the histopathological types of OC and their role as putative therapeutic targets. In Depth Review of Existing Data: In 2012, the vascular endothelial growth factor (VEGF inhibitor, bevacizumab, was approved for OC treatment. Bevacizumab has shown promising results as single agent and in combination with conventional chemotherapy, but its target is not distinctive when analyzed before treatment. At present, mammalian target of rapamycin (mTOR inhibitors, poly-ADP-ribose polymerase (PARP inhibitors and components of the EGFR pathway are in the focus of clinical research. Interestingly, some phytochemical substances show good synergistic effects when used in combination with chemotherapy. Conclusion: Ongoing studies of targeted agents in conjunction with chemotherapy will show whether there are alternative options to bevacizumab available for OC patients. Novel targets which can be assessed before therapy to predict efficacy are needed. The assessment of therapeutic targets is continuously improved by molecular pathological analyses on tumor tissue. A careful selection of patients for personalized treatment will help to reduce putative side effects and toxicity.

  5. A proteomic analysis of LRRK2 binding partners reveals interactions with multiple signaling components of the WNT/PCP pathway.

    Science.gov (United States)

    Salašová, Alena; Yokota, Chika; Potěšil, David; Zdráhal, Zbyněk; Bryja, Vítězslav; Arenas, Ernest

    2017-07-11

    Autosomal-dominant mutations in the Park8 gene encoding Leucine-rich repeat kinase 2 (LRRK2) have been identified to cause up to 40% of the genetic forms of Parkinson's disease. However, the function and molecular pathways regulated by LRRK2 are largely unknown. It has been shown that LRRK2 serves as a scaffold during activation of WNT/β-catenin signaling via its interaction with the β-catenin destruction complex, DVL1-3 and LRP6. In this study, we examine whether LRRK2 also interacts with signaling components of the WNT/Planar Cell Polarity (WNT/PCP) pathway, which controls the maturation of substantia nigra dopaminergic neurons, the main cell type lost in Parkinson's disease patients. Co-immunoprecipitation and tandem mass spectrometry was performed in a mouse substantia nigra cell line (SN4741) and human HEK293T cell line in order to identify novel LRRK2 binding partners. Inhibition of the WNT/β-catenin reporter, TOPFlash, was used as a read-out of WNT/PCP pathway activation. The capacity of LRRK2 to regulate WNT/PCP signaling in vivo was tested in Xenopus laevis' early development. Our proteomic analysis identified that LRRK2 interacts with proteins involved in WNT/PCP signaling such as the PDZ domain-containing protein GIPC1 and Integrin-linked kinase (ILK) in dopaminergic cells in vitro and in the mouse ventral midbrain in vivo. Moreover, co-immunoprecipitation analysis revealed that LRRK2 binds to two core components of the WNT/PCP signaling pathway, PRICKLE1 and CELSR1, as well as to FLOTILLIN-2 and CULLIN-3, which regulate WNT secretion and inhibit WNT/β-catenin signaling, respectively. We also found that PRICKLE1 and LRRK2 localize in signalosomes and act as dual regulators of WNT/PCP and β-catenin signaling. Accordingly, analysis of the function of LRRK2 in vivo, in X. laevis revelaed that LRKK2 not only inhibits WNT/β-catenin pathway, but induces a classical WNT/PCP phenotype in vivo. Our study shows for the first time that LRRK2 activates the WNT

  6. Wnt Signaling Translocates Lys48-Linked Polyubiquitinated Proteins to the Lysosomal Pathway

    Directory of Open Access Journals (Sweden)

    Hyunjoon Kim

    2015-05-01

    Full Text Available Cellular proteins are degraded in either proteasomes or lysosomes depending on the types of ubiquitin chains that covalently modify them. It is not known whether the choice between these two pathways is physiologically regulated. The Lys48-polyubiquitin chain is the major signal directing proteins for degradation in proteasomes. Here, we report the unexpected finding that canonical Wnt signaling translocates some K48-linked polyubiquitinated proteins to the endolysosomal pathway. Proteasomal target proteins, such as β-catenin, Smad1, and Smad4, were targeted into endolysosomes in a process dependent on GSK3 activity. Relocalization was also dependent on Axin1 and the multivesicular body (MVB proteins HRS/Vps27 and Vps4. The Wnt-induced accumulation of K48-linked polyubiquitinated proteins in endolysosomal organelles was accompanied by a transient decrease in cellular levels of free mono-ubiquitin, which may contribute to Wnt-regulated stabilization of proteins (Wnt/STOP. We conclude that Wnt redirects Lys48-polyubiquitinated proteins that are normally degraded in proteasomes to endolysosomes.

  7. Chapter 10 the primary cilium coordinates signaling pathways in cell cycle control and migration during development and tissue repair

    DEFF Research Database (Denmark)

    Christensen, Søren T; Pedersen, Stine F; Satir, Peter

    2008-01-01

    Cell cycle control and migration are critical processes during development and maintenance of tissue functions. Recently, primary cilia were shown to take part in coordination of the signaling pathways that control these cellular processes in human health and disease. In this review, we present...... an overview of the function of primary cilia and the centrosome in the signaling pathways that regulate cell cycle control and migration with focus on ciliary signaling via platelet-derived growth factor receptor alpha (PDGFRalpha). We also consider how the primary cilium and the centrosome interact...... with the extracellular matrix, coordinate Wnt signaling, and modulate cytoskeletal changes that impinge on both cell cycle control and cell migration....

  8. Targetome Analysis Revealed Involvement of MiR-126 in Neurotrophin Signaling Pathway: A Possible Role in Prevention of Glioma Development.

    Science.gov (United States)

    Rouigari, Maedeh; Dehbashi, Moein; Ghaedi, Kamran; Pourhossein, Meraj

    2018-07-01

    For the first time, we used molecular signaling pathway enrichment analysis to determine possible involvement of miR-126 and IRS-1 in neurotrophin pathway. In this prospective study, Validated and predicted targets (targetome) of miR-126 were collected following searching miRtarbase (http://mirtarbase.mbc.nctu.edu.tw/) and miRWalk 2.0 databases, respectively. Then, approximate expression of miR-126 targeting in Glioma tissue was examined using UniGene database (http://www.ncbi. nlm.nih.gov/unigene). In silico molecular pathway enrichment analysis was carried out by DAVID 6.7 database (http://david. abcc.ncifcrf.gov/) to explore which signaling pathway is related to miR-126 targeting and how miR-126 attributes to glioma development. MiR-126 exerts a variety of functions in cancer pathogenesis via suppression of expression of target gene including PI3K, KRAS, EGFL7, IRS-1 and VEGF. Our bioinformatic studies implementing DAVID database, showed the involvement of miR-126 target genes in several signaling pathways including cancer pathogenesis, neurotrophin functions, Glioma formation, insulin function, focal adhesion production, chemokine synthesis and secretion and regulation of the actin cytoskeleton. Taken together, we concluded that miR-126 enhances the formation of glioma cancer stem cell probably via down regulation of IRS-1 in neurotrophin signaling pathway. Copyright© by Royan Institute. All rights reserved.

  9. microRNA-based identification of pulmonary signaling pathways in experimental asthma

    OpenAIRE

    Bartel, Sabine

    2015-01-01

    Asthma is characterized by chronic airway inflammation; mucus hypersecretion and episodes of airway obstruction. It is the most common chronic disease in children and its incidence and prevalence have been markedly increasing over the last few decades. While the pathophysiology has been intensively studied, the underlying causes for asthma development remain largely unknown. Hence there is an unmet, clinical need to identify novel, so far non-characterized pathways, relevant for this disease,...

  10. Secreted phospholipase A2 of Clonorchis sinensis activates hepatic stellate cells through a pathway involving JNK signalling.

    Science.gov (United States)

    Wu, Yinjuan; Li, Ye; Shang, Mei; Jian, Yu; Wang, Caiqin; Bardeesi, Adham Sameer A; Li, Zhaolei; Chen, Tingjin; Zhao, Lu; Zhou, Lina; He, Ai; Huang, Yan; Lv, Zhiyue; Yu, Xinbing; Li, Xuerong

    2017-03-16

    Secreted phospholipase A2 (sPLA2) is a protein secreted by Clonorchis sinensis and is a component of excretory and secretory products (CsESPs). Phospholipase A2 is well known for its role in liver fibrosis and inhibition of tumour cells. The JNK signalling pathway is involved in hepatic stellate cells (HSCs) activation. Blocking JNK activity with SP600125 inhibits HSCs activation. In a previous study, the protein CssPLA2 was expressed in insoluble inclusion bodies. Therefore, it's necessary to express CssPLA2 in water-soluble form and determine whether the enzymatic activity of CssPLA2 or cell signalling pathways is involved in liver fibrosis caused by clonorchiasis. Balb/C mice were given an abdominal injection of MBP-CssPLA2. Liver sections with HE and Masson staining were observed to detect accumulation of collagen. Western blot of mouse liver was done to detect the activation of JNK signalling pathway. In vitro, HSCs were incubated with MBP-CssPLA2 to detect the activation of HSCs as well as the activation of JNK signalling pathway. The mutant of MBP-CssPLA2 without enzymatic activity was constructed and was also incubated with HSCs to check whether activation of the HSCs was related to the enzymatic activity of MBP-CssPLA2. The recombinant protein MBP-CssPLA2 was expressed soluble and of good enzymatic activity. A mutant of CssPLA2, without enzymatic activity, was also constructed. In vivo liver sections of Balb/C mice that were given an abdominal injection of 50 μg/ml MBP-CssPLA2 showed an obvious accumulation of collagen and a clear band of P-JNK1 could be seen by western blot of the liver tissue. In vitro, MBP-CssPLA2, as well as the mutant, was incubated with HSCs and it was proved that activation of HSCs was related to activation of the JNK signalling pathway instead of the enzymatic activity of MBP-CssPLA2. Activation of HSCs by CssPLA2 is related to the activation of the JNK signalling pathway instead of the enzymatic activity of CssPLA2. This finding

  11. Emodin suppresses TGF-β1-induced epithelial-mesenchymal transition in alveolar epithelial cells through Notch signaling pathway

    International Nuclear Information System (INIS)

    Gao, Rundi; Chen, Ruilin; Cao, Yu; Wang, Yuan; Song, Kang; Zhang, Ya; Yang, Junchao

    2017-01-01

    Pulmonary fibrosis is characterized by the destruction of lung tissue architecture and the formation of fibrous foci, currently has no satisfactory treatment. Emodin is a component of Chinese herb that has been reported to be medicament on pancreatic fibrosis and liver fibrosis. However, its role in pulmonary fibrosis has not been established yet. In the present study, we investigated the hypothesis that Emodin plays an inhibitory role in TGF-β1 induced epithelial-mesenchymal transition (EMT) of alveolar epithelial cell, and Emodin exerts its effect through the Notch signaling pathway. Emodin inhibits the proliferation of Rat alveolar type II epithelial cells RLE-6TN in a concentration-dependent manner; reduces the expression of Collagen I, α-SMA and Vimentin, promotes the expression of E-cadherin. Moreover, Emodin could regulate the expression patterns of the Notch signaling pathway-related factors and reduce the Notch-1 nucleus translocation. Knockdown of Notch-1 enhances the inhibitory effect of Emodin on TGF-β1-induced EMT in RLE-6TN cells. In conclusion, the data of the present study suggests that Emodin suppresses TGF-β1-induced EMT in alveolar epithelial cells through Notch signaling pathway and shows the potential to be effective in the treatment of pulmonary fibrosis. - Highlights: • Emodin inhibits TGF-β1-induced EMT in alveolar epithelial cells. • Emodin regulates the expression patterns of the Notch signaling pathway-related factors. • Emodin inhibits TGF-β1-induced Notch-1 nucleus translocation and activation.

  12. Emodin suppresses TGF-β1-induced epithelial-mesenchymal transition in alveolar epithelial cells through Notch signaling pathway

    Energy Technology Data Exchange (ETDEWEB)

    Gao, Rundi; Chen, Ruilin; Cao, Yu [Department of Respiration, The First Affiliated Hospital of Zhejiang Chinese Medicine University, NO. 56, Youdian Road, Shangcheng District, Hangzhou, Zhejiang Province 310006 (China); Wang, Yuan [Department of Pulmonary Function, The First Affiliated Hospital of Zhejiang Chinese Medicine University, NO. 56, Youdian Road, Shangcheng District, Hangzhou, Zhejiang Province 310006 (China); Song, Kang [Department of Respiration, The First Affiliated Hospital of Zhejiang Chinese Medicine University, NO. 56, Youdian Road, Shangcheng District, Hangzhou, Zhejiang Province 310006 (China); Zhang, Ya [Zhejiang Chinese Medicine University, No. 548, Binwen Road, Binjiang District, Hangzhou, Zhejiang Province 310006 (China); Yang, Junchao, E-mail: yangjunchaozj@zcmu.edu.cn [Department of Respiration, The First Affiliated Hospital of Zhejiang Chinese Medicine University, NO. 56, Youdian Road, Shangcheng District, Hangzhou, Zhejiang Province 310006 (China)

    2017-03-01

    Pulmonary fibrosis is characterized by the destruction of lung tissue architecture and the formation of fibrous foci, currently has no satisfactory treatment. Emodin is a component of Chinese herb that has been reported to be medicament on pancreatic fibrosis and liver fibrosis. However, its role in pulmonary fibrosis has not been established yet. In the present study, we investigated the hypothesis that Emodin plays an inhibitory role in TGF-β1 induced epithelial-mesenchymal transition (EMT) of alveolar epithelial cell, and Emodin exerts its effect through the Notch signaling pathway. Emodin inhibits the proliferation of Rat alveolar type II epithelial cells RLE-6TN in a concentration-dependent manner; reduces the expression of Collagen I, α-SMA and Vimentin, promotes the expression of E-cadherin. Moreover, Emodin could regulate the expression patterns of the Notch signaling pathway-related factors and reduce the Notch-1 nucleus translocation. Knockdown of Notch-1 enhances the inhibitory effect of Emodin on TGF-β1-induced EMT in RLE-6TN cells. In conclusion, the data of the present study suggests that Emodin suppresses TGF-β1-induced EMT in alveolar epithelial cells through Notch signaling pathway and shows the potential to be effective in the treatment of pulmonary fibrosis. - Highlights: • Emodin inhibits TGF-β1-induced EMT in alveolar epithelial cells. • Emodin regulates the expression patterns of the Notch signaling pathway-related factors. • Emodin inhibits TGF-β1-induced Notch-1 nucleus translocation and activation.

  13. Kirenol inhibits adipogenesis through activation of the Wnt/β-catenin signaling pathway in 3T3-L1 adipocytes

    Energy Technology Data Exchange (ETDEWEB)

    Kim, Mi-Bo [Department of Biomaterials Science and Engineering, Yonsei University, Seoul 120-749 (Korea, Republic of); Song, Youngwoo; Kim, Changhee [Department of Biotechnology, College of Life Science and Biotechnology, Yonsei University, Seoul 120-749 (Korea, Republic of); Hwang, Jae-Kwan, E-mail: jkhwang@yonsei.ac.kr [Department of Biomaterials Science and Engineering, Yonsei University, Seoul 120-749 (Korea, Republic of); Department of Biotechnology, College of Life Science and Biotechnology, Yonsei University, Seoul 120-749 (Korea, Republic of)

    2014-03-07

    Highlights: • Kirenol inhibits the adipogenic transcription factors and lipogenic enzymes. • Kirenol stimulates the Wnt/β-catenin signaling pathway components. • Kirenol inhibits adipogenesis through activation of the Wnt/β-catenin signaling pathway. - Abstract: Kirenol, a natural diterpenoid compound, has been reported to possess anti-oxidant, anti-inflammatory, anti-allergic, and anti-arthritic activities; however, its anti-adipogenic effect remains to be studied. The present study evaluated the effect of kirenol on anti-adipogenesis through the activation of the Wnt/β-catenin signaling pathway. Kirenol prevented intracellular lipid accumulation by down-regulating key adipogenesis transcription factors [peroxisome proliferator-activated receptor γ (PPARγ), CCAAT/enhancer binding proteins α (C/EBPα), and sterol regulatory element binding protein-1c (SREBP-1c)] and lipid biosynthesis-related enzymes [fatty acid synthase (FAS) and acetyl-CoA carboxylase (ACC)], as well as adipocytokines (adiponectin and leptin). Kirenol effectively activated the Wnt/β-catenin signaling pathway, in which kirenol up-regulated the expression of low density lipoprotein receptor related protein 6 (LRP6), disheveled 2 (DVL2), β-catenin, and cyclin D1 (CCND1), while it inactivated glycogen synthase kinase 3β (GSK3β) by increasing its phosphorylation. Kirenol down-regulated the expression levels of PPARγ and C/EBPα, which were up-regulated by siRNA knockdown of β-catenin. Overall, kirenol is capable of inhibiting the differentiation and lipogenesis of 3T3-L1 adipocytes through the activation of the Wnt/β-catenin signaling pathway, suggesting its potential as natural anti-obesity agent.

  14. The crosstalk between α-irradiated Beas-2B cells and its bystander U937 cells through MAPK and NF-κB signaling pathways

    Energy Technology Data Exchange (ETDEWEB)

    Fu, Jiamei; Yuan, Dexiao; Xiao, Linlin; Tu, Wenzhi; Dong, Chen; Liu, Weili; Shao, Chunlin, E-mail: clshao@shmu.edu.cn

    2016-01-15

    Highlights: • α-irradiated Beas-2B cells induced bystander effects in macrophage U937 cells. • The neighboring macrophages enhanced the damage of α-irradiated Beas-2B cells. • MAPK and NF-κB pathways were activated in U937 cells after cell co-culture. • NF-κB and MAPK pathways participated in the bilateral bystander responses. - Abstract: Although accumulated evidence suggests that α-particle irradiation induced bystander effect may relevant to lung injury and cancer risk assessment, the exact mechanisms are not yet elucidated. In the present study, a cell co-culture system was used to investigate the interaction between α-particle irradiated human bronchial epithelial cells (Beas-2B) and its bystander macrophage U937 cells. It was found that the cell co-culture amplified the detrimental effects of α-irradiation including cell viability decrease and apoptosis promotion on both irradiated cells and bystander cells in a feedback loop which was closely relevant to the activation of MAPK and NF-κB pathways in the bystander U937 cells. When these two pathways in U937 cells were disturbed by special pharmacological inhibitors before cell co-culture, it was found that a NF-κB inhibitor of BAY 11-7082 further enhanced the proliferation inhibition and apoptosis induction in bystander U937 cells, but MAPK inhibitors of SP600125 and SB203580 protected cells from viability loss and apoptosis and U0126 presented more beneficial effect on cell protection. For α-irradiated epithelial cells, the activation of NF-κB and MAPK pathways in U937 cells participated in detrimental cellular responses since the above inhibitors could largely attenuate cell viability loss and apoptosis of irradiated cells. Our results demonstrated that there are bilateral bystander responses between irradiated lung epithelial cells and macrophages through MAPK and NF-κB signaling pathways, which accounts for the enhancement of α-irradiation induced damage.

  15. The crosstalk between α-irradiated Beas-2B cells and its bystander U937 cells through MAPK and NF-κB signaling pathways

    International Nuclear Information System (INIS)

    Fu, Jiamei; Yuan, Dexiao; Xiao, Linlin; Tu, Wenzhi; Dong, Chen; Liu, Weili; Shao, Chunlin

    2016-01-01

    Highlights: • α-irradiated Beas-2B cells induced bystander effects in macrophage U937 cells. • The neighboring macrophages enhanced the damage of α-irradiated Beas-2B cells. • MAPK and NF-κB pathways were activated in U937 cells after cell co-culture. • NF-κB and MAPK pathways participated in the bilateral bystander responses. - Abstract: Although accumulated evidence suggests that α-particle irradiation induced bystander effect may relevant to lung injury and cancer risk assessment, the exact mechanisms are not yet elucidated. In the present study, a cell co-culture system was used to investigate the interaction between α-particle irradiated human bronchial epithelial cells (Beas-2B) and its bystander macrophage U937 cells. It was found that the cell co-culture amplified the detrimental effects of α-irradiation including cell viability decrease and apoptosis promotion on both irradiated cells and bystander cells in a feedback loop which was closely relevant to the activation of MAPK and NF-κB pathways in the bystander U937 cells. When these two pathways in U937 cells were disturbed by special pharmacological inhibitors before cell co-culture, it was found that a NF-κB inhibitor of BAY 11-7082 further enhanced the proliferation inhibition and apoptosis induction in bystander U937 cells, but MAPK inhibitors of SP600125 and SB203580 protected cells from viability loss and apoptosis and U0126 presented more beneficial effect on cell protection. For α-irradiated epithelial cells, the activation of NF-κB and MAPK pathways in U937 cells participated in detrimental cellular responses since the above inhibitors could largely attenuate cell viability loss and apoptosis of irradiated cells. Our results demonstrated that there are bilateral bystander responses between irradiated lung epithelial cells and macrophages through MAPK and NF-κB signaling pathways, which accounts for the enhancement of α-irradiation induced damage.

  16. The TGF-β/Smad4 Signaling Pathway in Pancreatic Carcinogenesis and Its Clinical Significance

    Directory of Open Access Journals (Sweden)

    Sunjida Ahmed

    2017-01-01

    Full Text Available Pancreatic ductal adenocarcinoma (PDAC is one of the most fatal human cancers due to its complicated genomic instability. PDAC frequently presents at an advanced stage with extensive metastasis, which portends a poor prognosis. The known risk factors associated with PDAC include advanced age, smoking, long-standing chronic pancreatitis, obesity, and diabetes. Its association with genomic and somatic mutations is the most important factor for its aggressiveness. The most common gene mutations associated with PDAC include KRas2, p16, TP53, and Smad4. Among these, Smad4 mutation is relatively specific and its inactivation is found in more than 50% of invasive pancreatic adenocarcinomas. Smad4 is a member of the Smad family of signal transducers and acts as a central mediator of transforming growth factor beta (TGF-β signaling pathways. The TGF-β signaling pathway promotes many physiological processes, including cell growth, differentiation, proliferation, fibrosis, and scar formation. It also plays a major role in the development of tumors through induction of angiogenesis and immune suppression. In this review, we will discuss the molecular mechanism of TGF-β/Smad4 signaling in the pathogenesis of pancreatic adenocarcinoma and its clinical implication, particularly potential as a prognostic factor and a therapeutic target.

  17. [Effects of electromagnetic radiation on RAF/MEK/ERK signaling pathway in rats hippocampus].

    Science.gov (United States)

    Zuo, Hong-yan; Wang, De-wen; Peng, Rui-yun; Wang, Shui-ming; Gao, Ya-bing; Xu, Xin-ping; Ma, Jun-Jie

    2009-05-01

    To study the development of changes for signaling molecules related to Raf/MEK/ERK pathway in hippocampus of rats after electromagnetic radiation, and investigate the mechanisms of radiation injury. Rats were exposed to X-HPM, S-HPM and EMP radiation source respectively, and animal model of electromagnetic radiation was established. Western blot was used to detect the expression of Raf-1, phosphorylated Raf-1 and phospholylated ERK. The expression of Raf-1 down-regulated during 6 h-14 d after radiation, most significantly at 7 d, and recovered at 28 d. There was no significant difference between the radiation groups. The expression of phosphorylated Raf-1 and phosphorylated ERK both up-regulated at 6 h and 7 d after radiation, more significantly at 6 h, and the two microwave groups were more serious for phosphorylated ERK. During 6 h-14 d after S-HPM radiation, the expression of phosphorylated Raf-1 increased continuously, but phosphorylated ERK changed wavily, 6 h and 7 d were expression peak. Raf/MEK/ERK signaling pathway participates in the hippocampus injury induced by electromagnetic radiation. The excessive activation of ERK pathway may result in the apoptosis and death of neurons, which is the important mechanism of recognition disfunction caused by electromagnetic radiation.

  18. Different effection of p.1125Val>Ala and rs11954856 in APC on Wnt signaling pathway.

    Science.gov (United States)

    Li, Fei-Feng; Zhao, Zhi-Xun; Yan, Peng; Wang, Song; Liu, Zheng; Zhang, Qiong; Zhang, Xiao-Ning; Sun, Chang-Hao; Wang, Xi-Shan; Wang, Gui-Yu; Liu, Shu-Lin

    2017-09-19

    Colorectal cancer (CRC) is among the most common and fatal forms of solid tumors worldwide and more than two thirds of CRC and adenomas patients have APC gene mutations. APC is a key regulator in the Wnt/β-catenin signaling pathway but its roles in CRC remains to be elucidated. In this study, we compared APC genes between CRC patients and controls to determine possible associations of nucleotide changes in the APC gene with the pathways involved in CRC pathogenesis. All participants received physical and enteroscopic examinations. The APC gene was sequenced for 300 Chinese Han CRC patients and 411 normal controls, and the expression levels of genes in the signaling pathway were analyzed using Western Blotting. Statistical analyses were conducted using SPSS (version 19.0) software. We found that rs11954856 in the APC gene was associated with colorectal cancer and could increase the expression levels of APC , β-catenin , TCF7L1 , TCF7L2 and LEF1 genes in the pathway in the CRC patients, demonstrating the involvement of APC in the pathological processes leading to CRC.

  19. Regulation of muscle stem cell functions: a focus on the p38 MAPK signaling pathway

    Directory of Open Access Journals (Sweden)

    Jessica Segales

    2016-08-01

    Full Text Available Formation of skeletal muscle fibers (myogenesis during development and after tissue injury in the adult constitutes an excellent paradigm to investigate the mechanisms whereby environmental cues control gene expression programs in muscle stem cells (satellite cells by acting on transcriptional and epigenetic effectors. Here we will review the molecular mechanisms implicated in the transition of satellite cells throughout the distinct myogenic stages (i.e., activation from quiescence, proliferation, differentiation and self-renewal. We will also discuss recent findings on the causes underlying satellite cell functional decline with aging. In particular, our review will focus on the epigenetic changes underlying fate decisions and on how the p38 MAPK signaling pathway integrates the environmental signals at the chromatin to build up satellite cell adaptive responses during the process of muscle regeneration, and how these responses are altered in aging. A better comprehension of the signaling pathways connecting external and intrinsic factors will illuminate the path for improving muscle regeneration in the aged.

  20. Dysfunction of the RAR/RXR signaling pathway in the forebrain impairs hippocampal memory and synaptic plasticity

    Directory of Open Access Journals (Sweden)

    Nomoto Masanori

    2012-02-01

    Full Text Available Abstract Background Retinoid signaling pathways mediated by retinoic acid receptor (RAR/retinoid × receptor (RXR-mediated transcription play critical roles in hippocampal synaptic plasticity. Furthermore, recent studies have shown that treatment with retinoic acid alleviates age-related deficits in hippocampal long-term potentiation (LTP and memory performance and, furthermore, memory deficits in a transgenic mouse model of Alzheimer's disease. However, the roles of the RAR/RXR signaling pathway in learning and memory at the behavioral level have still not been well characterized in the adult brain. We here show essential roles for RAR/RXR in hippocampus-dependent learning and memory. In the current study, we generated transgenic mice in which the expression of dominant-negative RAR (dnRAR could be induced in the mature brain using a tetracycline-dependent transcription factor and examined the effects of RAR/RXR loss. Results The expression of dnRAR in the forebrain down-regulated the expression of RARβ, a target gene of RAR/RXR, indicating that dnRAR mice exhibit dysfunction of the RAR/RXR signaling pathway. Similar with previous findings, dnRAR mice displayed impaired LTP and AMPA-mediated synaptic transmission in the hippocampus. More importantly, these mutant mice displayed impaired hippocampus-dependent social recognition and spatial memory. However, these deficits of LTP and memory performance were rescued by stronger conditioning stimulation and spaced training, respectively. Finally, we found that pharmacological blockade of RARα in the hippocampus impairs social recognition memory. Conclusions From these observations, we concluded that the RAR/RXR signaling pathway greatly contributes to learning and memory, and LTP in the hippocampus in the adult brain.

  1. Study of gene expression alteration in male androgenetic alopecia: evidence of predominant molecular signalling pathways.

    Science.gov (United States)

    Michel, L; Reygagne, P; Benech, P; Jean-Louis, F; Scalvino, S; Ly Ka So, S; Hamidou, Z; Bianovici, S; Pouch, J; Ducos, B; Bonnet, M; Bensussan, A; Patatian, A; Lati, E; Wdzieczak-Bakala, J; Choulot, J-C; Loing, E; Hocquaux, M

    2017-11-01

    Male androgenetic alopecia (AGA) is the most common form of hair loss in men. It is characterized by a distinct pattern of progressive hair loss starting from the frontal area and the vertex of the scalp. Although several genetic risk loci have been identified, relevant genes for AGA remain to be defined. To identify biomarkers associated with AGA. Molecular biomarkers associated with premature AGA were identified through gene expression analysis using cDNA generated from scalp vertex biopsies of hairless or bald men with premature AGA, and healthy volunteers. This monocentric study reveals that genes encoding mast cell granule enzymes, inflammatory mediators and immunoglobulin-associated immune mediators were significantly overexpressed in AGA. In contrast, underexpressed genes appear to be associated with the Wnt/β-catenin and bone morphogenic protein/transforming growth factor-β signalling pathways. Although involvement of these pathways in hair follicle regeneration is well described, functional interpretation of the transcriptomic data highlights different events that account for their inhibition. In particular, one of these events depends on the dysregulated expression of proopiomelanocortin, as confirmed by polymerase chain reaction and immunohistochemistry. In addition, lower expression of CYP27B1 in patients with AGA supports the notion that changes in vitamin D metabolism contributes to hair loss. This study provides compelling evidence for distinct molecular events contributing to alopecia that may pave the way for new therapeutic approaches. © 2017 British Association of Dermatologists.

  2. Altered Wnt Signaling Pathway in Cognitive Impairment Caused by Chronic Intermittent Hypoxia: Focus on Glycogen Synthase Kinase-3β and β-catenin

    Directory of Open Access Journals (Sweden)

    Yue-Ying Pan

    2016-01-01

    Conclusions: Wnt/β-catenin signaling pathway abnormalities possibly play an important role in the development of cognitive deficits among mice exposed to CIH and that LiCl might attenuate CIH-induced cognitive impairment via Wnt/β-catenin signaling pathway.

  3. Chronic Intake of Commercial Sweeteners Induces Changes in Feeding Behavior and Signaling Pathways Related to the Control of Appetite in BALB/c Mice.

    Science.gov (United States)

    Barrios-Correa, Alberto A; Estrada, José A; Martel, Caroline; Olivier, Martin; López-Santiago, Rubén; Contreras, Irazú

    2018-01-01

    Nonnutritive sweetener use is a common practice worldwide. Although considered safe for human consumption, accumulating evidence suggests these compounds may affect metabolic homeostasis; however, there is no consensus on the role of frequent sweetener intake in appetite and weight loss. We sought to determine whether frequent intake of commercial sweeteners induces changes in the JAK2/STAT3 signaling pathway in the brain of mice, as it is involved in the regulation of appetite and body composition. We supplemented adult BALB/c mice with sucrose, steviol glycosides (SG), or sucralose, daily, for 6 weeks. After supplementation, we evaluated body composition and expression of total and phosphorylated JAK2, STAT3, and Akt, as well as SOCS3 and ObRb, in brain tissue. Our results show that frequent intake of commercial SG decreases energy intake, adiposity, and weight gain in male animals, while increasing the expression of pJAK2 and pSTAT3 in the brain, whereas sucralose increases weight gain and pJAK2 expression in females. Our results suggest that chronic intake of commercial sweeteners elicits changes in signaling pathways that have been related to the control of appetite and energy balance in vivo , which may have relevant consequences for the nutritional state and long term health of the organism.

  4. PI3K-AKT signaling pathway is involved in hypoxia/thermal-induced immunosuppression of small abalone Haliotis diversicolor.

    Science.gov (United States)

    Sun, Yulong; Zhang, Xin; Wang, Guodong; Lin, Shi; Zeng, Xinyang; Wang, Yilei; Zhang, Ziping

    2016-12-01

    The PI3K-AKT signal pathway has been found to be involved in many important physiological and pathological processes of the innate immune system of vertebrates and invertebrates. In this study, the AKT (HdAKT) and PI3K (HdPI3K) gene of small abalone Haliotis diversicolor were cloned and characterized for the important status of PI3K and AKT protein in PI3K-AKT signaling pathway. The full length cDNAs of HdAKT and HdPI3K are 2126 bp and 6052 bp respectively, encoding proteins of 479 amino acids and 1097 amino acids, respectively. The mRNA expression level of fourteen genes in the PI3K-AKT signaling pathway were detected by quantitative real-time PCR. The results showed that all these fourteen genes were ubiquitously expressed in seven selected tissues. Meanwhile, HdAKT was expressed in haemocytes with the highest expression level (p abalone. The mRNA expression of these genes in gills, haemocytes and hepatopancreas was significantly down-regulated after the Vibrio parahaemolyticus stimulation with environment stimulation (thermal, hypoxia and thermal & hypoxia). These results indicate that the dual/multiple stresses defeat the immune system and lead to immunosuppression in abalone. PI3K-AKT signaling pathway may be involved in hypoxia/thermal-induced immunosuppression of small abalone Haliotis diversicolor. Copyright © 2016 Elsevier Ltd. All rights reserved.

  5. The TOR Signaling Pathway in Spatial and Temporal Control of Cell Size and Growth

    Directory of Open Access Journals (Sweden)

    Suam Gonzalez

    2017-06-01

    Full Text Available Cell size is amenable by genetic and environmental factors. The highly conserved nutrient-responsive Target of Rapamycin (TOR signaling pathway regulates cellular metabolic status and growth in response to numerous inputs. Timing and duration of TOR pathway activity is pivotal for both cell mass built up as well as cell cycle progression and is controlled and fine-tuned by the abundance and quality of nutrients, hormonal signals, growth factors, stress, and oxygen. TOR kinases function within two functionally and structurally discrete multiprotein complexes, TORC1 and TORC2, that are implicated in temporal and spatial control of cell size and growth respectively; however, recent data indicate that such functional distinctions are much more complex. Here, we briefly review roles of the two complexes in cellular growth and cytoarchitecture in various experimental model systems.

  6. Hydrogen-rich medium protects mouse embryonic fibroblasts from oxidative stress by activating LKB1-AMPK-FoxO1 signal pathway.

    Science.gov (United States)

    Lee, Jihyun; Yang, Goowon; Kim, Young-Joo; Tran, Quynh Hoa; Choe, Wonchae; Kang, Insug; Kim, Sung Soo; Ha, Joohun

    2017-09-23

    Persistent oxidative stress is recognized as a major cause of many pathological conditions as well as ageing. However, most clinical trials of dietary antioxidants have failed to produce successful outcomes in treating oxidative stress-induced diseases. Molecular hydrogen (H 2 ) has recently received considerable attention as a therapeutic agent owing to its novel antioxidant properties, a selective scavenger of hydroxyl and peroxynitrite radicals. Beyond this, numerous reports support that H 2 can modulate the activity of various cellular signal pathways. However, its effect on AMP-activated protein kinase (AMPK) signal pathway, a central regulator of energy hemostasis, has remained almost elusive. Here, we report that hydrogen-rich medium activated LKB1-AMPK signal pathway without ATP depletion, which in turn induced FoxO1-dependent transcription of manganese superoxide dismutase and catalase in mouse embryonic fibroblasts. Moreover, hydrogen-rich media effectively reduced the level of reactive oxygen species in cells treated with hydrogen peroxide and protected these cells from apoptosis in an AMPK-dependent manner. These results suggest that the LKB1-AMPK-FoxO1 signaling pathway is a critical mediator of the antioxidant properties of H 2 , further supporting the idea that H 2 acts as a signaling molecule to serve various physiological functions. Copyright © 2017 Elsevier Inc. All rights reserved.

  7. Saw Palmetto Extract Inhibits Metastasis and Antiangiogenesis through STAT3 Signal Pathway in Glioma Cell.

    Science.gov (United States)

    Ding, Hong; Shen, Jinglian; Yang, Yang; Che, Yuqin

    2015-01-01

    Signal transducer and activator of transcription factor 3 (STAT3) plays an important role in the proliferation and angiogenesis in human glioma. Previous research indicated that saw palmetto extract markedly inhibited the proliferation of human glioma cells through STAT3 signal pathway. But its effect on tumor metastasis and antiangiogenesis is not clear. This study is to further clear the impact of saw palmetto extract on glioma cell metastasis, antiangiogenesis, and its mechanism. TUNEL assay indicated that the apoptotic cells in the saw palmetto treated group are higher than that in the control group (p saw palmetto extract inhibits the proliferation of human glioma. Meanwhile pSTAT3 is lower in the experimental group and CD34 is also inhibited in the saw palmetto treated group. This means that saw palmetto extract could inhibit the angiogenesis in glioma. We found that saw palmetto extract was an important phytotherapeutic drug against the human glioma through STAT3 signal pathway. Saw palmetto extract may be useful as an adjunctive therapeutic agent for treatment of individuals with glioma and other types of cancer in which STAT3 signaling is activated.

  8. Targeting Glutamatergic Signaling and the PI3 Kinase Pathway to Halt Melanoma Progression

    Directory of Open Access Journals (Sweden)

    Stephen A. Rosenberg

    2015-02-01

    Full Text Available Our group has previously reported that the majority of human melanomas (>60% express the metabotropic glutamate receptor 1 (GRM1 and that the glutamate release inhibitor riluzole, a drug currently used to treat amyotrophic lateral sclerosis, can induce apoptosis in GRM1-expressing melanoma cells. Our group previously reported that in vitro riluzole treatment reduces cell growth in three-dimensional (3D soft agar colony assays by 80% in cells with wildtype phosphoinositide 3-kinase (PI3K pathway activation. However, melanoma cell lines harboring constitutive activating mutations of the PI3K pathway (PTEN and NRAS mutations showed only a 35% to 40% decrease in colony formation in soft agar in the presence of riluzole. In this study, we have continued our preclinical studies of riluzole and its effect on melanoma cells alone and in combination with inhibitors of the PI3 kinase pathway: the AKT inhibitor, API-2, and the mammalian target of rapamycin (mTOR inhibitor, rapamycin. We modeled these combinatorial therapies on various melanoma cell lines in 3D and 2D systems and in vivo. Riluzole combined with mTOR inhibition is more effective at halting melanoma anchorage-independent growth and xenograft tumor progression than either agent alone. PI3K signaling changes associated with this combinatorial treatment shows that 3D (nanoculture modeling of cell signaling more closely resembles in vivo signaling than monolayer models. Riluzole combined with mTOR inhibition is effective at halting tumor cell progression independent of BRAF mutational status. This makes this combinatorial therapy a potentially viable alternative for metastatic melanoma patients who are BRAF WT and are therefore ineligible for vemurafenib therapy.

  9. Calcium-sensing receptor (CaSR): pharmacological properties and signaling pathways.

    Science.gov (United States)

    Conigrave, Arthur D; Ward, Donald T

    2013-06-01

    In this article we consider the mechanisms by which the calcium-sensing receptor (CaSR) induces its cellular responses via the control (activation or inhibition) of signaling pathways. We consider key features of CaSR-mediated signaling including its control of the heterotrimeric G-proteins Gq/11, Gi/o and G12/13 and the downstream consequences recognizing that very few CaSR-mediated cell phenomena have been fully described. We also consider the manner in which the CaSR contributes to the formation of specific signaling scaffolds via peptide recognition sequences in its intracellular C-terminal along with the origins of its high level of cooperativity, particularly for Ca(2+)o, and its remarkable resistance to desensitization. We also consider the nature of the mechanisms by which the CaSR controls oscillatory and sustained Ca(2+)i mobilizing responses and inhibits or elevates cyclic adenosine monophosphate (cAMP) levels dependent on the cellular and signaling context. Finally, we consider the diversity of the receptor's ligands, ligand binding sites and broader compartment-dependent physiological roles leading to the identification of pronounced ligand-biased signaling for agonists including Sr(2+) and modulators including l-amino acids and the clinically effective calcimimetic cinacalcet. We note the implications of these findings for the development of new designer drugs that might target the CaSR in pathophysiological contexts beyond those established for the treatment of disorders of calcium metabolism. Copyright © 2013 Elsevier Ltd. All rights reserved.

  10. TCR-CXCR4 signaling stabilizes cytokine mRNA transcripts via a PREX1-Rac1 pathway: implications for CTCL.

    Science.gov (United States)

    Kremer, Kimberly N; Dinkel, Brittney A; Sterner, Rosalie M; Osborne, Douglas G; Jevremovic, Dragan; Hedin, Karen E

    2017-08-24

    As with many immunopathologically driven diseases, the malignant T cells of cutaneous T-cell lymphomas (CTCLs), such as Sézary syndrome, display aberrant cytokine secretion patterns that contribute to pathology and disease progression. Targeting this disordered release of cytokines is complicated by the changing cytokine milieu that drives the phenotypic changes of CTCLs. Here, we characterize a novel signaling pathway that can be targeted to inhibit the secretion of cytokines by modulating either CXCR4 or CXCR4-mediated signaling. We demonstrate that upon ligation of the T-cell antigen receptor (TCR), the TCR associates with and transactivates CXCR4 via phosphorylation of S339-CXCR4 in order to activate a PREX1-Rac1-signaling pathway that stabilizes interleukin-2 (IL-2) , IL-4 , and IL-10 messenger RNA (mRNA) transcripts. Pharmacologic inhibition of either TCR-CXCR4 complex formation or PREX1-Rac1 signaling in primary human T cells decreased mRNA stability and inhibited secretion of IL-2, IL-4, and IL-10. Applying this knowledge to Sézary syndrome, we demonstrate that targeting various aspects of this signaling pathway blocks both TCR-dependent and TCR-independent cytokine secretion from a Sézary syndrome-derived cell line and patient isolates. Together, these results identify multiple aspects of a novel TCR-CXCR4-signaling pathway that could be targeted to inhibit the aberrant cytokine secretion that drives the immunopathogenesis of Sézary syndrome and other immunopathological diseases. © 2017 by The American Society of Hematology.

  11. Multiple signal transduction pathways in okadaic acid induced apoptosis in HeLa cells

    International Nuclear Information System (INIS)

    Jayaraj, R.; Gupta, Nimesh; Rao, P.V. Lakshmana

    2009-01-01

    Okadaic acid (OA) is the major component of diarrhetic shell fish poisoning toxins and a potent inhibitor of protein phosphatase 1 and 2A. We investigated the signal transduction pathways involved in OA induced cell death in HeLa cells. OA induced cytotoxicity and apoptosis at IC50 of 100 nM. OA treatment resulted in time dependent increase in reactive oxygen species and depleted intracellular glutathione levels. Loss of mitochondrial membrane permeability led to translocation of bax, cytochrome-c and AIF from mitochondria to cytosol. The cells under fluorescence microscope showed typical apoptotic morphology with condensed chromatin, and nuclear fragmentation. We investigated the mitochondrial-mediated caspase cascade. The time dependent activation and cleavage of of bax, caspases-8, 10, 9, 3 and 7 was observed in Western blot analysis. In addition to caspase-dependent pathway AIF mediated caspase-independent pathway was involved in OA mediated cell death. OA also caused time dependent inhibition of protein phosphatase 2A activity and phosphorylation of p38 and p42/44 MAP kinases. Inhibitor studies with Ac-DEVO-CHO and Z-VAD-FMK could not prevent the phosphorylation of p38 and p42/44 MAP kinases. Our experiments with caspase inhibitors Ac-DEVD-CHO, Z-IETD-FMK and Z-VAD-FMK inhibited capsase-3, 8 cleavages but did not prevent OA-induced apoptosis and DNA fragmentation. Similarly, pretreatment with cyclosporin-A and N-acetylcysteine could not prevent the DNA fragmentation. In summary, the results of our study show that OA induces multiple signal transduction pathways acting either independently or simultaneously leading to apoptosis

  12. MicroRNA Roles in the NF-κB Signaling Pathway during Viral Infections

    Directory of Open Access Journals (Sweden)

    Zeqian Gao

    2014-01-01

    Full Text Available NF-κB signaling network is a crucial component of innate immunity. miRNAs are a subtype of small noncoding RNAs, involved in regulation of gene expression at the posttranscriptional level. Increasing evidence has emerged that miRNAs play an important role in regulation of NF-κB signaling pathway during viral infections. Both host and viral miRNAs are attributed to modulation of NF-κB activity, thus affecting viral infection and clearance. Understandings of the mechanisms of these miRNAs will open a direction for development of novel antivirus drugs.

  13. Sub-chronic agmatine treatment modulates hippocampal neuroplasticity and cell survival signaling pathways in mice.

    Science.gov (United States)

    Freitas, Andiara E; Bettio, Luis E B; Neis, Vivian B; Moretti, Morgana; Ribeiro, Camille M; Lopes, Mark W; Leal, Rodrigo B; Rodrigues, Ana Lúcia S

    2014-11-01

    Agmatine is an endogenous neuromodulator which, based on animal and human studies, is a putative novel antidepressant drug. In this study, we investigated the ability of sub-chronic (21 days) p.o. agmatine administration to produce an antidepressant-like effect in the tail suspension test and examined the hippocampal cell signaling pathways implicated in such an effect. Agmatine at doses of 0.01 and 0.1 mg/kg (p.o.) produced a significant antidepressant-like effect in the tail suspension test and no effect in the open-field test. Additionally, agmatine (0.001-0.1 mg/kg, p.o.) increased the phosphorylation of protein kinase A substrates (237-258% of control), protein kinase B/Akt (Ser(473)) (116-127% of control), glycogen synthase kinase-3β (Ser(9)) (110-113% of control), extracellular signal-regulated kinases 1/2 (119-137% and 121-138% of control, respectively) and cAMP response elements (Ser(133)) (127-152% of control), and brain-derived-neurotrophic factor (137-175% of control) immunocontent in a dose-dependent manner in the hippocampus. Agmatine (0.001-0.1 mg/kg, p.o.) also reduced the c-jun N-terminal kinase 1/2 phosphorylation (77-71% and 65-51% of control, respectively). Neither protein kinase C nor p38(MAPK) phosphorylation was altered under any experimental conditions. Taken together, the present study extends the available data on the mechanisms that underlie the antidepressant action of agmatine by showing an antidepressant-like effect following sub-chronic administration. In addition, our results are the first to demonstrate the ability of agmatine to elicit the activation of cellular signaling pathways associated with neuroplasticity/cell survival and the inhibition of signaling pathways associated with cell death in the hippocampus. Copyright © 2014 Elsevier Ltd. All rights reserved.

  14. Interactions of Notch1 and TLR4 signaling pathways in DRG neurons of in vivo and in vitro models of diabetic neuropathy.

    Science.gov (United States)

    Chen, Tianhua; Li, Hao; Yin, Yiting; Zhang, Yuanpin; Liu, Zhen; Liu, Huaxiang

    2017-11-02

    Understanding the interactions between Notch1 and toll-like receptor 4 (TLR4) signaling pathways in the development of diabetic peripheral neuropathy may lead to interpretation of the mechanisms and novel approaches for preventing diabetic neuropathic pain. In the present study, the interactions between Notch1 and TLR4 signaling pathways were investigated by using dorsal root ganglion (DRG) from diabetic neuropathic pain rats and cultured DRG neurons under high glucose challenge. The results showed that high glucose induced not only Notch1 mRNA, HES1 mRNA, and TLR4 mRNA expression, but also Notch1 intracellular domain (NICD1) and TLR4 protein expression in DRG neurons. The proportion of NICD1-immunoreactive (IR) and TLR4-IR neurons in DRG cultures was also increased after high glucose challenge. The above alterations could be partially reversed by inhibition of either Notch1 or TLR4 signaling pathway. Inhibition of either Notch1 or TLR4 signaling pathway could improve mechanical allodynia and thermal hyperalgesia thresholds. Inhibition of Notch1 or TLR4 signaling also decreased tumor necrosis factor-α (TNF-α) levels in DRG from diabetic neuropathic rats. These data imply that the interaction between Notch1 and TLR4 signaling pathways is one of the important mechanisms in the development or progression of diabetic neuropathy.

  15. Ferulic acid attenuates diabetes-induced cognitive impairment in rats via regulation of PTP1B and insulin signaling pathway.

    Science.gov (United States)

    Wang, Hao; Sun, Xiaoxu; Zhang, Ning; Ji, Zhouye; Ma, Zhanqiang; Fu, Qiang; Qu, Rong; Ma, Shiping

    2017-12-01

    Cognitive impairment has been recognized as a typical characteristic of neurodegenerative disease in diabetes mellitus (DM) and this cognitive dysfunction may be a risk factor for Alzheimer's disease (AD). Ferulic acid, a phenolic compound commonly found in a range of plants, has emerged various properties including anti-inflammatory and neuroprotective effects. In the present study, the protective activities and relevant mechanisms of ferulic acid were evaluated in diabetic rats with cognitive deficits, which were induced by a high-glucose-fat (HGF) diet and low dose of streptozotocin (STZ). It was observed that ferulic acid significantly increased body weight and decreased blood glucose levels. Meanwhile, ferulic acid could markedly ameliorate spatial memory of diabetic rats in Morris water maze (MWM) and decrease AD-like pathologic changes (Aβ deposition and Tau phosphorylation) in the hippocampus, which might be correlated with the inhibition of inflammatory cytokines release and reduction of protein tyrosine phosphatase 1B (PTP1B) expression. Moreover, the levels of brain insulin signal molecules p-IRS, p-Akt and p-GSK3β were also investigated. We found that ferulic acid administration restored the alterations in insulin signaling. In conclusion, ferulic acid exhibited beneficial effects on diabetes-induced cognition lesions, which was involved in the regulation of PTP1B and insulin signaling pathway. We suppose that PTP1B inhibition may represent a promising approach to correct abnormal signaling linked to diabetes-induced cognitive impairment. Copyright © 2017. Published by Elsevier Inc.

  16. Dioscorin isolated from Dioscorea alata activates TLR4-signaling pathways and induces cytokine expression in macrophages.

    Science.gov (United States)

    Fu, Shu-Ling; Hsu, Ya-Hui; Lee, Pei-Yeh; Hou, Wen-Chi; Hung, Ling-Chien; Lin, Chao-Hsiung; Chen, Chiu-Ming; Huang, Yu-Jing

    2006-01-06

    The Toll-like receptor 4 (TLR4)-signaling pathway is crucial for activating both innate and adaptive immunity. TLR4 is a promising molecular target for immune-modulating drugs, and TLR4 agonists are of therapeutic potential for treating immune diseases and cancers. Several medicinal herb-derived components have recently been reported to act via TLR4-dependent pathways, suggesting that medicinal plants are potential resources for identifying TLR4 activators. We have applied a screening procedure to systematically identify herbal constituents that activate TLR4. To exclude possible LPS contamination in these plant-derived components, a LPS inhibitor, polymyxin B, was added during screening. One of the plant components we identified from the screening was dioscorin, the glycoprotein isolated from Dioscorea alata. It induced TLR4-downstream cytokine expression in bone marrow cells isolated from TLR4-functional C3H/HeN mice but not from TLR4-defective C3H/HeJ mice. Dioscorin also stimulated multiple signaling molecules (NF-kappaB, ERK, JNK, and p38) and induced the expression of cytokines (TNF-alpha, IL-1beta, and IL-6) in murine RAW 264.7 macrophages. Furthermore, the ERK, p38, JNK, and NF-kappaB-mediated pathways are all involved in dioscorin-mediated TNF-alpha production. In summary, our results demonstrate that dioscorin is a novel TLR4 activator and induces macrophage activation via typical TLR4-signaling pathways.

  17. The effects of lossy compression on diagnostically relevant seizure information in EEG signals.

    Science.gov (United States)

    Higgins, G; McGinley, B; Faul, S; McEvoy, R P; Glavin, M; Marnane, W P; Jones, E

    2013-01-01

    This paper examines the effects of compression on EEG signals, in the context of automated detection of epileptic seizures. Specifically, it examines the use of lossy compression on EEG signals in order to reduce the amount of data which has to be transmitted or stored, while having as little impact as possible on the information in the signal relevant to diagnosing epileptic seizures. Two popular compression methods, JPEG2000 and SPIHT, were used. A range of compression levels was selected for both algorithms in order to compress the signals with varying degrees of loss. This compression was applied to the database of epileptiform data provided by the University of Freiburg, Germany. The real-time EEG analysis for event detection automated seizure detection system was used in place of a trained clinician for scoring the reconstructed data. Results demonstrate that compression by a factor of up to 120:1 can be achieved, with minimal loss in seizure detection performance as measured by the area under the receiver operating characteristic curve of the seizure detection system.

  18. New Challenges in Targeting Signaling Pathways in Acute Lymphoblastic Leukemia by NGS Approaches: An Update

    Science.gov (United States)

    Hernández-Rivas, Jesús María

    2018-01-01

    The identification and study of genetic alterations involved in various signaling pathways associated with the pathogenesis of acute lymphoblastic leukemia (ALL) and the application of recent next-generation sequencing (NGS) in the identification of these lesions not only broaden our understanding of the involvement of various genetic alterations in the pathogenesis of the disease but also identify new therapeutic targets for future clinical trials. The present review describes the main deletions, amplifications, sequence mutations, epigenetic lesions, and new structural DNA rearrangements detected by NGS in B-ALL and T-ALL and their clinical importance for therapeutic procedures. We reviewed the molecular basis of pathways including transcriptional regulation, lymphoid differentiation and development, TP53 and the cell cycle, RAS signaling, JAK/STAT, NOTCH, PI3K/AKT/mTOR, Wnt/β-catenin signaling, chromatin structure modifiers, and epigenetic regulators. The implementation of NGS strategies has enabled important mutated genes in each pathway, their associations with the genetic subtypes of ALL, and their outcomes, which will be described further. We also discuss classic and new cryptic DNA rearrangements in ALL identified by mRNA-seq strategies. Novel cooperative abnormalities in ALL could be key prognostic and/or predictive biomarkers for selecting the best frontline treatment and for developing therapies after the first relapse or refractory disease. PMID:29642462

  19. Ascorbate oxidase is the potential conductor of a symphony of signaling pathways.

    Science.gov (United States)

    De Tullio, Mario C; Guether, Mike; Balestrini, Raffaella

    2013-03-01

    The functional role of ascorbate oxidase (AO; EC 1.10.3.3) has never been fully explained so far, due to the difficulties in understanding the presence of an enzyme specifically oxidizing ascorbate with no obvious advantage, and the apparent disadvantage of lowering plant stress resistance as a consequence of ascorbate consumption. Here we suggest a complete change of perspective, by proposing an essential role of AO as a modulator of both ascorbate and oxygen content, with relevant implications related to signaling. By affecting the overall redox state, AO is actually involved in redox regulation in the extracellular matrix. In addition, AO can contribute to creating a hypoxic microenvironment, especially relevant in the maintenance of meristem identity and the establishment of mutualistic plant-microbe interactions. We also hypothesize the possible involvement of AO in the activation of a signaling cascade analogous to the mechanism of prolyl hydroxylases/Hypoxia Inducible Factors in animals.

  20. Hydrolysis products generated by lipoprotein lipase and endothelial lipase differentially impact THP-1 macrophage cell signalling pathways.

    Science.gov (United States)

    Essaji, Yasmin; Yang, Yanbo; Albert, Carolyn J; Ford, David A; Brown, Robert J

    2013-08-01

    Macrophages express lipoprotein lipase (LPL) and endothelial lipase (EL) within atherosclerotic plaques; however, little is known about how lipoprotein hydrolysis products generated by these lipases might affect macrophage cell signalling pathways. We hypothesized that hydrolysis products affect macrophage cell signalling pathways associated with atherosclerosis. To test our hypothesis, we incubated differentiated THP-1 macrophages with products from total lipoprotein hydrolysis by recombinant LPL or EL. Using antibody arrays, we found that the phosphorylation of six receptor tyrosine kinases and three signalling nodes--most associated with atherosclerotic processes--was increased by LPL derived hydrolysis products. EL derived hydrolysis products only increased the phosphorylation of tropomyosin-related kinase A, which is also implicated in playing a role in atherosclerosis. Using electrospray ionization-mass spectrometry, we identified the species of triacylglycerols and phosphatidylcholines that were hydrolyzed by LPL and EL, and we identified the fatty acids liberated by gas chromatography-mass spectrometry. To determine if the total liberated fatty acids influenced signalling pathways, we incubated differentiated THP-1 macrophages with a mixture of the fatty acids that matched the concentrations of liberated fatty acids from total lipoproteins by LPL, and we subjected cell lysates to antibody array analyses. The analyses showed that only the phosphorylation of Akt was significantly increased in response to fatty acid treatment. Overall, our study shows that macrophages display potentially pro-atherogenic signalling responses following acute treatments with LPL and EL lipoprotein hydrolysis products.

  1. Pronounced Phenotypic Changes in Transgenic Tobacco Plants Overexpressing Sucrose Synthase May Reveal a Novel Sugar Signaling Pathway

    Science.gov (United States)

    Nguyen, Quynh Anh; Luan, Sheng; Wi, Seung G.; Bae, Hanhong; Lee, Dae-Seok; Bae, Hyeun-Jong

    2016-01-01

    Soluble sugars not only serve as nutrients, but also act as signals for plant growth and development, but how sugar signals are perceived and translated into physiological responses in plants remains unclear. We manipulated sugar levels in transgenic plants by overexpressing sucrose synthase (SuSy), which is a key enzyme believed to have reversible sucrose synthesis and sucrose degradation functions. The ectopically expressed SuSy protein exhibited sucrose-degrading activity, which may change the flux of sucrose demand from photosynthetic to non-photosynthetic cells, and trigger an unknown sucrose signaling pathway that lead to increased sucrose content in the transgenic plants. An experiment on the transition from heterotrophic to autotrophic growth demonstrated the existence of a novel sucrose signaling pathway, which stimulated photosynthesis, and enhanced photosynthetic synthesis of sucrose, which was the direct cause or the sucrose increase. In addition, a light/dark time treatment experiment, using different day length ranges for photosynthesis/respiration showed the carbohydrate pattern within a 24-h day and consolidated the role of sucrose signaling pathway as a way to maintain sucrose demand, and indicated the relationships between increased sucrose and upregulation of genes controlling development of the shoot apical meristem (SAM). As a result, transgenic plants featured a higher biomass and a shorter time required to switch to reproduction compared to those of control plants, indicating altered phylotaxis and more rapid advancement of developmental stages in the transgenic plants. PMID:26793204

  2. The notch and TGF-β signaling pathways contribute to the aggressiveness of clear cell renal cell carcinoma.

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    Jonas Sjölund

    Full Text Available BACKGROUND: Despite recent progress, therapy for metastatic clear cell renal cell carcinoma (CCRCC is still inadequate. Dysregulated Notch signaling in CCRCC contributes to tumor growth, but the full spectrum of downstream processes regulated by Notch in this tumor form is unknown. METHODOLOGY/PRINCIPAL FINDINGS: We show that inhibition of endogenous Notch signaling modulates TGF-β dependent gene regulation in CCRCC cells. Analysis of gene expression data representing 176 CCRCCs showed that elevated TGF-β pathway activity correlated significantly with shortened disease specific survival (log-rank test, p = 0.006 and patients with metastatic disease showed a significantly elevated TGF-β signaling activity (two-sided Student's t-test, p = 0.044. Inhibition of Notch signaling led to attenuation of both basal and TGF-β1 induced TGF-β signaling in CCRCC cells, including an extensive set of genes known to be involved in migration and invasion. Functional analyses revealed that Notch inhibition decreased the migratory and invasive capacity of CCRCC cells. CONCLUSION: An extensive cross-talk between the Notch and TGF-β signaling cascades is present in CCRCC and the functional properties of these two pathways are associated with the aggressiveness of this disease.

  3. The dipeptide Pro-Asp promotes IGF-1 secretion and expression in hepatocytes by enhancing JAK2/STAT5 signaling pathway.

    Science.gov (United States)

    Wang, Songbo; Wang, Guoqing; Zhang, Mengyuan; Zhuang, Lu; Wan, Xiaojuan; Xu, Jingren; Wang, Lina; Zhu, Xiaotong; Gao, Ping; Xi, Qianyun; Zhang, Yongliang; Shu, Gang; Jiang, Qingyan

    2016-11-15

    It has been implicated that IGF-1 secretion can be regulated by dietary protein. However, whether the dipeptides, one of digested products of dietary protein, have influence on IGF-1 secretion remain largely unknown. Our study aimed to investigate the effects of the dipeptide Pro-Asp on IGF-1 secretion and expression in hepatocytes and to explore the possible underlying mechanisms. Our findings demonstrated that Pro-Asp promoted the secretion and gene expression of IGF-1 in HepG2 cells and primary porcine hepatocytes. Meanwhile, Pro-Asp activated the ERK and Akt signaling pathways, downstream of IGF-1. In addition, Pro-Asp enhanced GH-mediated JAK2/STAT5 signaling pathway, while inhibition of JAK2/STAT5 blocked the promotive effect of Pro-Asp on IGF-1 secretion and expression. Moreover, acute injection of Pro-Asp stimulated IGF-1 expression and activated JAK2/STAT5 signaling pathway in mice liver. Together, these results suggested that the dipeptide Pro-Asp promoted IGF-1 secretion and expression in hepatocytes by enhancing GH-mediated JAK2/STAT5 signaling pathway. Copyright © 2016. Published by Elsevier Ireland Ltd.

  4. Inflammatory stress increases hepatic CD36 translational efficiency via activation of the mTOR signalling pathway.

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    Chuan Wang

    Full Text Available Inflammatory stress is an independent risk factor for the development of non-alcoholic fatty liver disease (NAFLD. Although CD36 is known to facilitate long-chain fatty acid uptake and contributes to NAFLD progression, the mechanisms that link inflammatory stress to hepatic CD36 expression and steatosis remain unclear. As the mammalian target of rapamycin (mTOR signalling pathway is involved in CD36 translational activation, this study was undertaken to investigate whether inflammatory stress enhances hepatic CD36 expression via mTOR signalling pathway and the underlying mechanisms. To induce inflammatory stress, we used tumour necrosis factor alpha (TNF-α and interleukin-6 (IL-6 stimulation of the human hepatoblastoma HepG2 cells in vitro and casein injection in C57BL/6J mice in vivo. The data showed that inflammatory stress increased hepatic CD36 protein levels but had no effect on mRNA expression. A protein degradation assay revealed that CD36 protein stability was not different between HepG2 cells treated with or without TNF-α or IL-6. A polysomal analysis indicated that CD36 translational efficiency was significantly increased by inflammatory stress. Additionally, inflammatory stress enhanced the phosphorylation of mTOR and its downstream translational regulators including p70S6K, 4E-BP1 and eIF4E. Rapamycin, an mTOR-specific inhibitor, reduced the phosphorylation of mTOR signalling pathway and decreased the CD36 translational efficiency and protein level even under inflammatory stress resulting in the alleviation of inflammatory stress-induced hepatic lipid accumulation. This study demonstrates that the activation of the mTOR signalling pathway increases hepatic CD36 translational efficiency, resulting in increased CD36 protein expression under inflammatory stress.

  5. Aurora-A overexpression enhances cell-aggregation of Ha-ras transformants through the MEK/ERK signaling pathway

    International Nuclear Information System (INIS)

    Tseng, Ya-Shih; Lee, Jenq-Chang; Huang, Chi-Ying F; Liu, Hsiao-Sheng

    2009-01-01

    Overexpression of Aurora-A and mutant Ras (Ras V12 ) together has been detected in human bladder cancer tissue. However, it is not clear whether this phenomenon is a general event or not. Although crosstalk between Aurora-A and Ras signaling pathways has been reported, the role of these two genes acting together in tumorigenesis remains unclear. Real-time PCR and sequence analysis were utilized to identify Ha- and Ki-ras mutation (Gly -> Val). Immunohistochemistry staining was used to measure the level of Aurora-A expression in bladder and colon cancer specimens. To reveal the effect of overexpression of the above two genes on cellular responses, mouse NIH3T3 fibroblast derived cell lines over-expressing either Ras V12 and wild-type Aurora-A (designated WT) or Ras V12 and kinase-inactivated Aurora-A (KD) were established. MTT and focus formation assays were conducted to measure proliferation rate and focus formation capability of the cells. Small interfering RNA, pharmacological inhibitors and dominant negative genes were used to dissect the signaling pathways involved. Overexpression of wild-type Aurora-A and mutation of Ras V12 were detected in human bladder and colon cancer tissues. Wild-type Aurora-A induces focus formation and aggregation of the Ras V12 transformants. Aurora-A activates Ral A and the phosphorylation of AKT as well as enhances the phosphorylation of MEK, ERK of WT cells. Finally, the Ras/MEK/ERK signaling pathway is responsible for Aurora-A induced aggregation of the Ras V12 transformants. Wild-type-Aurora-A enhances focus formation and aggregation of the Ras V12 transformants and the latter occurs through modulating the Ras/MEK/ERK signaling pathway

  6. Proteomic Identification of DNA-PK Involvement within the RET Signaling Pathway.

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    Lyle J Burdine

    Full Text Available Constitutive activation of the Rearranged during Transfection (RET proto-oncogene leads to the development of MEN2A medullary thyroid cancer (MTC. The relatively clear genotype/phenotype relationship seen with RET mutations and the development of MEN2A is unusual in the fact that a single gene activity can drive the progression towards metastatic disease. Despite knowing the oncogene responsible for MEN2A, MTC, like most tumors of neural crest origin, remains largely resistant to chemotherapy. Constitutive activation of RET in a SK-N-MC cell line model reduces cell sensitivity to chemotherapy. In an attempt to identify components of the machinery responsible for the observed RET induced chemoresistance, we performed a proteomic screen of histones and associated proteins in cells with a constitutively active RET signaling pathway. The proteomic approach identified DNA-PKcs, a DNA damage response protein, as a target of the RET signaling pathway. Active DNA-PKcs, which is phosphorylated at site serine 2056 and localized to chromatin, was elevated within our model. Treatment with the RET inhibitor RPI-1 significantly reduced s2056 phosphorylation in RET cells as well as in a human medullary thyroid cancer cell line. Additionally, inhibition of DNA-PKcs activity diminished the chemoresistance observed in both cell lines. Importantly, we show that activated DNA-PKcs is elevated in medullary thyroid tumor samples and that expression correlates with expression of RET in thyroid tumors. These results highlight one mechanism by which RET signaling likely primes cells for rapid response to DNA damage and suggests DNA-PKcs as an additional target in MTC.

  7. Regulation of the Wnt/β-Catenin Signaling Pathway by Human Papillomavirus E6 and E7 Oncoproteins

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    Jesus Omar Muñoz Bello

    2015-08-01

    Full Text Available Cell signaling pathways are the mechanisms by which cells transduce external stimuli, which control the transcription of genes, to regulate diverse biological effects. In cancer, distinct signaling pathways, such as the Wnt/β-catenin pathway, have been implicated in the deregulation of critical molecular processes that affect cell proliferation and differentiation. For example, changes in β-catenin localization have been identified in Human Papillomavirus (HPV-related cancers as the lesion progresses. Specifically, β-catenin relocates from the membrane/cytoplasm to the nucleus, suggesting that this transcription regulator participates in cervical carcinogenesis. The E6 and E7 oncoproteins are responsible for the transforming activity of HPV, and some studies have implicated these viral oncoproteins in the regulation of the Wnt/β-catenin pathway. Nevertheless, new interactions of HPV oncoproteins with cellular proteins are emerging, and the study of the biological effects of such interactions will help to understand HPV-related carcinogenesis. Viruses 2015, 7 4735 This review addresses the accumulated evidence of the involvement of the HPV E6 and E7 oncoproteins in the activation of the Wnt/β-catenin pathway.

  8. Action of Phytochemicals on Insulin Signaling Pathways Accelerating Glucose Transporter (GLUT4 Protein Translocation

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    Abu Sadat Md Sayem

    2018-01-01

    Full Text Available Diabetes is associated with obesity, generally accompanied by a chronic state of oxidative stress and redox imbalances which are implicated in the progression of micro- and macro-complications like heart disease, stroke, dementia, cancer, kidney failure and blindness. All these complications rise primarily due to consistent high blood glucose levels. Insulin and glucagon help to maintain the homeostasis of glucose and lipids through signaling cascades. Pancreatic hormones stimulate translocation of the glucose transporter isoform 4 (GLUT4 from an intracellular location to the cell surface and facilitate the rapid insulin-dependent storage of glucose in muscle and fat cells. Malfunction in glucose uptake mechanisms, primarily contribute to insulin resistance in type 2 diabetes. Plant secondary metabolites, commonly known as phytochemicals, are reported to have great benefits in the management of type 2 diabetes. The role of phytochemicals and their action on insulin signaling pathways through stimulation of GLUT4 translocation is crucial to understand the pathogenesis of this disease in the management process. This review will summarize the effects of phytochemicals and their action on insulin signaling pathways accelerating GLUT4 translocation based on the current literature.

  9. Regulation of Brain-Derived Neurotrophic Factor and Growth Factor Signaling Pathways by Tyrosine Phosphatase Shp2 in the Retina: A Brief Review

    Directory of Open Access Journals (Sweden)

    Mojdeh Abbasi

    2018-03-01

    Full Text Available SH2 domain-containing tyrosine phosphatase-2 (PTPN11 or Shp2 is a ubiquitously expressed protein that plays a key regulatory role in cell proliferation, differentiation and growth factor (GF signaling. This enzyme is well expressed in various retinal neurons and has emerged as an important player in regulating survival signaling networks in the neuronal tissues. The non-receptor phosphatase can translocate to lipid rafts in the membrane and has been implicated to regulate several signaling modules including PI3K/Akt, JAK-STAT and Mitogen Activated Protein Kinase (MAPK pathways in a wide range of biochemical processes in healthy and diseased states. This review focuses on the roles of Shp2 phosphatase in regulating brain-derived neurotrophic factor (BDNF neurotrophin signaling pathways and discusses its cross-talk with various GF and downstream signaling pathways in the retina.

  10. Aluminum stress and its role in the phospholipid signaling pathway in plants and possible biotechnological applications.

    Science.gov (United States)

    Poot-Poot, Wilberth; Hernandez-Sotomayor, Soledad M Teresa

    2011-10-01

    An early response of plants to environmental signals or abiotic stress suggests that the phospholipid signaling pathway plays a pivotal role in these mechanisms. The phospholipid signaling cascade is one of the main systems of cellular transduction and is related to other signal transduction mechanisms. These other mechanisms include the generation of second messengers and their interactions with various proteins, such as ion channels. This phospholipid signaling cascade is activated by changes in the environment, such as phosphate starvation, water, metals, saline stres, and plant-pathogen interactions. One important factor that impacts agricultural crops is metal-induced stress. Because aluminum has been considered to be a major toxic factor for agriculture conducted in acidic soils, many researchers have focused on understanding the mechanisms of aluminum toxicity in plants. We have contributed the last fifteen years in this field by studying the effects of aluminum on phospholipid signaling in coffee, one of the Mexico's primary crops. We have focused our research on aluminum toxicity mechanisms in Coffea arabica suspension cells as a model for developing future contributions to the biotechnological transformation of coffee crops such that they can be made resistant to aluminum toxicity. We conclude that aluminum is able to not only generate a signal cascade in plants but also modulate other signal cascades generated by other types of stress in plants. The aim of this review is to discuss possible involvement of the phospholipid signaling pathway in the aluminum toxicity response of plant cells. Copyright © 2011 Wiley Periodicals, Inc.

  11. Ghrelin augments murine T-cell proliferation by activation of the phosphatidylinositol-3-kinase, extracellular signal-regulated kinase and protein kinase C signaling pathways

    Science.gov (United States)

    Lee, Jun Ho; Patel, Kalpesh; Tae, Hyun Jin; Lustig, Ana; Kim, Jie Wan; Mattson, Mark P.; Taub, Dennis D.

    2014-01-01

    Thymic atrophy occurs during normal aging, and is accelerated by exposure to chronic stressors that elevate glucocorticoid levelsand impair the naïve T cell output. The orexigenic hormone ghrelin was recently shown to attenuate age-associated thymic atrophy. Here, we report that ghrelin enhances the proliferation of murine CD4+ primary T cells and a CD4+ T-cell line. Ghrelin induced activation of the ERK1/2 and Akt signaling pathways, via upstream activation of phosphatidylinositol-3-kinase and protein kinase C, to enhance T-cell proliferation. Moreover, ghrelin induced expression of the cell cycle proteins cyclin D1, cyclin E, cyclin-dependent kinase 2 (CDK2) and retinoblastoma phosphorylation. Finally, ghrelin activated the above-mentioned signaling pathways and stimulated thymocyte proliferation in young and older mice in vivo. PMID:25447526

  12. Gene Expression Profile Reveals Abnormalities of Multiple Signaling Pathways in Mesenchymal Stem Cell Derived from Patients with Systemic Lupus Erythematosus

    Directory of Open Access Journals (Sweden)

    Yu Tang

    2012-01-01

    Full Text Available We aimed to compare bone-marrow-derived mesenchymal stem cells (BMMSCs between systemic lupus erythematosus (SLE and normal controls by means of cDNA microarray, immunohistochemistry, immunofluorescence, and immunoblotting. Our results showed there were a total of 1, 905 genes which were differentially expressed by BMMSCs derived from SLE patients, of which, 652 genes were upregulated and 1, 253 were downregulated. Gene ontology (GO analysis showed that the majority of these genes were related to cell cycle and protein binding. Pathway analysis exhibited that differentially regulated signal pathways involved actin cytoskeleton, focal adhesion, tight junction, and TGF-β pathway. The high protein level of BMP-5 and low expression of Id-1 indicated that there might be dysregulation in BMP/TGF-β signaling pathway. The expression of Id-1 in SLE BMMSCs was reversely correlated with serum TNF-α levels. The protein level of cyclin E decreased in the cell cycling regulation pathway. Moreover, the MAPK signaling pathway was activated in BMMSCs from SLE patients via phosphorylation of ERK1/2 and SAPK/JNK. The actin distribution pattern of BMMSCs from SLE patients was also found disordered. Our results suggested that there were distinguished differences of BMMSCs between SLE patients and normal controls.

  13. Methylprednisolone promotes recovery of neurological function after spinal cord injury: association with Wnt/β-catenin signaling pathway activation

    Science.gov (United States)

    Lu, Gong-biao; Niu, Fu-wen; Zhang, Ying-chun; Du, Lin; Liang, Zhi-yuan; Gao, Yuan; Yan, Ting-zhen; Nie, Zhi-kui; Gao, Kai

    2016-01-01

    Some studies have indicated that the Wnt/β-catenin signaling pathway is activated following spinal cord injury, and expression levels of specific proteins, including low-density lipoprotein receptor related protein-6 phosphorylation, β-catenin, and glycogen synthase kinase-3β, are significantly altered. We hypothesized that methylprednisolone treatment contributes to functional recovery after spinal cord injury by inhibiting apoptosis and activating the Wnt/β-catenin signaling pathway. In the current study, 30 mg/kg methylprednisolone was injected into rats with spinal cord injury immediately post-injury and at 1 and 2 days post-injury. Basso, Beattie, and Bresnahan scores showed that methylprednisolone treatment significantly promoted locomotor functional recovery between 2 and 6 weeks post-injury. The number of surviving motor neurons increased, whereas the lesion size significantly decreased following methylprednisolone treatment at 7 days post-injury. Additionally, caspase-3, caspase-9, and Bax protein expression levels and the number of apoptotic cells were reduced at 3 and 7 days post-injury, while Bcl-2 levels at 7 days post-injury were higher in methylprednisolone-treated rats compared with saline-treated rats. At 3 and 7 days post-injury, methylprednisolone up-regulated expression and activation of the Wnt/β-catenin signaling pathway, including low-density lipoprotein receptor related protein-6 phosphorylation, β-catenin, and glycogen synthase kinase-3β phosphorylation. These results indicate that methylprednisolone-induced neuroprotection may correlate with activation of the Wnt/β-catenin signaling pathway. PMID:28123427

  14. cAMP/PKA signaling pathway contributes to neuronal apoptosis via regulating IDE expression in a mixed model of type 2 diabetes and Alzheimer's disease.

    Science.gov (United States)

    Li, Huajie; Yang, Song; Wu, Jian; Ji, Lei; Zhu, Linfeng; Cao, Liping; Huang, Jinzhong; Jiang, Qingqing; Wei, Jiang; Liu, Meng; Mao, Keshi; Wei, Ning; Xie, Wei; Yang, Zhilong

    2018-02-01

    Type 2 diabetes (T2D) may play a relevant role in the development of Alzheimer's disease (AD), however, the underlying mechanism was not clear yet. We developed an animal model presenting both AD and T2D, morris water maze (MWM) test and recognition task were performed to trace the cognitive function. Fasting plasma glucose (FPG) and oral glucose tolerance test (OGTT) were determined to trace the metabolism evolution. TUNEL assay and apoptosis-related protein levels were analyzed for the detection of neuronal apoptosis. Cyclic adenosine monophosphate (cAMP) agonist bucladesine or protein kinase (PKA) inhibitor H-89 were used to determine the effects of cAMP/PKA signaling pathway on IDE expression and neuronal apoptosis. The results showed that T2D contributes to the AD progress by accelerating and worsening spatial memory and recognition dysfunctions. Metabolic parameters and glucose tolerance were significantly changed in the presence of the AD and T2D. The significantly induced neuronal apoptosis and increased pro-apoptotic proteins in mice with AD and T2D were also observed. We showed the decreased expression level of IDE and the activating of cAMP/PKA signaling pathway in AD and T2D mice. Further studies indicated that cAMP agonist decreased the expression level of IDE and induced the neuronal apoptosis in mice with AD and T2D; whereas PKA inhibitor H-89 treatment showed the completely opposite results. Our study indicated that, in the T2D and AD mice, cAMP/PKA signaling pathway and IDE may participate in the contribute role of T2D in accelerating the pathological process of AD via causing the accumulation of Aβ and neuronal apoptosis. © 2017 Wiley Periodicals, Inc.

  15. BMP and TGFbeta pathways in human central chondrosarcoma: enhanced endoglin and Smad 1 signaling in high grade tumors

    International Nuclear Information System (INIS)

    Boeuf, Stephane; Bovée, Judith VMG; Lehner, Burkhard; Akker, Brendy van den; Ruler, Maayke van; Cleton-Jansen, Anne-Marie; Richter, Wiltrud

    2012-01-01

    As major regulators of normal chondrogenesis, the bone morphogenic protein (BMP) and transforming growth factor β (TGFB) signaling pathways may be involved in the development and progression of central chondrosarcoma. In order to uncover their possible implication, the aim of this study was to perform a systematic quantitative study of the expression of BMPs, TGFBs and their receptors and to assess activity of the corresponding pathways in central chondrosarcoma. Gene expression analysis was performed by quantitative RT-PCR in 26 central chondrosarcoma and 6 healthy articular cartilage samples. Expression of endoglin and nuclear localization of phosphorylated Smad1/5/8 and Smad2 was assessed by immunohistochemical analysis. The expression of TGFB3 and of the activin receptor-like kinase ALK2 was found to be significantly higher in grade III compared to grade I chondrosarcoma. Nuclear phosphorylated Smad1/5/8 and Smad2 were found in all tumors analyzed and the activity of both signaling pathways was confirmed by functional reporter assays in 2 chondrosarcoma cell lines. Immunohistochemical analysis furthermore revealed that phosphorylated Smad1/5/8 and endoglin expression were significantly higher in high-grade compared to low-grade chondrosarcoma and correlated to each other. The BMP and TGFβ signaling pathways were found to be active in central chondrosarcoma cells. The correlation of Smad1/5/8 activity to endoglin expression suggests that, as described in other cell types, endoglin could enhance Smad1/5/8 signaling in high-grade chondrosarcoma cells. Endoglin expression coupled to Smad1/5/8 activation could thus represent a functionally important signaling axis for the progression of chondrosarcoma and a regulator of the undifferentiated phenotype of high-grade tumor cells

  16. The Transcriptional Landscape of p53 Signalling Pathway

    Directory of Open Access Journals (Sweden)

    Chizu Tanikawa

    2017-06-01

    Full Text Available Although recent cancer genomics studies have identified a large number of genes that were mutated in human cancers, p53 remains as the most frequently mutated gene. To further elucidate the p53-signalling network, we performed transcriptome analysis on 24 tissues in p53+/+ or p53−/− mice after whole-body X-ray irradiation. Here we found transactivation of a total of 3551 genes in one or more of the 24 tissues only in p53+/+ mice, while 2576 genes were downregulated. p53 mRNA expression level in each tissue was significantly associated with the number of genes upregulated by irradiation. Annotation using TCGA (The Cancer Genome Atlas database revealed that p53 negatively regulated mRNA expression of several cancer therapeutic targets or pathways such as BTK, SYK, and CTLA4 in breast cancer tissues. In addition, stomach exhibited the induction of Krt6, Krt16, and Krt17 as well as loricrin, an epidermal differentiation marker, after the X-ray irradiation only in p53+/+ mice, implying a mechanism to protect damaged tissues by rapid induction of differentiation. Our comprehensive transcriptome analysis elucidated tissue specific roles of p53 and its signalling networks in DNA-damage response that will enhance our understanding of cancer biology.

  17. Modular and Stochastic Approaches to Molecular Pathway Models of ATM, TGF beta, and WNT Signaling

    Science.gov (United States)

    Cucinotta, Francis A.; O'Neill, Peter; Ponomarev, Artem; Carra, Claudio; Whalen, Mary; Pluth, Janice M.

    2009-01-01

    Deterministic pathway models that describe the biochemical interactions of a group of related proteins, their complexes, activation through kinase, etc. are often the basis for many systems biology models. Low dose radiation effects present a unique set of challenges to these models including the importance of stochastic effects due to the nature of radiation tracks and small number of molecules activated, and the search for infrequent events that contribute to cancer risks. We have been studying models of the ATM, TGF -Smad and WNT signaling pathways with the goal of applying pathway models to the investigation of low dose radiation cancer risks. Modeling challenges include introduction of stochastic models of radiation tracks, their relationships to more than one substrate species that perturb pathways, and the identification of a representative set of enzymes that act on the dominant substrates. Because several pathways are activated concurrently by radiation the development of modular pathway approach is of interest.

  18. Small molecule inhibitors of the Candida albicans budded-to-hyphal transition act through multiple signaling pathways.

    Directory of Open Access Journals (Sweden)

    John Midkiff

    Full Text Available The ability of the pathogenic yeast Candida albicans to interconvert between budded and hyphal growth states, herein termed the budded-to-hyphal transition (BHT, is important for C. albicans development and virulence. The BHT is under the control of multiple cell signaling pathways that respond to external stimuli, including nutrient availability, high temperature, and pH. Previous studies identified 21 small molecules that could inhibit the C. albicans BHT in response to carbon limitation in Spider media. However, the studies herein show that the BHT inhibitors had varying efficacies in other hyphal-inducing media, reflecting their varying abilities to block signaling pathways associated with the different media. Chemical epistasis analyses suggest that most, but not all, of the BHT inhibitors were acting through either the Efg1 or Cph1 signaling pathways. Notably, the BHT inhibitor clozapine, a FDA-approved drug used to treat atypical schizophrenia by inhibiting G-protein-coupled dopamine receptors in the brain, and several of its functional analogs were shown to act at the level of the Gpr1 G-protein-coupled receptor. These studies are the first step in determining the target and mechanism of action of these BHT inhibitors, which may have therapeutic anti-fungal utility in the future.

  19. Using High-Precision Signaling Activity Imaging to Personalize Ras Pathway Inhibition Strategies in Neurofibromatosis

    Science.gov (United States)

    2017-06-01

    cell types and genetic contexts relevant to NF1. During this award period, we have improved methodologies for introducing genetically encoded...shown that the kinetics of ERK and Akt activation, including the intensity, duration, and probability of response, are critical for deciding how the...and genetic configurations relevant to NF1. We will assess whether NF1 mutants cells differ in signaling intensity, duration, threshold, or basal

  20. Caenorhabditis elegans as Model System in Pharmacology and Toxicology: Effects of Flavonoids on Redox-Sensitive Signalling Pathways and Ageing

    Directory of Open Access Journals (Sweden)

    Karoline Koch

    2014-01-01

    Full Text Available Flavonoids are secondary plant compounds that mediate diverse biological activities, for example, by scavenging free radicals and modulating intracellular signalling pathways. It has been shown in various studies that distinct flavonoid compounds enhance stress resistance and even prolong the life span of organisms. In the last years the model organism C. elegans has gained increasing importance in pharmacological and toxicological sciences due to the availability of various genetically modified nematode strains, the simplicity of modulating genes by RNAi, and the relatively short life span. Several studies have been performed demonstrating that secondary plant compounds influence ageing, stress resistance, and distinct signalling pathways in the nematode. Here we present an overview of the modulating effects of different flavonoids on oxidative stress, redox-sensitive signalling pathways, and life span in C. elegans introducing the usability of this model system for pharmacological and toxicological research.

  1. Caenorhabditis elegans as Model System in Pharmacology and Toxicology: Effects of Flavonoids on Redox-Sensitive Signalling Pathways and Ageing

    Science.gov (United States)

    Koch, Karoline; Havermann, Susannah; Büchter, Christian

    2014-01-01

    Flavonoids are secondary plant compounds that mediate diverse biological activities, for example, by scavenging free radicals and modulating intracellular signalling pathways. It has been shown in various studies that distinct flavonoid compounds enhance stress resistance and even prolong the life span of organisms. In the last years the model organism C. elegans has gained increasing importance in pharmacological and toxicological sciences due to the availability of various genetically modified nematode strains, the simplicity of modulating genes by RNAi, and the relatively short life span. Several studies have been performed demonstrating that secondary plant compounds influence ageing, stress resistance, and distinct signalling pathways in the nematode. Here we present an overview of the modulating effects of different flavonoids on oxidative stress, redox-sensitive signalling pathways, and life span in C. elegans introducing the usability of this model system for pharmacological and toxicological research. PMID:24895670

  2. Lindersin B from Lindernia crustacea induces neuritogenesis by activation of tyrosine kinase A/phosphatidylinositol 3 kinase/extracellular signal-regulated kinase signaling pathway.

    Science.gov (United States)

    Cheng, Lihong; Ye, Ying; Xiang, Lan; Osada, Hiroyuki; Qi, Jianhua

    2017-01-15

    Neurotrophic factors such as nerve growth factor (NGF) play important roles in nervous system. NGF is a potential therapeutic drug for treatment of neurodegenerative diseases. However, because of physicochemical property, NGF cannot pass through the blood-brain barrier (BBB). Hence, small molecules which exhibit NGF-mimic activity and can pass through the BBB are considered to be promising drug candidates for treatment of such diseases. The present study was designed to isolate NGF-mimic substance from extract of natural products, determine their structures and investigate mechanism of action of the active substance. Extract of Lindernia crustacean was partitioned between water and ethyl acetate to obtain water layer and ethyl acetate layer samples, respectively, and then evaluated their neuritogenic activity in PC12 cells. The active sample was separated by open columns, followed by HPLC purification to obtain active compound. Then, specific inhibitors were used to investigate signaling pathway of neurite outgrowth induced by the active compound. Finally, western blot analysis was performed to confirm the pathway proposed by inhibitor experiments. The ethyl acetate layer sample of extract of Lindernia crustacea exhibited significant neuritogenic activity. Two new compounds, named as linderside A and lindersin B, were isolated; their structures were elucidated by spectroscopic and chemical derivatization methods. Linderside A is a cucurbitane glycoside, whereas lindersin B is a cucurbitane triterpenoid. Each compound has an unusual isopentene unit, namely, a double bond bound to an unmodified isopropyl group at the end of cucurbitane triterpenoid side chain. Among them, lindersin B induced significant neurite outgrowth in PC12 cells, while linderside A was inactive against PC12 cells. Western blotting analysis results showed that lindersin B-induced neuritogenic activity depended on the activation of the mitogen-activated protein kinase (MAPK)/extracellular signal

  3. Relevance of the palatal protein kinase A pathway to the pathogenesis of cleft palate by secalonic acid D in mice

    International Nuclear Information System (INIS)

    Dhulipala, Vamsidhara C.; Hanumegowda, Umesh M.; Balasubramanian, Ganesh; Reddy, Chada S.

    2004-01-01

    Secalonic acid-D (SAD) is a teratogenic mycotoxin inducing cleft palate (CP) in the offspring of the exposed mice by reducing palatal shelf size secondary to reduced proliferation of the palatal mesenchymal (PM) cells. Co-administration of dimethylsulfoxide (DMSO) reversed the CP-inducing effect of SAD. Although SAD has been shown to affect both protein kinases A (PKA) and C (PKC) pathways, the relevance of each of these pathways to its CP induction is unknown. The present studies were designed to test the hypothesis that the protective effect of DMSO is mediated by its specific reversal of the effect(s) of SAD on one of these two pathways using ELISA-based activity assays, Western blot analysis, electrophoretic mobility shift assays (EMSA), and murine embryonic PM (MEPM) cell growth in culture. Within the PKA pathway, SAD inhibited the activity of the catalytic subunit of PKA and its migration into the nucleus, elevated phosphorylated cyclic AMP (cAMP) response element (CRE)-binding protein (pCREB) level, and reduced the binding of CREB to CRE. In the PKC pathway, SAD reduced the activity of PKC and the binding of transcription factors (TF) to 12-O-tetradecanoate-13 phorbol acetate-response element (TRE). SAD also inhibited MEPM cell growth and the expression of the CRE- and TRE-containing gene, proliferating cell nuclear antigen (PCNA). Reversal, by DMSO, of the effects of SAD on MEPM cell growth, on PCNA expression and on all components of the PKA, but not of PKC, pathway suggests that the perturbation of the PKA pathway by SAD is relevant to its induction of CP in mice

  4. R-spondin1 Controls Muscle Cell Fusion through Dual Regulation of Antagonistic Wnt Signaling Pathways

    Directory of Open Access Journals (Sweden)

    Floriane Lacour

    2017-03-01

    Full Text Available Wnt-mediated signals are involved in many important steps in mammalian regeneration. In multiple cell types, the R-spondin (Rspo family of secreted proteins potently activates the canonical Wnt/β-catenin pathway. Here, we identify Rspo1 as a mediator of skeletal muscle tissue repair. First, we show that deletion of Rspo1 results in global alteration of muscle regeneration kinetics following acute injury. We find that muscle progenitor cells lacking Rspo1 show delayed differentiation due to reduced activation of Wnt/β-catenin target genes. Furthermore, muscle cells lacking Rspo1 have a fusion phenotype leading to larger myotubes containing supernumerary nuclei both in vitro and in vivo. The increase in muscle fusion was dependent on downregulation of Wnt/β-catenin and upregulation of non-canonical Wnt7a/Fzd7/Rac1 signaling. We conclude that reciprocal control of antagonistic Wnt signaling pathways by Rspo1 in muscle stem cell progeny is a key step ensuring normal tissue architecture restoration following acute damage.

  5. The hedgehog-signaling pathway is repressed during the osteogenic differentiation of dental follicle cells

    DEFF Research Database (Denmark)

    Morsczeck, Christian; Reck, A; Beck, H C

    2017-01-01

    of repressors of the hedgehog-signaling pathway such as Patched 1 (PTCH1), Suppressor of Fused (SUFU), and Parathyroid Hormone-Related Peptide (PTHrP). Previous studies suggested that hedgehog proteins induce the osteogenic differentiation of mesenchymal stem cells via a paracrine pathway. Indian hedgehog (IHH......) induced the expression of the osteogenic transcription factor RUNX2. However, a supplementation of the BMP2-based osteogenic differentiation medium with IHH did not induce the expression of RUNX2. Moreover, IHH inhibited slightly the ALP activity and the mineralization of osteogenic-differentiated DFCs...

  6. Omentin-1 Stimulates Human Osteoblast Proliferation through PI3K/Akt Signal Pathway

    Directory of Open Access Journals (Sweden)

    Shan-Shan Wu

    2013-01-01

    Full Text Available It has been presumed that adipokines deriving from adipose tissue may play important roles in bone metabolism. Omentin-1, a novel adipokine, which is selectively expressed in visceral adipose tissue, has been reported to stimulate proliferation and inhibit differentiation of mouse osteoblast. However, little information refers to the effect of omentin-1 on human osteoblast (hOB proliferation. The current study examined the potential effects of omentin-1 on proliferation in hOB and the signal pathway involved. Omentin-1 promoted hOB proliferation in a dose-dependent manner as determined by [3H]thymidine incorporation. Western blot analysis revealed that omentin-1 induced activation of Akt (phosphatidylinositol-3 kinase downstream effector and such effect was impeded by transfection of hOB with Akt-siRNA. Furthermore, LY294002 (a selective PI3K inhibitor and HIMO (a selective Akt inhibitor abolished the omentin-1-induced hOB proliferation. These findings indicate that omentin-1 induces hOB proliferation via the PI3K/Akt signaling pathway and suggest that osteoblast is a direct target of omentin-1.

  7. Identification of mechanosensitive genes during skeletal development: alteration of genes associated with cytoskeletal rearrangement and cell signalling pathways.

    Science.gov (United States)

    Rolfe, Rebecca A; Nowlan, Niamh C; Kenny, Elaine M; Cormican, Paul; Morris, Derek W; Prendergast, Patrick J; Kelly, Daniel; Murphy, Paula

    2014-01-20

    Mechanical stimulation is necessary for regulating correct formation of the skeleton. Here we test the hypothesis that mechanical stimulation of the embryonic skeletal system impacts expression levels of genes implicated in developmentally important signalling pathways in a genome wide approach. We use a mutant mouse model with altered mechanical stimulation due to the absence of limb skeletal muscle (Splotch-delayed) where muscle-less embryos show specific defects in skeletal elements including delayed ossification, changes in the size and shape of cartilage rudiments and joint fusion. We used Microarray and RNA sequencing analysis tools to identify differentially expressed genes between muscle-less and control embryonic (TS23) humerus tissue. We found that 680 independent genes were down-regulated and 452 genes up-regulated in humeri from muscle-less Spd embryos compared to littermate controls (at least 2-fold; corrected p-value ≤0.05). We analysed the resulting differentially expressed gene sets using Gene Ontology annotations to identify significant enrichment of genes associated with particular biological processes, showing that removal of mechanical stimuli from muscle contractions affected genes associated with development and differentiation, cytoskeletal architecture and cell signalling. Among cell signalling pathways, the most strongly disturbed was Wnt signalling, with 34 genes including 19 pathway target genes affected. Spatial gene expression analysis showed that both a Wnt ligand encoding gene (Wnt4) and a pathway antagonist (Sfrp2) are up-regulated specifically in the developing joint line, while the expression of a Wnt target gene, Cd44, is no longer detectable in muscle-less embryos. The identification of 84 genes associated with the cytoskeleton that are down-regulated in the absence of muscle indicates a number of candidate genes that are both mechanoresponsive and potentially involved in mechanotransduction, converting a mechanical stimulus

  8. Saw Palmetto Extract Inhibits Metastasis and Antiangiogenesis through STAT3 Signal Pathway in Glioma Cell

    Directory of Open Access Journals (Sweden)

    Hong Ding

    2015-01-01

    Full Text Available Signal transducer and activator of transcription factor 3 (STAT3 plays an important role in the proliferation and angiogenesis in human glioma. Previous research indicated that saw palmetto extract markedly inhibited the proliferation of human glioma cells through STAT3 signal pathway. But its effect on tumor metastasis and antiangiogenesis is not clear. This study is to further clear the impact of saw palmetto extract on glioma cell metastasis, antiangiogenesis, and its mechanism. TUNEL assay indicated that the apoptotic cells in the saw palmetto treated group are higher than that in the control group (p<0.05. The apoptosis related protein is detected and the results revealed that saw palmetto extract inhibits the proliferation of human glioma. Meanwhile pSTAT3 is lower in the experimental group and CD34 is also inhibited in the saw palmetto treated group. This means that saw palmetto extract could inhibit the angiogenesis in glioma. We found that saw palmetto extract was an important phytotherapeutic drug against the human glioma through STAT3 signal pathway. Saw palmetto extract may be useful as an adjunctive therapeutic agent for treatment of individuals with glioma and other types of cancer in which STAT3 signaling is activated.

  9. Silver Nanoparticles Induce HePG-2 Cells Apoptosis Through ROS-Mediated Signaling Pathways

    Science.gov (United States)

    Zhu, Bing; Li, Yinghua; Lin, Zhengfang; Zhao, Mingqi; Xu, Tiantian; Wang, Changbing; Deng, Ning

    2016-04-01

    Recently, silver nanoparticles (AgNPs) have been shown to provide a novel approach to overcome tumors, especially those of hepatocarcinoma. However, the anticancer mechanism of silver nanoparticles is unclear. Thus, the purpose of this study was to estimate the effect of AgNPs on proliferation and activation of ROS-mediated signaling pathway on human hepatocellular carcinoma HePG-2 cells. A simple chemical method for preparing AgNPs with superior anticancer activity has been showed in this study. AgNPs were detected by transmission electronic microscopy (TEM) and energy dispersive X-ray (EDX). The size distribution and zeta potential of silver nanoparticles were detected by Zetasizer Nano. The average size of AgNPs (2 nm) observably increased the cellular uptake by endocytosis. AgNPs markedly inhibited the proliferation of HePG-2 cells through induction of apoptosis with caspase-3 activation and PARP cleavage. AgNPs with dose-dependent manner significantly increased the apoptotic cell population (sub-G1). Furthermore, AgNP-induced apoptosis was found dependent on the overproduction of reactive oxygen species (ROS) and affecting of MAPKs and AKT signaling and DNA damage-mediated p53 phosphorylation to advance HePG-2 cells apoptosis. Therefore, our results show that the mechanism of ROS-mediated signaling pathways may provide useful information in AgNP-induced HePG-2 cell apoptosis.

  10. The evolution of the TOR pathway and its role in cancer.

    Science.gov (United States)

    Beauchamp, E M; Platanias, L C

    2013-08-22

    The target of rapamycin (TOR) pathway is highly conserved among eukaryotes and has evolved to couple nutrient sensing to cellular growth. TOR is found in two distinct signaling complexes in cells, TOR complex 1 (TORC1) and TOR complex 2 (TORC2). These complexes are differentially regulated and act as effectors for the generation of signals that drive diverse cellular processes such as growth, proliferation, protein synthesis, rearrangement of the cytoskeleton, autophagy, metabolism and survival. Mammalian TOR (mTOR) is very important for development in embryos, while in adult organisms it is linked to aging and lifespan effects. In humans, the mTOR pathway is implicated in the tumorigenesis of multiple cancer types and its deregulation is associated with familial cancer syndromes. Because of its high biological relevance, different therapeutic strategies have been developed to target this signaling cascade, resulting in the emergence of unique pharmacological inhibitors that are either already approved for use in clinical oncology or currently under preclinical or clinical development. Multimodal treatment strategies that simultaneously target multiple nodes of the pathway and/or negative feedback regulatory loops may ultimately provide the best therapeutic advantage in targeting this pathway for the treatment of malignancies.

  11. Arabidopsis CPR5 independently regulates seed germination and postgermination arrest of development through LOX pathway and ABA signaling.

    Directory of Open Access Journals (Sweden)

    Guilan Gao

    Full Text Available The phytohormone abscisic acid (ABA and the lipoxygenases (LOXs pathway play important roles in seed germination and seedling growth and development. Here, we reported on the functional characterization of Arabidopsis CPR5 in the ABA signaling and LOX pathways. The cpr5 mutant was hypersensitive to ABA in the seed germination, cotyledon greening and root growth, whereas transgenic plants overexpressing CPR5 were insensitive. Genetic analysis demonstrated that CPR5 gene may be located downstream of the ABI1 in the ABA signaling pathway. However, the cpr5 mutant showed an ABA independent drought-resistant phenotype. It was also found that the cpr5 mutant was hypersensitive to NDGA and NDGA treatment aggravated the ABA-induced delay in the seed germination and cotyledon greening. Taken together, these results suggest that the CPR5 plays a regulatory role in the regulation of seed germination and early seedling growth through ABA and LOX pathways independently.

  12. Saw Palmetto Extract Inhibits Metastasis and Antiangiogenesis through STAT3 Signal Pathway in Glioma Cell

    OpenAIRE

    Ding, Hong; Shen, Jinglian; Yang, Yang; Che, Yuqin

    2015-01-01

    Signal transducer and activator of transcription factor 3 (STAT3) plays an important role in the proliferation and angiogenesis in human glioma. Previous research indicated that saw palmetto extract markedly inhibited the proliferation of human glioma cells through STAT3 signal pathway. But its effect on tumor metastasis and antiangiogenesis is not clear. This study is to further clear the impact of saw palmetto extract on glioma cell metastasis, antiangiogenesis, and its mechanism. TUNEL ass...

  13. A pedagogical walkthrough of computational modeling and simulation of Wnt signaling pathway using static causal models in MATLAB.

    Science.gov (United States)

    Sinha, Shriprakash

    2016-12-01

    Simulation study in systems biology involving computational experiments dealing with Wnt signaling pathways abound in literature but often lack a pedagogical perspective that might ease the understanding of beginner students and researchers in transition, who intend to work on the modeling of the pathway. This paucity might happen due to restrictive business policies which enforce an unwanted embargo on the sharing of important scientific knowledge. A tutorial introduction to computational modeling of Wnt signaling pathway in a human colorectal cancer dataset using static Bayesian network models is provided. The walkthrough might aid biologists/informaticians in understanding the design of computational experiments that is interleaved with exposition of the Matlab code and causal models from Bayesian network toolbox. The manuscript elucidates the coding contents of the advance article by Sinha (Integr. Biol. 6:1034-1048, 2014) and takes the reader in a step-by-step process of how (a) the collection and the transformation of the available biological information from literature is done, (b) the integration of the heterogeneous data and prior biological knowledge in the network is achieved, (c) the simulation study is designed, (d) the hypothesis regarding a biological phenomena is transformed into computational framework, and (e) results and inferences drawn using d -connectivity/separability are reported. The manuscript finally ends with a programming assignment to help the readers get hands-on experience of a perturbation project. Description of Matlab files is made available under GNU GPL v3 license at the Google code project on https://code.google.com/p/static-bn-for-wnt-signaling-pathway and https: //sites.google.com/site/shriprakashsinha/shriprakashsinha/projects/static-bn-for-wnt-signaling-pathway. Latest updates can be found in the latter website.

  14. Efficient retina formation requires suppression of both Activin and BMP signaling pathways in pluripotent cells

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    Kimberly A. Wong

    2015-03-01

    Full Text Available Retina formation requires the correct spatiotemporal patterning of key regulatory factors. While it is known that repression of several signaling pathways lead to specification of retinal fates, addition of only Noggin, a known BMP antagonist, can convert pluripotent Xenopus laevis animal cap cells to functional retinal cells. The aim of this study is to determine the intracellular molecular events that occur during this conversion. Surprisingly, blocking BMP signaling alone failed to mimic Noggin treatment. Overexpressing Noggin in pluripotent cells resulted in a concentration-dependent suppression of both Smad1 and Smad2 phosphorylation, which act downstream of BMP and Activin signaling, respectively. This caused a decrease in downstream targets: endothelial marker, xk81, and mesodermal marker, xbra. We treated pluripotent cells with dominant-negative receptors or the chemical inhibitors, dorsomorphin and SB431542, which each target either the BMP or Activin signaling pathway. We determined the effect of these treatments on retina formation using the Animal Cap Transplant (ACT assay; in which treated pluripotent cells were transplanted into the eye field of host embryos. We found that inhibition of Activin signaling, in the presence of BMP signaling inhibition, promotes efficient retinal specification in Xenopus tissue, mimicking the affect of adding Noggin alone. In whole embryos, we found that the eye field marker, rax, expanded when adding both dominant-negative Smad1 and Smad2, as did treating the cells with both dorsomorphin and SB431542. Future studies could translate these findings to a mammalian culture assay, in order to more efficiently produce retinal cells in culture.

  15. Low-intensity pulsed ultrasound accelerates tooth movement via activation of the BMP-2 signaling pathway.

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    Hui Xue

    Full Text Available The present study was designed to determine the underlying mechanism of low-intensity pulsed ultrasound (LIPUS induced alveolar bone remodeling and the role of BMP-2 expression in a rat orthodontic tooth movement model. Orthodontic appliances were placed between the homonymy upper first molars and the upper central incisors in rats under general anesthesia, followed by daily 20-min LIPUS or sham LIPUS treatment beginning at day 0. Tooth movement distances and molecular changes were evaluated at each observation point. In vitro and in vivo studies were conducted to detect HGF (Hepatocyte growth factor/Runx2/BMP-2 signaling pathways and receptor activator of NFκB ligand (RANKL expression by quantitative real time PCR (qRT-PCR, Western blot and immunohistochemistry. At day 3, LIPUS had no effect on the rat orthodontic tooth movement distance and BMP-2-induced alveolar bone remodeling. However, beginning at day 5 and for the following time points, LIPUS significantly increased orthodontic tooth movement distance and BMP-2 signaling pathway and RANKL expression compared with the control group. The qRT-PCR and Western blot data in vitro and in vivo to study BMP-2 expression were consistent with the immunohistochemistry observations. The present study demonstrates that LIPUS promotes alveolar bone remodeling by stimulating the HGF/Runx2/BMP-2 signaling pathway and RANKL expression in a rat orthodontic tooth movement model, and LIPUS increased BMP-2 expression via Runx2 regulation.

  16. The regulation effect of STAT 5 signaling pathway on the cell cycle progression of irradiated KG-1 cells

    International Nuclear Information System (INIS)

    Guo Dehuang; Dong Bo; Luo Qingliang; Wen Gengyun; Mao Bingzhi

    2000-01-01

    The author investigated the role of the JAK/STAT signaling pathway regulating cell cycle progression in the irradiated KG-1 cells. By permanent transfecting the cells with DN-STAT 5 cDNA to block the JAK/STAT signaling pathway and then transient transfecting with cyclin D 1 or cyclin B 1 cDNA, the effects of cyclin D 1 protein and cyclin B 1 protein on the cell cycle progression were examined. Results showed that after irradiation with 8Gy 60 Co rays, the irradiated KG-1 cells transfected with only DN-STAT 5 cDNA can not recover form the G 1 arrest, even though GM-CSF was added. Meanwhile, the cells transfected with both the DN-STAT 5 cDNA and cyclin D 1 cDNA or cyclin B 1 cDNA can recover from the G 1 arrest or the G 2 arrest to a great extent. Thus, it was proved indirectly that the JAK/STAT signaling pathway activated by GM-CSF regulated the cell cycle progression through cyclin D 1 and cyclin B 1 protein

  17. The Role of MAPK and Dopaminergic Synapse Signaling Pathways in Antidepressant Effect of Electroacupuncture Pretreatment in Chronic Restraint Stress Rats

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    Xinjing Yang

    2017-01-01

    Full Text Available Acupuncture has demonstrated the function in ameliorating depressive-like behaviors via modulating PKA/CREB signaling pathway. To further confirm the antidepressant mechanism of EA on the mitogen-activated protein kinase (MAPK and dopaminergic synapse signaling pathways, 4 target proteins were detected based on our previous iTRAQ analysis. Rats were randomly divided into control group, model group, and electroacupuncture (EA group. Except for the control group, all rats were subjected to 28 days of chronic restraint stress (CRS protocols to induce depression. In the EA group, EA pretreatment at Baihui (GV20 and Yintang (GV29 was performed daily (1 mA, 2 Hz, discontinuous wave, 20 minutes prior to restraint. The antidepressant-like effect of EA was measured by body weight and open-field test. The protein levels of DAT, Th, Mapt, and Prkc in the hippocampus were examined by using Western blot. The results showed EA could ameliorate the depression-like behaviors and regulate the expression levels of Prkc and Mapt in CRS rats. The effect of EA on DAT and Th expression was minimal. These findings implied that EA pretreatment could alleviate depression through modulating MAPK signaling pathway. The role of EA on dopaminergic synapse signaling pathways needs to be further explored.

  18. Modeling of the Dorsal Gradient across Species Reveals Interaction between Embryo Morphology and Toll Signaling Pathway during Evolution

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    Koslen, Hannah R.; Chiel, Hillel J.; Mizutani, Claudia Mieko

    2014-01-01

    Morphogenetic gradients are essential to allocate cell fates in embryos of varying sizes within and across closely related species. We previously showed that the maternal NF-κB/Dorsal (Dl) gradient has acquired different shapes in Drosophila species, which result in unequally scaled germ layers along the dorso-ventral axis and the repositioning of the neuroectodermal borders. Here we combined experimentation and mathematical modeling to investigate which factors might have contributed to the fast evolutionary changes of this gradient. To this end, we modified a previously developed model that employs differential equations of the main biochemical interactions of the Toll (Tl) signaling pathway, which regulates Dl nuclear transport. The original model simulations fit well the D. melanogaster wild type, but not mutant conditions. To broaden the applicability of this model and probe evolutionary changes in gradient distributions, we adjusted a set of 19 independent parameters to reproduce three quantified experimental conditions (i.e. Dl levels lowered, nuclear size and density increased or decreased). We next searched for the most relevant parameters that reproduce the species-specific Dl gradients. We show that adjusting parameters relative to morphological traits (i.e. embryo diameter, nuclear size and density) alone is not sufficient to reproduce the species Dl gradients. Since components of the Tl pathway simulated by the model are fast-evolving, we next asked which parameters related to Tl would most effectively reproduce these gradients and identified a particular subset. A sensitivity analysis reveals the existence of nonlinear interactions between the two fast-evolving traits tested above, namely the embryonic morphological changes and Tl pathway components. Our modeling further suggests that distinct Dl gradient shapes observed in closely related melanogaster sub-group lineages may be caused by similar sequence modifications in Tl pathway components, which

  19. Evolution of multiple phosphodiesterase isoforms in stickleback involved in cAMP signal transduction pathway.

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    Sato, Yukuto; Hashiguchi, Yasuyuki; Nishida, Mutsumi

    2009-02-20

    Duplicate genes are considered to have evolved through the partitioning of ancestral functions among duplicates (subfunctionalization) and/or the acquisition of novel functions from a beneficial mutation (neofunctionalization). Additionally, an increase in gene dosage resulting from duplication may also confer an advantageous effect, as has been suggested for histone, tRNA, and rRNA genes. Currently, there is little understanding of the effect of increased gene dosage on subcellular networks like signal transduction pathways. Addressing this issue may provide further insights into the evolution by gene duplication. We analyzed the evolution of multiple stickleback phosphodiesterase (PDE, EC: 3.1.4.17) 1C genes involved in the cyclic nucleotide signaling pathway. Stickleback has 8-9 copies of this gene, whereas only one or two loci exist in other model vertebrates. Our phylogenetic and synteny analyses suggested that the multiple PDE1C genes in stickleback were generated by repeated duplications of >100-kbp chromosome segments. Sequence evolution analysis did not provide strong evidence for neofunctionalization in the coding sequences of stickleback PDE1C isoforms. On the other hand, gene expression analysis suggested that the derived isoforms acquired expression in new organs, implying their neofunctionalization in terms of expression patterns. In addition, at least seven isoforms of the stickleback PDE1C were co-expressed with olfactory-type G-proteins in the nose, suggesting that PDE1C dosage is increased in the stickleback olfactory transduction (OT) pathway. In silico simulations of OT implied that the increased PDE1C dosage extends the longevity of the depolarization signals of the olfactory receptor neuron. The predicted effect of the increase in PDE1C products on the OT pathway may play an important role in stickleback behavior and ecology. However, this possibility should be empirically examined. Our analyses imply that an increase in gene product sometimes

  20. Evolution of multiple phosphodiesterase isoforms in stickleback involved in cAMP signal transduction pathway

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    Nishida Mutsumi

    2009-02-01

    Full Text Available Abstract Background Duplicate genes are considered to have evolved through the partitioning of ancestral functions among duplicates (subfunctionalization and/or the acquisition of novel functions from a beneficial mutation (neofunctionalization. Additionally, an increase in gene dosage resulting from duplication may also confer an advantageous effect, as has been suggested for histone, tRNA, and rRNA genes. Currently, there is little understanding of the effect of increased gene dosage on subcellular networks like signal transduction pathways. Addressing this issue may provide further insights into the evolution by gene duplication. Results We analyzed the evolution of multiple stickleback phosphodiesterase (PDE, EC: 3.1.4.17 1C genes involved in the cyclic nucleotide signaling pathway. Stickleback has 8–9 copies of this gene, whereas only one or two loci exist in other model vertebrates. Our phylogenetic and synteny analyses suggested that the multiple PDE1C genes in stickleback were generated by repeated duplications of >100-kbp chromosome segments. Sequence evolution analysis did not provide strong evidence for neofunctionalization in the coding sequences of stickleback PDE1C isoforms. On the other hand, gene expression analysis suggested that the derived isoforms acquired expression in new organs, implying their neofunctionalization in terms of expression patterns. In addition, at least seven isoforms of the stickleback PDE1C were co-expressed with olfactory-type G-proteins in the nose, suggesting that PDE1C dosage is increased in the stickleback olfactory transduction (OT pathway. In silico simulations of OT implied that the increased PDE1C dosage extends the longevity of the depolarization signals of the olfactory receptor neuron. Conclusion The predicted effect of the increase in PDE1C products on the OT pathway may play an important role in stickleback behavior and ecology. However, this possibility should be empirically examined. Our