WorldWideScience

Sample records for cell signal transduction

  1. Cell cycle and cell signal transduction in marine phytoplankton

    Institute of Scientific and Technical Information of China (English)

    LIU Jingwen; JIAO Nianzhi; CAI Huinong

    2006-01-01

    As unicellular phytoplankton, the growth of a marine phytoplankton population results directly from the completion of a cell cycle, therefore, cell-environment communication is an important way which involves signal transduction pathways to regulate cell cycle progression and contribute to growth, metabolism and primary production and respond to their surrounding environment in marine phytoplankton. Cyclin-CDK and CaM/Ca2+ are essentially key regulators in control of cell cycle and signal transduction pathway, which has important values on both basic research and applied biotechnology. This paper reviews progress made in this research field, which involves the identification and characterization of cyclins and cell signal transduction system, cell cycle control mechanisms in marine phytoplankton cells, cell cycle proteins as a marker of a terminal event to estimate the growth rate of phytoplankton at the species level, cell cycle-dependent toxin production of toxic algae and cell cycle progression regulated by environmental factors.

  2. Modeling Signal Transduction and Lipid Rafts in Immune Cells

    Science.gov (United States)

    Prasad, Ashok

    2011-03-01

    Experimental evidence increasingly suggests that lipid rafts are nanometer sized cholesterol dependent dynamic assemblies enriched in sphingolipids and associated proteins. Lipid rafts are dynamic structures that break-up and reform on a relatively short time-scale, and are believed to facilitate the interactions of raft-associated proteins. The role of these rafts in signaling has been controversial, partly due to controversies regarding the existence and nature of the rafts themselves. Experimental evidence has indicated that in several cell types, especially T cells, rafts do influence signal transduction and T cell activation. Given the emerging consensus on the biophysical character of lipid rafts, the question can be asked as to what roles they possibly play in signal transduction. Here we carry out simulations of minimal models of the signal transduction network that regulates Src-family kinase dynamics in T cells and other cell types. By separately treating raft-based biochemical interactions, we find that rafts can indeed putatively play an important role in signal transduction, and in particular may affect the sensitivity of signal transduction. This illuminates possible functional consequences of membrane heterogeneities on signal transduction and points towards mechanisms for spatial control of signaling by cells.

  3. Diffusion wave and signal transduction in biological live cells

    CERN Document Server

    Fan, Tian You

    2012-01-01

    Transduction of mechanical stimuli into biochemical signals is a fundamental subject for cell physics. In the experiments of FRET signal in cells a wave propagation in nanoscope was observed. We here develop a diffusion wave concept and try to give an explanation to the experimental observation. The theoretical prediction is in good agreement to result of the experiment.

  4. MAPK Cascades in Guard Cell Signal Transduction

    Science.gov (United States)

    Lee, Yuree; Kim, Yun Ju; Kim, Myung-Hee; Kwak, June M.

    2016-01-01

    Guard cells form stomata on the epidermis and continuously respond to endogenous and environmental stimuli to fine-tune the gas exchange and transpirational water loss, processes which involve mitogen-activated protein kinase (MAPK) cascades. MAPKs form three-tiered kinase cascades with MAPK kinases and MAPK kinase kinases, by which signals are transduced to the target proteins. MAPK cascade genes are highly conserved in all eukaryotes, and they play crucial roles in myriad developmental and physiological processes. MAPK cascades function during biotic and abiotic stress responses by linking extracellular signals received by receptors to cytosolic events and gene expression. In this review, we highlight recent findings and insights into MAPK-mediated guard cell signaling, including the specificity of MAPK cascades and the remaining questions. PMID:26904052

  5. MAPK cascades in guard cell signal transduction

    Directory of Open Access Journals (Sweden)

    Yuree eLee

    2016-02-01

    Full Text Available Guard cells form stomata on the epidermis and continuously respond to endogenous and environmental stimuli to fine-tune the gas exchange and transpirational water loss, processes which involve mitogen-activated protein kinase (MAPK cascades. MAPKs form three-tiered kinase cascades with MAPK kinases and MAPK kinase kinases, by which signals are transduced to the target proteins. MAPK cascade genes are highly conserved in all eukaryotes, and they play crucial roles in myriad developmental and physiological processes. MAPK cascades function during biotic and abiotic stress responses by linking extracellular signals received by receptors to cytosolic events and gene expression. In this review, we highlight recent findings and insights into MAPK-mediated guard cell signaling, including the specificity of MAPK cascades and the remaining questions.

  6. Molecular signal transduction in vascular cell apoptosis

    Institute of Scientific and Technical Information of China (English)

    2001-01-01

    Apoptosis is a form of genetically programmed cell death, which plays a key role in regulation of cellularity in a variety of tissue and cell types including the cardiovascular tissues. Under both physiological and pathophysiological conditions, various biophysiological and biochemical factors, including mechanical forces, reactive oxygen and nitrogen species, cytokines, growth factors, oxidized lipoproteins, etc., may influence apoptosis of vascular cells. The Fas/Fas ligand/caspase death-signaling pathway, Bcl-2 protein family/mitochondria, the tumor suppressive gene p53, and the proto-oncogene c-myc may be activated in atherosclerotic lesions, and mediates vascular apoptosis during the development of atherosclerosis. Abnormal expression and dysfunction of these apoptosis-regulating genes may attenuate or accelerate vascular cell apoptosis and affect the integrity and stability of atherosclerotic plaques. Clarification of the molecular mechanism that regulates apoptosis may help design a new strategy for treatment of atherosclerosis and its major complication, the acute vascular syndromes.

  7. Hypergravity signal transduction and gene expression in cultured mammalian cells

    Science.gov (United States)

    Kumei, Y.; Whitson, P. A.

    1994-01-01

    A number of studies have been conducted during space flight and with clinostats and centrifuges, suggesting that gravity effects the proliferation and differentiation of mammalian cells in vitro. However, little is known about the mechanisms by which mammalian cells respond to changes in gravitational stress. This paper summarizes studies designed to clarify the effects of hypergravity on the cultured human HeLa cells and to investigate the mechanism of hypergravity signal transduction in these cells.

  8. Key cancer cell signal transduction pathways as therapeutic targets.

    Science.gov (United States)

    Bianco, Roberto; Melisi, Davide; Ciardiello, Fortunato; Tortora, Giampaolo

    2006-02-01

    Growth factor signals are propagated from the cell surface, through the action of transmembrane receptors, to intracellular effectors that control critical functions in human cancer cells, such as differentiation, growth, angiogenesis, and inhibition of cell death and apoptosis. Several kinases are involved in transduction pathways via sequential signalling activation. These kinases include transmembrane receptor kinases (e.g., epidermal growth factor receptor EGFR); or cytoplasmic kinases (e.g., PI3 kinase). In cancer cells, these signalling pathways are often altered and results in a phenotype characterized by uncontrolled growth and increased capability to invade surrounding tissue. Therefore, these crucial transduction molecules represent attractive targets for cancer therapy. This review will summarize current knowledge of key signal transduction pathways, that are altered in cancer cells, as therapeutic targets for novel selective inhibitors. The most advanced targeted agents currently under development interfere with function and expression of several signalling molecules, including the EGFR family; the vascular endothelial growth factor and its receptors; and cytoplasmic kinases such as Ras, PI3K and mTOR.

  9. Gravity perception and signal transduction in single cells

    Science.gov (United States)

    Block, I.; Wolke, A.; Briegleb, W.; Ivanova, K.

    Cellular signal processing in multi-, as well as in unicellular organisms, has to rely on fundamentally similar mechanisms. Free-living single cells often use the gravity vector for their spatial orientation (gravitaxis) and show distinct gravisensitivities. In this investigation the gravisensitive giant ameboid cell Physarum polycephalum (Myxomycetes, acellular slime molds) is used. Its gravitaxis and the modulation of its intrinsic rhythmic contraction activity by gravity was demonstrated in 180 °turn experiments and in simulated, as well as in actual, near-weightlessness studies (fast-rotating clinostat; Spacelab D1, IML-1). The stimulus perception was addressed in an IML-2 experiment, which provided information on the gravireceptor itself by the determination of the cell's acceleration-sensitivity threshold. Ground-based experiments designed to elucidate the subsequent steps in signal transduction leading to a motor response, suggest that an acceleration stimulus induces changes in the level of second messenger, adenosine 3',5'-cyclic monophosphate (cAMP), indicating also that the acceleration-stimulus signal transduction chain of Physarum uses an ubiquitous second messenger pathway.

  10. Solar ultraviolet radiation as a trigger of cell signal transduction

    International Nuclear Information System (INIS)

    Ultraviolet light radiation in sunlight is known to cause major alterations in growth and differentiation patterns of exposed human tissues. The specific effects depend on the wavelengths and doses of the light, and the nature of the exposed tissue. Both growth inhibition and proliferation are observed, as well as inflammation and immune suppression. Whereas in the clinical setting, these responses may be beneficial, for example, in the treatment of psoriasis and atopic dermatitis, as an environmental toxicant, ultraviolet light can induce significant tissue damage. Thus, in the eye, ultraviolet light causes cataracts, while in the skin, it induces premature aging and the development of cancer. Although ultraviolet light can damage many tissue components including membrane phospholipids, proteins, and nucleic acids, it is now recognized that many of its cellular effects are due to alterations in growth factor- and cytokine-mediated signal transduction pathways leading to aberrant gene expression. It is generally thought that reactive oxygen intermediates are mediators of some of the damage induced by ultraviolet light. Generated when ultraviolet light is absorbed by endogenous photosensitizers in the presence of molecular oxygen, reactive oxygen intermediates and their metabolites induce damage by reacting with cellular electrophiles, some of which can directly initiate cell signaling processes. In an additional layer of complexity, ultraviolet light-damaged nucleic acids initiate signaling during the activation of repair processes. Thus, mechanisms by which solar ultraviolet radiation triggers cell signal transduction are multifactorial. The present review summarizes some of the mechanisms by which ultraviolet light alters signaling pathways as well as the genes important in the beneficial and toxic effects of ultraviolet light

  11. Signal transduction in cells of the immune system in microgravity

    Directory of Open Access Journals (Sweden)

    Huber Kathrin

    2008-10-01

    Full Text Available Abstract Life on Earth developed in the presence and under the constant influence of gravity. Gravity has been present during the entire evolution, from the first organic molecule to mammals and humans. Modern research revealed clearly that gravity is important, probably indispensable for the function of living systems, from unicellular organisms to men. Thus, gravity research is no more or less a fundamental question about the conditions of life on Earth. Since the first space missions and supported thereafter by a multitude of space and ground-based experiments, it is well known that immune cell function is severely suppressed in microgravity, which renders the cells of the immune system an ideal model organism to investigate the influence of gravity on the cellular and molecular level. Here we review the current knowledge about the question, if and how cellular signal transduction depends on the existence of gravity, with special focus on cells of the immune system. Since immune cell function is fundamental to keep the organism under imnological surveillance during the defence against pathogens, to investigate the effects and possible molecular mechanisms of altered gravity is indispensable for long-term space flights to Earth Moon or Mars. Thus, understanding the impact of gravity on cellular functions on Earth will provide not only important informations about the development of life on Earth, but also for therapeutic and preventive strategies to cope successfully with medical problems during space exploration.

  12. Sensors and signal transduction pathways in vertebrate cell volume regulation

    DEFF Research Database (Denmark)

    Hoffmann, Else K; Pedersen, Stine F

    2006-01-01

    to the identification of transporter binding partners such as protein kinases and phosphatases, cytoskeletal elements and lipids. Considerable progress has also been made recently in understanding the upstream elements in volume sensing and volume-sensitive signal transduction, and salient features of these systems...

  13. Signal transduction events in aluminum-induced cell death in tomato suspension cells

    NARCIS (Netherlands)

    Iakimova, E.T.; Kapchina-Toteva, V.M.; Woltering, E.J.

    2007-01-01

    In this study, some of the signal transduction events involved in AlCl3-induced cell death in tomato (Lycopersicon esculentum Mill.) suspension cells were elucidated. Cells treated with 100 ¿M AlCl3 showed typical features of programmed cell death (PCD) such as nuclear and cytoplasmic condensation.

  14. Signal Transduction at the Single-Cell Level: Approaches to Study the Dynamic Nature of Signaling Networks.

    Science.gov (United States)

    Handly, L Naomi; Yao, Jason; Wollman, Roy

    2016-09-25

    Signal transduction, or how cells interpret and react to external events, is a fundamental aspect of cellular function. Traditional study of signal transduction pathways involves mapping cellular signaling pathways at the population level. However, population-averaged readouts do not adequately illuminate the complex dynamics and heterogeneous responses found at the single-cell level. Recent technological advances that observe cellular response, computationally model signaling pathways, and experimentally manipulate cells now enable studying signal transduction at the single-cell level. These studies will enable deeper insights into the dynamic nature of signaling networks.

  15. Integrins mediating bone signal transduction

    Institute of Scientific and Technical Information of China (English)

    HE Chuanglong; WANG Yuanliang; YANG Lihua; ZHANG Jun

    2004-01-01

    Integrin-mediated adhesions play critical roles in diverse cell functions. Integrins offers a platform on which mechanical stimuli, cytoskeletal organization, biochemical signals can concentrate. Mechanical stimuli transmitted by integrins influence the cytoskeleton, in turn, the cytoskeleton influences cell adhesion via integrins, then cell adhesion results in a series of signal transduction cascades. In skeleton, integrins also have a key role for bone resoption by osteoclasts and reformation by osteoblasts. In present review, the proteins involved in integrin signal transduction and integrin signal transduction pathways were discussed, mainly on the basic mechanisms of integrin signaling and the roles of integrins in bone signal transduction, which may give insight into new therapeutic agents to all kinds of skeletal diseases and new strategies for bone tissue engineering.

  16. Image informatics for studying signal transduction in cells interacting with 3D matrices

    Science.gov (United States)

    Tzeranis, Dimitrios S.; Guo, Jin; Chen, Chengpin; Yannas, Ioannis V.; Wei, Xunbin; So, Peter T. C.

    2014-03-01

    Cells sense and respond to chemical stimuli on their environment via signal transduction pathways, complex networks of proteins whose interactions transmit chemical information. This work describes an implementation of image informatics, imaging-based methodologies for studying signal transduction networks. The methodology developed focuses on studying signal transduction networks in cells that interact with 3D matrices. It utilizes shRNA-based knock down of network components, 3D high-content imaging of cells inside the matrix by spectral multi-photon microscopy, and single-cell quantification using features that describe both cell morphology and cell-matrix adhesion pattern. The methodology is applied in a pilot study of TGFβ signaling via the SMAD pathway in fibroblasts cultured inside porous collagen-GAG scaffolds, biomaterials similar to the ones used clinically to induce skin regeneration. Preliminary results suggest that knocking down all rSMAD components affects fibroblast response to TGFβ1 and TGFβ3 isoforms in different ways, and suggest a potential role for SMAD1 and SMAD5 in regulating TGFβ isoform response. These preliminary results need to be verified with proteomic results that can provide solid evidence about the particular role of individual components of the SMAD pathway.

  17. Osmotin, a plant antifungal protein, subverts signal transduction to enhance fungal cell susceptibility.

    Science.gov (United States)

    Yun, D J; Ibeas, J I; Lee, H; Coca, M A; Narasimhan, M L; Uesono, Y; Hasegawa, P M; Pardo, J M; Bressan, R A

    1998-05-01

    The plant pathogenesis-related protein osmotin is an antifungal cytotoxic agent that causes rapid cell death in the yeast S. cerevisiae. We show here that osmotin uses a signal transduction pathway to weaken defensive cell wall barriers and increase its cytotoxic efficacy. The pathway activated by osmotin includes the regulatory elements of the mating pheromone response STE4, STE18, STE20, STE5, STE11, STE7, FUS3, KSS1, and STE12. Neither the pheromone receptor nor its associated G protein alpha subunit GPA1 are required for osmotin action. However, mutation of SST2, a negative regulator of G alpha proteins, resulted in supersensitivity to osmotin. Phosphorylation of STE7 was rapidly stimulated by osmotin preceding any changes in cell vitality or morphology. These results demonstrate that osmotin subverts target cell signal transduction as part of its mechanism of action. PMID:9660964

  18. Predicting essential components of signal transduction networks: a dynamic model of guard cell abscisic acid signaling.

    Directory of Open Access Journals (Sweden)

    Song Li

    2006-10-01

    Full Text Available Plants both lose water and take in carbon dioxide through microscopic stomatal pores, each of which is regulated by a surrounding pair of guard cells. During drought, the plant hormone abscisic acid (ABA inhibits stomatal opening and promotes stomatal closure, thereby promoting water conservation. Dozens of cellular components have been identified to function in ABA regulation of guard cell volume and thus of stomatal aperture, but a dynamic description is still not available for this complex process. Here we synthesize experimental results into a consistent guard cell signal transduction network for ABA-induced stomatal closure, and develop a dynamic model of this process. Our model captures the regulation of more than 40 identified network components, and accords well with previous experimental results at both the pathway and whole-cell physiological level. By simulating gene disruptions and pharmacological interventions we find that the network is robust against a significant fraction of possible perturbations. Our analysis reveals the novel predictions that the disruption of membrane depolarizability, anion efflux, actin cytoskeleton reorganization, cytosolic pH increase, the phosphatidic acid pathway, or K(+ efflux through slowly activating K(+ channels at the plasma membrane lead to the strongest reduction in ABA responsiveness. Initial experimental analysis assessing ABA-induced stomatal closure in the presence of cytosolic pH clamp imposed by the weak acid butyrate is consistent with model prediction. Simulations of stomatal response as derived from our model provide an efficient tool for the identification of candidate manipulations that have the best chance of conferring increased drought stress tolerance and for the prioritization of future wet bench analyses. Our method can be readily applied to other biological signaling networks to identify key regulatory components in systems where quantitative information is limited.

  19. The merged basins of signal transduction pathways in spatiotemporal cell biology.

    Science.gov (United States)

    Hou, Yingchun; Hou, Yang; He, Siyu; Ma, Caixia; Sun, Mengyao; He, Huimin; Gao, Ning

    2014-03-01

    Numerous evidences have indicated that a signal system is composed by signal pathways, each pathway is composed by sub-pathways, and the sub-pathway is composed by the original signal terminals initiated with a protein/gene. We infer the terminal signals merged signal transduction system as "signal basin". In this article, we discussed the composition and regulation of signal basins, and the relationship between the signal basin control and triple W of spatiotemporal cell biology. Finally, we evaluated the importance of the systemic regulation to gene expression by signal basins under triple W. We hope our discussion will be the beginning to cause the attention for this area from the scientists of life science.

  20. CD28 and T cell antigen receptor signal transduction coordinately regulate interleukin 2 gene expression in response to superantigen stimulation

    OpenAIRE

    1992-01-01

    Activation of an immune response requires intercellular contact between T lymphocytes and antigen-presenting cells (APC). Interaction of the T cell antigen receptor (TCR) with antigen in the context of major histocompatibility molecules mediates signal transduction, but T cell activation appears to require the induction of a second costimulatory signal transduction pathway. Recent studies suggest that interaction of CD28 with B7 on APC might deliver such a costimulatory signal. To investigate...

  1. Mitochondria-derived hydrogen peroxide selectively enhances T cell receptor-initiated signal transduction.

    Science.gov (United States)

    Gill, Tejpal; Levine, Alan D

    2013-09-01

    T cell receptor (TCR)-initiated signal transduction is reported to increase production of intracellular reactive oxygen species, such as superoxide (O2˙(-)) and hydrogen peroxide (H2O2), as second messengers. Although H2O2 can modulate signal transduction by inactivating protein phosphatases, the mechanism and the subcellular localization of intracellular H2O2 as a second messenger of the TCR are not known. The antioxidant enzyme superoxide dismutase (SOD) catalyzes the dismutation of highly reactive O2˙(-) into H2O2 and thus acts as an intracellular generator of H2O2. As charged O2˙(-) is unable to diffuse through intracellular membranes, cells express distinct SOD isoforms in the cytosol (Cu,Zn-SOD) and mitochondria (Mn-SOD), where they locally scavenge O2˙(-) leading to production of H2O2. A 2-fold organelle-specific overexpression of either SOD in Jurkat T cell lines increases intracellular production of H2O2 but does not alter the levels of intracellular H2O2 scavenging enzymes such as catalase, membrane-bound peroxiredoxin1 (Prx1), and cytosolic Prx2. We report that overexpression of Mn-SOD enhances tyrosine phosphorylation of TCR-associated membrane proximal signal transduction molecules Lck, LAT, ZAP70, PLCγ1, and SLP76 within 1 min of TCR cross-linking. This increase in mitochondrial H2O2 specifically modulates MAPK signaling through the JNK/cJun pathway, whereas overexpressing Cu,Zn-SOD had no effect on any of these TCR-mediated signaling molecules. As mitochondria translocate to the immunological synapse during TCR activation, we hypothesize this translocation provides the effective concentration of H2O2 required to selectively modulate downstream signal transduction pathways.

  2. STAT1 is involved in signal transduction in the EPO induced HEL cells

    Institute of Scientific and Technical Information of China (English)

    JIANGCHU; CHANGYUNGUI; 等

    1998-01-01

    Erythropoietin(EPO) is the major regulator of mamalian erythropoisis,which stimulates the growth and differentiation of hematopoietic cells through interaction with its receptor(EPO-R),Here we use HEL cells (a human erythro-leukemia cell line) as a model to elucidate the pathway of signal transduction in the EPO-induced HEL cells.Our data show that the EPOR (EPO receptor) on the surface of HEL cells interacts with the Janus tyrosine protein kinase(Jak2) to transduce intracellular signals through phosphorylation of cytoplasmic proteins in EPO-treated HEL cells.Both STAT1 and STAT5 in this cell line are tyrosine-phosphorylated and translocated to nucleus following the dinding of EPO to HEL cells.Furthermore,the dinding of both STAT1 and STAT5 proteins to specific DNA elements(SIE and PIE elements) is revealed in an EPO-dependent manner,Our data demonstrate that the pathway of signal transduction following the binding of EPO to HEL cells is similar to immature eryhroid cell from the spleen of mice infected with anemia strain of Friend virus.

  3. The signal transduction pathway in the proliferation of airway smooth muscle cells induced by urotensin Ⅱ

    Institute of Scientific and Technical Information of China (English)

    陈亚红; 赵鸣武; 姚婉贞; 庞永政; 唐朝枢

    2004-01-01

    Background Human urotensin Ⅱ (UⅡ) is the most potent mammalian vasoconstrictor identified so far. Our previous study showed that UⅡ is a potent mitogen of airway smooth muscle cells (ASMC) inducing ASMC proliferation in a dose-dependent manner. The signal transduction pathway of UⅡ mitogenic effect remains to be clarified. This study was conducted to investigate the signal transduction pathway in the proliferation of ASMC induced by UⅡ.Methods In primary cultures of rat ASMCs, activities of protein kinase C (PKC), mitogen-activated protein kinase (MAPK) and calcineurin (CaN) induced by UⅡ were measured. The effect of CaN on PKC and MAPK was studied by adding cyclosporin A (CsA), a specific inhibitor of CaN. Using H7 and PD98059, inhibitors of PKC and MAPK, respectively, to study the effect of PKC and MAPK on CaN. The cytosolic free calcium concentration induced by UⅡ was measured using Fura-2/AM. Results UⅡ 10-7 mol/L stimulated ASMC PKC and MAPK activities by 44% and 24% (P0.05). CsA 10-6 mol/L inhibited UⅡ-stimulated PKC activity by 14% (P0.05).Conclusions UⅡ increases cytosolic free calcium concentration and activates PKC, MAPK and CaN. The signal transduction pathway between PKC and CaN has cross-talk.

  4. Reliable Signal Transduction

    Science.gov (United States)

    Wollman, Roy

    Stochasticity inherent to biochemical reactions (intrinsic noise) and variability in cellular states (extrinsic noise) degrade information transmitted through signaling networks. We analyzed the ability of temporal signal modulation - that is dynamics - to reduce noise-induced information loss. In the extracellular signal-regulated kinase (ERK), calcium (Ca(2 +)) , and nuclear factor kappa-B (NF- κB) pathways, response dynamics resulted in significantly greater information transmission capacities compared to nondynamic responses. Theoretical analysis demonstrated that signaling dynamics has a key role in overcoming extrinsic noise. Experimental measurements of information transmission in the ERK network under varying signal-to-noise levels confirmed our predictions and showed that signaling dynamics mitigate, and can potentially eliminate, extrinsic noise-induced information loss. By curbing the information-degrading effects of cell-to-cell variability, dynamic responses substantially increase the accuracy of biochemical signaling networks.

  5. A CRISPR-Based Toolbox for Studying T Cell Signal Transduction

    Science.gov (United States)

    Chi, Shen; Weiss, Arthur; Wang, Haopeng

    2016-01-01

    CRISPR/Cas9 system is a powerful technology to perform genome editing in a variety of cell types. To facilitate the application of Cas9 in mapping T cell signaling pathways, we generated a toolbox for large-scale genetic screens in human Jurkat T cells. The toolbox has three different Jurkat cell lines expressing distinct Cas9 variants, including wild-type Cas9, dCas9-KRAB, and sunCas9. We demonstrated that the toolbox allows us to rapidly disrupt endogenous gene expression at the DNA level and to efficiently repress or activate gene expression at the transcriptional level. The toolbox, in combination with multiple currently existing genome-wide sgRNA libraries, will be useful to systematically investigate T cell signal transduction using both loss-of-function and gain-of-function genetic screens. PMID:27057542

  6. A CRISPR-Based Toolbox for Studying T Cell Signal Transduction

    Directory of Open Access Journals (Sweden)

    Shen Chi

    2016-01-01

    Full Text Available CRISPR/Cas9 system is a powerful technology to perform genome editing in a variety of cell types. To facilitate the application of Cas9 in mapping T cell signaling pathways, we generated a toolbox for large-scale genetic screens in human Jurkat T cells. The toolbox has three different Jurkat cell lines expressing distinct Cas9 variants, including wild-type Cas9, dCas9-KRAB, and sunCas9. We demonstrated that the toolbox allows us to rapidly disrupt endogenous gene expression at the DNA level and to efficiently repress or activate gene expression at the transcriptional level. The toolbox, in combination with multiple currently existing genome-wide sgRNA libraries, will be useful to systematically investigate T cell signal transduction using both loss-of-function and gain-of-function genetic screens.

  7. MAPKs and Signal Transduction in the Control of Gastrointestinal Epithelial Cell Proliferation and Differentiation

    Directory of Open Access Journals (Sweden)

    Luciana H. Osaki

    2013-05-01

    Full Text Available Mitogen-activated protein kinase (MAPK pathways are activated by several stimuli and transduce the signal inside cells, generating diverse responses including cell proliferation, differentiation, migration and apoptosis. Each MAPK cascade comprises a series of molecules, and regulation takes place at different levels. They communicate with each other and with additional pathways, creating a signaling network that is important for cell fate determination. In this review, we focus on ERK, JNK, p38 and ERK5, the major MAPKs, and their interactions with PI3K-Akt, TGFβ/Smad and Wnt/β-catenin pathways. More importantly, we describe how MAPKs regulate cell proliferation and differentiation in the rapidly renewing epithelia that lines the gastrointestinal tract and, finally, we highlight the recent findings on nutritional aspects that affect MAPK transduction cascades.

  8. Signal transduction pathway of nitric oxide inducing PC12 cell death

    Institute of Scientific and Technical Information of China (English)

    2001-01-01

    Objective: To study signal transduction pathway of nitric oxideinducing death of PC12 cells.Methods: Cell survival rate was measured with MTT assay, and caspase-3 activity with caspase-3 assay kits after PC12 cells were incubated with sodium nitroprusside (SNP), caspase-3 inhibitor Ⅱ plus SNP or p38 inhibitor-SB203580 plus SNP.Results: SNP induced death of PC12 cells in dose- and time-dependent manner and enhanced caspase-3 activity gradually. Both caspase-3 inhibitor Ⅱ and SB203580 reduced cell death, but SB203580 reduced caspase-3 activity significantly.Conclusions: NO may induce death of PC12 cells through activation of p38 and caspase-3.

  9. THE TRANSMEMBRANE SIGNAL TRANSDUCTION IN HEp-2 CELLS INDUCED BY BACTERIAL ADHERENCE

    Institute of Scientific and Technical Information of China (English)

    2000-01-01

    @@ In order to understand the role of transmembrane signal transduction of host cells in the early steps of infection,the adherence of E. coli to HEp-2 cells and the change of activity of phospholipase C-γ (PLC-γ) induced by the adherence were investigated.The adherence of enteropathogenic E.coli (EPEC), strain E.7, induced a significant increase of inositol-triphosphat (IP-3) level in HEp-2 cells. The adherence of the bacteria and the increase of IP-3 was kinetically correlated. Whereas the increase of IP3 level induced by the adherence of the control strain EPEC (H511), a non-piliated strain, was much meager than that by E7, a piliated strain. The results highlighted an important role of transmembrane signals like IP-3 in the pathogenesis of EPEC.

  10. Comprehensive analysis of signal transduction in three-dimensional ECM-based tumor cell cultures

    Directory of Open Access Journals (Sweden)

    Iris Eke

    2015-11-01

    Full Text Available Analysis of signal transduction and protein phosphorylation is fundamental to understand physiological and pathological cell behavior as well as identification of novel therapeutic targets. Despite the fact that more physiological three-dimensional cell culture assays are increasingly used, particularly proteomics and phosphoproteomics remain challenging due to easy, robust and reproducible sample preparation. Here, we present an easy-to-perform, reliable and time-efficient method for the production of 3D cell lysates without compromising cell adhesion before cell lysis. The samples can be used for Western blotting as well as phosphoproteome array technology. This technique would be of interest for researchers working in all fields of biology and drug development.

  11. Novel optical methodologies in studying mechanical signal transduction in mammalian cells

    Science.gov (United States)

    Stamatas, G. N.; McIntire, L. V.

    1999-01-01

    For the last 3 decades evidence has been accumulating that some types of mammalian cells respond to their mechanically active environment by altering their morphology, growth rate, and metabolism. The study of such responses is very important in understanding, physiological and pathological conditions ranging from bone formation to atherosclerosis. Obtaining this knowledge has been the goal for an active research area in bioengineering termed cell mechanotransduction. The advancement of optical methodologies used in cell biology research has given the tools to elucidate cellular mechanisms that would otherwise be impossible to visualize. Combined with molecular biology techniques, they give engineers invaluable tools in understanding the chemical pathways involved in mechanotransduction. Herein we briefly review the current knowledge on mechanical signal transduction in mammalian cells, focusing on the application of novel optical techniques in the ongoing research.

  12. The signal transduction pathways and molecules for ES cells self-renewal

    Institute of Scientific and Technical Information of China (English)

    LIU Na; LU Min

    2005-01-01

    Embryonic stem cells (ES cells) are derived from the inner cell mass (ICM) of blastocysts. ES cells can divide and produce identical copies of them over and over again (self-renewal) in vitro for a long time, and retain the capability of differentiating into all cell types when induced by appropriate signals. Their capability of multilineage differentiation might be exploited for cell-based therapies. Therefore, ES cells have a broad prospect in many clinical applications. To achieve success in the clinical applications, we have to understand how ES cells propagate and differentiate into specific cell types. The cytokine LIF can sustain the self-renewal of certain mouse ES cells (mES cells) through activation of the signal transduction pathway LIF/gp130/ STAT3. In this pathway the transcription factor STAT3 is a crucial factor. Furthermore, Oct-3/4 plays a very important role in maintaining the ES cell pluripotency. Oct-3/4 regulates embryo development through its co-factor Sox2 and Rox-1. Recently nanog, a new homeodomain gene, was found and it has been shown to be crucial for the renewal and pluripotency of ES cells. Three other signals BMP, Wnt and ERK also can influence differentiation and propagation of ES cells. This review article summarizes recent progress in this area, mainly focusing on the LIF signaling pathway and the transcription factors Oct-3/4 and Nanog. Although it is still unclear how these components cooperate, a model is presented here to provide a design for solving this problem.

  13. Cellular semiotics and signal transduction

    DEFF Research Database (Denmark)

    Bruni, Luis Emilio

    2007-01-01

    to the processes of sign interpretation and transmission between organisms of the same or different species). In Biosemiotics it is customary to recognise the cell as the most elementary integration unit for semiosis. Therefore intra and intercellular communication constitute the departure point for the study......Semiosis, the processes of production, communication and interpretation of signs - coding and de-coding - takes place within and between organisms. The term "endosemiosis" refers to the processes of interpretation and sign transmission inside an organism (as opposed to "exosemiosis", which refers...... considering semiotic logic in order to construct our understanding of living phenomena. Given the central integrating role of signal transduction in physiological and ecological studies, this chapter outlines its semiotic implications. The multi-modality and modularity of signal molecules and relative...

  14. Real-time monitoring of intracellular signal transduction in PC12 cells by non-adiabatic tapered optical fiber biosensor

    Science.gov (United States)

    Zibaii, M. I.; Latifi, H.; Asadollahi, A.; Noraeipoor, Z.; Dargahi, L.

    2014-05-01

    Real-time observation of intracellular process of signal transduction is very useful for biomedical and pharmaceutical applications as well as for basic research work of cell biology. For feasible and reagentless observation of intracellular alterations in real time, we examined the use of a nonadiabatic tapered optical fiber (NATOF) biosensor for monitoring of intracellular signal transduction that was mainly translocation of protein kinase C via refractive index change in PC12 cells adhered on tapered fiber sensor without any indicator reagent. PC12 cells were stimulated with KCl . Our results suggest that complex intracellular reactions could be real-time monitored and characterized by NATOF biosensor.

  15. Syntrophin proteins as Santa Claus: role(s) in cell signal transduction.

    Science.gov (United States)

    Bhat, Hina F; Adams, Marvin E; Khanday, Firdous A

    2013-07-01

    Syntrophins are a family of cytoplasmic membrane-associated adaptor proteins, characterized by the presence of a unique domain organization comprised of a C-terminal syntrophin unique (SU) domain and an N-terminal pleckstrin homology (PH) domain that is split by insertion of a PDZ domain. Syntrophins have been recognized as an important component of many signaling events, and they seem to function more like the cell's own personal 'Santa Claus' that serves to 'gift' various signaling complexes with precise proteins that they 'wish for', and at the same time care enough for the spatial, temporal control of these signaling events, maintaining overall smooth functioning and general happiness of the cell. Syntrophins not only associate various ion channels and signaling proteins to the dystrophin-associated protein complex (DAPC), via a direct interaction with dystrophin protein but also serve as a link between the extracellular matrix and the intracellular downstream targets and cell cytoskeleton by interacting with F-actin. They play an important role in regulating the postsynaptic signal transduction, sarcolemmal localization of nNOS, EphA4 signaling at the neuromuscular junction, and G-protein mediated signaling. In our previous work, we reported a differential expression pattern of alpha-1-syntrophin (SNTA1) protein in esophageal and breast carcinomas. Implicated in several other pathologies, like cardiac dys-functioning, muscular dystrophies, diabetes, etc., these proteins provide a lot of scope for further studies. The present review focuses on the role of syntrophins in membrane targeting and regulation of cellular proteins, while highlighting their relevance in possible development and/or progression of pathologies including cancer which we have recently demonstrated. PMID:23263165

  16. Microgravity-induced alterations in signal transduction in cells of the immune system

    Science.gov (United States)

    Paulsen, Katrin; Thiel, Cora; Timm, Johanna; Schmidt, Peter M.; Huber, Kathrin; Tauber, Svantje; Hemmersbach, Ruth; Seibt, Dieter; Kroll, Hartmut; Grote, Karl-Heinrich; Zipp, Frauke; Schneider-Stock, Regine; Cogoli, Augusto; Hilliger, Andre; Engelmann, Frank; Ullrich, Oliver

    2010-11-01

    Since decades it is known that the activity of cells of the immune system is severely dysregulated in microgravity, however, the underlying molecular aspects have not been elucidated yet. The identification of gravity-sensitive molecular mechanisms in cells of the immune system is an important and indispensable prerequisite for the development of counteractive measures to prevent or treat disturbed immune cell function of astronauts during long-term space missions. Moreover, their sensitivity to altered gravity renders immune cells an ideal model system to understand if and how gravity on Earth is required for normal mammalian cell function and signal transduction. We investigated the effect of simulated weightlessness (2D clinostat) and of real microgravity (parabolic flights) on key signal pathways in a human monocytic and a T lymphocyte cell line. We found that cellular responses to microgravity strongly depend on the cell-type and the conditions in which the cells are subjected to microgravity. In Jurkat T cells, enhanced phosphorylation of the MAP kinases ERK-1/2, MEK and p38 and inhibition of nuclear translocation of NF-kB were the predominant responses to simulated weightlessness, in either stimulated or non-stimulated cells. In contrast, non-stimulated monocytic U937 cells responded to simulated weightlessness with enhanced overall tyrosine-phosphorylation and activation of c-jun, whereas PMA-stimulated U937 cells responded the opposite way with reduced tyrosine-phosphorylation and reduced activation of c-jun, compared with PMA-stimulated 1 g controls. P53 protein was phosphorylated rapidly in microgravity. The identification of gravi-sensitive mechanisms in cells of the immune system will not only enable us to understand and prevent the negative effects of long time exposure to microgravity on Astronauts, but could also lead to novel therapeutic targets in general.

  17. Gravitational Effects on Signal Transduction

    Science.gov (United States)

    Sytkowski, Arthur J.

    1999-01-01

    An understanding of the mechanisms by which individual cells perceive gravity and how these cells transduce and respond to gravitational stimuli is critical for the development of long-term manned space flight experiments. We now propose to use a well-characterized model erythroid cell system and to investigate gravitational perturbations of its erythropoietin (Epo) signaling pathway and gene regulation. Cells will be grown at 1-G and in simulated microgravity in the NASA Rotating Wall Vessel bioreactor (RWV). Cell growth and differentiation, the Epo-receptor, the protein kinase C pathway to the c-myc gene, and the protein phosphatase pathway to the c-myb gene will be studied and evaluated as reporters of gravitational stimuli. The results of these experiments will have impact on the problems of 1) gravitational sensing by individual cells, and 2) the anemia of space flight. This ground-based study also will serve as a Space Station Development Study in gravitational effects on intracellular signal transduction.

  18. Signal transduction induced in Trypanosoma cruzi metacyclic trypomastigotes during the invasion of mammalian cells

    Directory of Open Access Journals (Sweden)

    N. Yoshida

    2000-03-01

    Full Text Available Penetration of Trypanosoma cruzi into mammalian cells depends on the activation of the parasite's protein tyrosine kinase and on the increase in cytosolic Ca2+ concentration. We used metacyclic trypomastigotes, the T. cruzi developmental forms that initiate infection in mammalian hosts, to investigate the association of these two events and to identify the various components of the parasite signal transduction pathway involved in host cell invasion. We have found that i both the protein tyrosine kinase activation, as measured by phosphorylation of a 175-kDa protein (p175, and Ca2+ mobilization were induced in the metacyclic forms by the HeLa cell extract but not by the extract of T. cruzi-resistant K562 cells; ii treatment of parasites with the tyrosine kinase inhibitor genistein blocked both p175 phosphorylation and the increase in cytosolic Ca2+ concentration; iii the recombinant protein J18, which contains the full-length sequence of gp82, a metacyclic stage surface glycoprotein involved in target cell invasion, interfered with tyrosine kinase and Ca2+ responses, whereas the monoclonal antibody 3F6 directed at gp82 induced parasite p175 phosphorylation and Ca2+ mobilization; iv treatment of metacyclic forms with phospholipase C inhibitor U73122 blocked Ca2+ signaling and impaired the ability of the parasites to enter HeLa cells, and v drugs such as heparin, a competitive IP3-receptor blocker, caffeine, which affects Ca2+ release from IP3-sensitive stores, in addition to thapsigargin, which depletes intracellular Ca2+ compartments and lithium ion, reduced the parasite infectivity. Taken together, these data suggest that protein tyrosine kinase, phospholipase C and IP3 are involved in the signaling cascade that is initiated on the parasite cell surface by gp82 and leads to Ca2+ mobilization required for target cell invasion.

  19. MMP-1/PAR-1 signal transduction axis and its prognostic impact in esophageal squamous cell carcinoma

    Directory of Open Access Journals (Sweden)

    Hong-hua Peng

    2012-01-01

    Full Text Available The matrix metalloprotease-1 (MMP-1/protease-activated receptor-1 (PAR-1 signal transduction axis plays an important role in tumorigenesis. To explore the expression and prognostic value of MMP-1 and PAR-1 in esophageal squamous cell carcinoma (ESCC, we evaluated the expression of two proteins in resected specimens from 85 patients with ESCC by immunohistochemistry. Sixty-two (72.9% and 58 (68.2% tumors were MMP-1- and PAR-1-positive, respectively, while no significant staining was observed in normal esophageal squamous epithelium. MMP-1 and PAR-1 overexpression was significantly associated with tumor node metastasis (TNM stage and regional lymph node involvement. Patients with MMP-1- and PAR-1-positive tumors, respectively, had poorer disease-free survival (DFS than those with negative ESCC (P = 0.002 and 0.003, respectively. Univariate analysis showed a significant relationship between TNM stage [hazard ratio (HR = 2.836, 95% confidence interval (CI = 1.866-4.308], regional lymph node involvement (HR = 2.955, 95%CI = 1.713-5.068, MMP-1 expression (HR = 2.669, 95%CI = 1.229-6.127, and PAR-1 expression (HR = 1.762, 95%CI = 1.156-2.883 and DFS. Multivariate analysis including the above four parameters identified TNM stage (HR = 2.035, 95%CI = 1.167-3.681, MMP-1 expression (HR = 2.109, 95%CI = 1.293-3.279, and PAR-1 expression (HR = 1.967, 95%CI = 1.256-2.881 as independent and significant prognostic factors for DFS. Our data suggest for the first time that MMP-1 and PAR-1 were both overexpressed in ESCC and are novel predictors of poor patient prognosis after curative resection. The MMP-1/PAR-1 signal transduction axis might be a new therapeutic target for future therapies tailored against ESCC.

  20. MMP-1/PAR-1 signal transduction axis and its prognostic impact in esophageal squamous cell carcinoma

    Energy Technology Data Exchange (ETDEWEB)

    Peng, Hong-hua; Zhang, Xi; Cao, Pei-guo [Department of Oncology, the Third Xiangya Hospital, Central South University, Changsha, Hunan Province (China)

    2011-11-18

    The matrix metalloprotease-1 (MMP-1)/protease-activated receptor-1 (PAR-1) signal transduction axis plays an important role in tumorigenesis. To explore the expression and prognostic value of MMP-1 and PAR-1 in esophageal squamous cell carcinoma (ESCC), we evaluated the expression of two proteins in resected specimens from 85 patients with ESCC by immunohistochemistry. Sixty-two (72.9%) and 58 (68.2%) tumors were MMP-1- and PAR-1-positive, respectively, while no significant staining was observed in normal esophageal squamous epithelium. MMP-1 and PAR-1 overexpression was significantly associated with tumor node metastasis (TNM) stage and regional lymph node involvement. Patients with MMP-1- and PAR-1-positive tumors, respectively, had poorer disease-free survival (DFS) than those with negative ESCC (P = 0.002 and 0.003, respectively). Univariate analysis showed a significant relationship between TNM stage [hazard ratio (HR) = 2.836, 95% confidence interval (CI) = 1.866-4.308], regional lymph node involvement (HR = 2.955, 95%CI = 1.713-5.068), MMP-1 expression (HR = 2.669, 95%CI = 1.229-6.127), and PAR-1 expression (HR = 1.762, 95%CI = 1.156-2.883) and DFS. Multivariate analysis including the above four parameters identified TNM stage (HR = 2.035, 95%CI = 1.167-3.681), MMP-1 expression (HR = 2.109, 95%CI = 1.293-3.279), and PAR-1 expression (HR = 1.967, 95%CI = 1.256-2.881) as independent and significant prognostic factors for DFS. Our data suggest for the first time that MMP-1 and PAR-1 were both overexpressed in ESCC and are novel predictors of poor patient prognosis after curative resection. The MMP-1/PAR-1 signal transduction axis might be a new therapeutic target for future therapies tailored against ESCC.

  1. Lipid Rafts and Signal Transduction of Cell%脂筏与细胞信号转导

    Institute of Scientific and Technical Information of China (English)

    范玉贞

    2011-01-01

    论述了脂筏的组成、结构与功能,脂筏在细胞信号转导正负调控、T细胞的信号转导、精子膜的信号转导过程中的作用及其机制.小窝蛋白及其参与的信号转导过程与葡萄糖运输、糖尿病及其并发症有密切关系.%This article discusses the composition,structure and function of lipid rafts and the mechanism of lipid rafts in signal transduction plus or minus regulation,T cell signal transduction,signal transduction process of sperm membrane.Caveolins and its partic

  2. Gibberellin Signal Transduction in Rice

    Institute of Scientific and Technical Information of China (English)

    Liu-Min Fan; Xiaoyan Feng; Yu Wang; Xing Wang Deng

    2007-01-01

    In the past decade, significant knowledge has accumulated regarding gibberellin (GA) signal transduction in rice as a result of studies using multiple approaches, particularly molecular genetics. The present review highlights the recent developments in the identification of GA signaling pathway components, the discovery of GA-induced destruction of GA signaling represser (DELLA protein), and the possible mechanism underlying the regulation of GA-responsive gene expression in rice.

  3. Inquiry into Chemotherapy-Induced P53 Activation in Cancer Cells as a Model for Teaching Signal Transduction

    Science.gov (United States)

    Srougi, Melissa C.; Carson, Susan

    2013-01-01

    Intracellular and extracellular communication is conducted through an intricate and interwoven network of signal transduction pathways. The mechanisms for how cells speak with one another are of significant biological importance to both basic and industrial scientists from a number of different disciplines. We have therefore developed and…

  4. HLA-DR molecules enhance signal transduction through the CD3/Ti complex in activated T cells

    DEFF Research Database (Denmark)

    Odum, Niels; Martin, P J; Schieven, G L;

    1991-01-01

    Crosslinking HLA-DR molecules by monoclonal antibodies (mAb) induces protein tyrosine phosphorylation and results in a secondary elevation of free cytoplasmic Ca2+ concentration ([Ca2+]i) in activated human T cells. Here we have studied the effect of DR on CD3-induced signal transduction...

  5. Cell surface receptors for signal transduction and ligand transport: a design principles study.

    Directory of Open Access Journals (Sweden)

    Harish Shankaran

    2007-06-01

    Full Text Available Receptors constitute the interface of cells to their external environment. These molecules bind specific ligands involved in multiple processes, such as signal transduction and nutrient transport. Although a variety of cell surface receptors undergo endocytosis, the systems-level design principles that govern the evolution of receptor trafficking dynamics are far from fully understood. We have constructed a generalized mathematical model of receptor-ligand binding and internalization to understand how receptor internalization dynamics encodes receptor function and regulation. A given signaling or transport receptor system represents a particular implementation of this module with a specific set of kinetic parameters. Parametric analysis of the response of receptor systems to ligand inputs reveals that receptor systems can be characterized as being: i avidity-controlled where the response control depends primarily on the extracellular ligand capture efficiency, ii consumption-controlled where the ability to internalize surface-bound ligand is the primary control parameter, and iii dual-sensitivity where both the avidity and consumption parameters are important. We show that the transferrin and low-density lipoprotein receptors are avidity-controlled, the vitellogenin receptor is consumption-controlled, and the epidermal growth factor receptor is a dual-sensitivity receptor. Significantly, we show that ligand-induced endocytosis is a mechanism to enhance the accuracy of signaling receptors rather than merely serving to attenuate signaling. Our analysis reveals that the location of a receptor system in the avidity-consumption parameter space can be used to understand both its function and its regulation.

  6. Meeting Report: Teaching Signal Transduction

    Science.gov (United States)

    Kramer, IJsbrand; Thomas, Geraint

    2006-01-01

    In July, 2005, the European Institute of Chemistry and Biology at the campus of the University of Bordeaux, France, hosted a focused week of seminars, workshops, and discussions around the theme of "teaching signal transduction." The purpose of the summer school was to offer both junior and senior university instructors a chance to reflect on the…

  7. Signal transduction in Plasmodium-Red Blood Cells interactions and in cytoadherence

    Directory of Open Access Journals (Sweden)

    Laura N. Cruz

    2012-06-01

    Full Text Available Malaria is responsible for more than 1.5 million deaths each year, especially among children (Snow et al. 2005. Despite of the severity of malaria situation and great effort to the development of new drug targets (Yuan et al. 2011 there is still a relative low investment toward antimalarial drugs. Briefly there are targets classes of antimalarial drugs currently being tested including: kinases, proteases, ion channel of GPCR, nuclear receptor, among others (Gamo et al. 2010. Here we review malaria signal transduction pathways in Red Blood Cells (RBC as well as infected RBCs and endothelial cells interactions, namely cytoadherence. The last process is thought to play an important role in the pathogenesis of severe malaria. The molecules displayed on the surface of both infected erythrocytes (IE and vascular endothelial cells (EC exert themselves as important mediators in cytoadherence, in that they not only induce structural and metabolic changes on both sides, but also trigger multiple signal transduction processes, leading to alteration of gene expression, with the balance between positive and negative regulation determining endothelial pathology during a malaria infection.A Malária é responsavel por mais de 1.5 milhões de mortes anualmente, especialmente entre crianças (Snow et al. 2005. Apesar da gravidade da situação e grande esforço para o desenvolvimento de novas drogas (Yuan et al. 2011, os investimentos em drogas antimaláricas ainda é relativamente baixo. Brevemente, os alvos antimaláricos atualmente testados incluem: quinases, proteases, canais iônicos para GPCR, receptores nucleares entre outros (Gamo et al. 2010. No presente trabalho nós revisamos as vias de transdução de sinal em eritrócitos assim como eritrócitos infectados e interações com células endoteliais, denominada citoaderência. Este processo é conhecido por sua importante função na patogenicidade da malária severa. As moléculas expressas na superf

  8. Signal transduction factors on the modulation of radiosusceptibility in K562 cells

    Energy Technology Data Exchange (ETDEWEB)

    Yang, Kwang Mo; Jeong, Soo Jin [Korea Institute of Radiological and Medical Sciences, Seoul (Korea, Republic of); Youn, Seon Min [College of Medicine, Eulji Univ., Daejeon (Korea, Republic of)

    2003-09-01

    The human chronic myelogenous leukemia cell line, K562, expresses the chimeric bcr-abl oncoprotein, whose deregulated protein tyrosine kinase activity antagonizes the induction of apoptosis via DNA damaging agents. Previous experiments have shown that nanomolar concentrations of herbimycin A [HMA] coupled with X-irradiation have a synergistic effect in inducing apoptosis in the Ph-positive K562 leukemia cell line, but genistein, a PTK inhibitor, is non selective for the radiation-induced apoptosis of p210{sup bcr}/{sup abl} protected K562 cells. In these experiments, the cytoplasmic signal transduction pathways, the induction of a number of transcription factors and the differential gene expression in this model were investigated. K562 cells in the exponential growth phase were used in this study. The cells were irradiated with 0.5-12 Gy, using a 6 MeV Linac (Clinac 1800, Varian, USA). Immediately after irradiation, the cells were treated with 0.25{mu}M of HMA and 25{mu}M of genistein, and the expressions and the activities of ablkinase, MAPK family, NF-KB, c-fos, c-myc, and thymidine kinase1 (TK1) were examined. The differential gene expressions induced by PTK inhibitors were also investigated. The modulating effects of herbimycin A and genistein on the radiosensitivity of K562 cells were not related to the bcr-abl kinase activity. The signaling responses through the MAPK family of proteins, were not involved either. In association with the radiation-induced apoptosis, which is accelerated by HMA, the expression of c-myc was increased. The combined treatment of genistein, with irradiation, enhanced NF-KB activity and the TK 1 expression and activity. The effects of HMA and genistein on the radiosensitivity of the K562 cells were not related to the bcr-abl kinase activity. In this study, another signaling pathway, besides the MAPK family responses to radiation to K562 cells, was found. Further evaluation using this model will provide valuable information for the

  9. Signal transduction in T lymphocytes in microgravity

    Science.gov (United States)

    Cogoli, A.

    1997-01-01

    More than 120 experiments conducted in space in the last 15 years have shown that dramatic changes are occurring in several types of single cells during their exposure to microgravity. One focus of today's research on cells in space is on signal transduction, especially those steps involving the cytoskeleton and cell-cell interactions. Signal transduction is often altered in microgravity as well as in hypergravity. This leads to changes in cell proliferation, genetic expression and differentiation. Interesting examples are leukocytes, HeLa cells, epidermoid cells and osteoblastic cells. Signalling pathways were studied in T lymphocytes in microgravity by several investigators after the discovery that mitogenic activation in vitro is virtually nil at 0g. T cells are a good model to study signal transduction because three extracellular signals (mitogen, IL-1 and IL-2) are required for full activation, and two classical pathways (via proteins G and PKC) are activated within the cell. In addition, low molecular weight GTP-binding proteins (Ras and Rap) are interacting with the cytoskeleton. The data at 0g support the notion that the expression of IL-2 receptor is inhibited at 0g, while mitogen binding and the transmission of IL-1 by accessory cells occur normally. In addition, alterations of the cytoskeleton suggest that the interaction with Rap proteins is disturbed. Data obtained with phorbol esters indicate that the function of PKC is changed in microgravity. Similar conclusions are drawn from the results with epidermoid cells A431.

  10. Regulation of promyogenic signal transduction by cell-cell contact and adhesion

    Energy Technology Data Exchange (ETDEWEB)

    Krauss, Robert S., E-mail: Robert.Krauss@mssm.edu [Department of Developmental and Regenerative Biology, Mount Sinai School of Medicine, New York, NY 10029 (United States)

    2010-11-01

    Skeletal myoblast differentiation involves acquisition of the muscle-specific transcriptional program and morphological changes, including fusion into multinucleated myofibers. Differentiation is regulated by extracellular signaling cues, including cell-cell contact and adhesion. Cadherin and Ig adhesion receptors have been implicated in distinct but overlapping stages of myogenesis. N-cadherin signals through the Ig receptor Cdo to activate p38 MAP kinase, while the Ig receptor neogenin signals to activate FAK; both processes promote muscle-specific gene expression and myoblast fusion. M-cadherin activates Rac1 to enhance fusion. Specific Ig receptors (Kirre and Sns) are essential for myoblast fusion in Drosophila, also signaling through Rac, and vertebrate orthologs of Kirre and Sns have partially conserved function. Mice lacking specific cytoplasmic signaling factors activated by multiple receptors (e.g., Rac1) have strong muscle phenotypes in vivo. In contrast, mice lacking individual adhesion receptors that lie upstream of these factors have modest phenotypes. Redundancy among receptors may account for this. Many of the mammalian Ig receptors and cadherins associate with each other, and multivalent interactions within these complexes may require removal of multiple components to reveal dramatic defects in vivo. Nevertheless, it is possible that the murine adhesion receptors rate-limiting in vivo have not yet been identified or fully assessed.

  11. Signal transduction by the Fat cytoplasmic domain

    OpenAIRE

    Pan, Guohui; Feng, Yongqiang; Ambegaonkar, Abhijit A.; Sun, Gongping; Huff, Matthew; Rauskolb, Cordelia; Irvine, Kenneth D.

    2013-01-01

    The large atypical cadherin Fat is a receptor for both Hippo and planar cell polarity (PCP) pathways. Here we investigate the molecular basis for signal transduction downstream of Fat by creating targeted alterations within a genomic construct that contains the entire fat locus, and by monitoring and manipulating the membrane localization of the Fat pathway component Dachs. We establish that the human Fat homolog FAT4 lacks the ability to transduce Hippo signaling in Drosophila, but can trans...

  12. The biological networks in studying cell signal transduction complexity: The examples of sperm capacitation and of endocannabinoid system

    OpenAIRE

    Nicola Bernabò; Barbara Barboni; Mauro Maccarrone

    2014-01-01

    Cellular signal transduction is a complex phenomenon, which plays a central role in cell surviving and adaptation. The great amount of molecular data to date present in literature, together with the adoption of high throughput technologies, on the one hand, made available to scientists an enormous quantity of information, on the other hand, failed to provide a parallel increase in the understanding of biological events. In this context, a new discipline arose, the systems biology, aimed to ma...

  13. The ethylene signal transduction pathway in Arabidopsis

    Science.gov (United States)

    Kieber, J. J.; Evans, M. L. (Principal Investigator)

    1997-01-01

    The gaseous hormone ethylene is an important regulator of plant growth and development. Using a simple response of etiolated seedlings to ethylene as a genetic screen, genes involved in ethylene signal transduction have been identified in Arabidopsis. Analysis of two of these genes that have been cloned reveals that ethylene signalling involves a combination of a protein (ETR1) with similarity to bacterial histidine kinases and a protein (CTR1) with similarity to Raf-1, a protein kinase involved in multiple signalling cascades in eukaryotic cells. Several lines of investigation provide compelling evidence that ETR1 encodes an ethylene receptor. For the first time there is a glimpse of the molecular circuitry underlying the signal transduction pathway for a plant hormone.

  14. Effect of proline rich domain of an RNA-binding protein Sam68 in cell growth process, death and B cell signal transduction

    Institute of Scientific and Technical Information of China (English)

    LI Qing-hua; FAN Tian-xue; PANG Tian-xiang; YUAN Wen-su; HAN Zhong-chao

    2006-01-01

    Background Sam68 plays an important role as a multiple functional RNA binding nuclear protein in cell cycle progress, RNA usage, signal transduction, and tyrosine phosphorylation by Src during mitosis. However, its precise impact on these essential cellular functions remains unclear. The purpose of this study is to further elucidate Sam68 functions in RNA metabolism, signal transduction regulation of cell growth and cell proliferation in DT40 cell line.Methods By using gene targeting method, we isolated a mutation form of Sam68 in DT40 cells and described its effect on cell growth process and signal transduction. Southern, Northern, and Western blot, phosphorylation and flow-cytometfic analyses were performed to investigate the Sam68 functions.Results A slower growth rate (2.1 hours growth elongation) and longer S phase (1.7 hours elongation) was observed in the Sam68 mutant cells. Serum depletion resulted in increased amounts of dead cells, and expansion of S phase in mutant cells. Upon B cell cross-linking, the maximal level of tyrosine phosphorylation on BLNK was observed to be significantly lower in mutant cells.Conclusions The proline rich domain of Sam68 is involved in cell growth control by modulating the function of mRNAs in S phase or earlier and the functions as an adaptor molecule in B cell signal transduction pathways.

  15. Brassinosteroid signal transduction: An emerging picture

    Institute of Scientific and Technical Information of China (English)

    WANG Qiaomei; MA Ligeng

    2003-01-01

    Steroid hormones play essential roles in animal growth and development. Steroid signaling in animal system is focused on the direct gene regulation response mediated by its nuclear receptors. Recently, steroid hormones are also found in plants. Identification of BRI1 - a critical component of the plasma-membrane steroid receptor complex, and the related signal transduction pathway mediated by the membrane receptor have revealed an elementary picture of BR signaling from the cell surface perception to the activation of BR-responsive nuclear genes.

  16. A Case Study of Representing Signal Transduction in Liver Cells as a Feedback Control Problem

    Science.gov (United States)

    Singh, Abhay; Jayaraman, Arul; Hahn, Juergen

    2007-01-01

    Cell signaling pathways often contain feedback loops where proteins are produced that regulate signaling. While feedback regulatory mechanisms are commonly found in signaling pathways, there is no example available in the literature that is simple enough to be presented in an undergraduate control class. This paper presents a simulation study of…

  17. Signal transduction in cells induced by endotoxin%内毒素诱导的细胞内信息转导

    Institute of Scientific and Technical Information of China (English)

    单于; 陆大祥

    2001-01-01

    Depending on LBP/CD14 systems, LPS activates a series ofsignal-transducing systems in cells. Protein tyrosin kinase(PTK)system,ceramide activated kinase(CAK)system might play an important role in cells signal-transducing.This article give a summary about signal transduction in cells induced by endotoxin.

  18. Quantifying efficient information transduction of biochemical signaling cascades

    CERN Document Server

    Tsuruyama, Tatsuaki

    2016-01-01

    Cells can be considered as systems that utilize changes in thermodynamic entropy as information. Therefore, they serve as useful models for investigating the relationships between entropy production and information transmission, i.e., signal transduction. Based on the hypothesis that cells apply a chemical reaction cascade for the most efficient transduction of information, we adopted a coding design that minimizes the number of bits per concentration of molecules that are employed for information transduction. As a result, the average rate of entropy production is uniform across all cycles in a cascade reaction. Thus, the entropy production rate can be a valuable measure for the quantification of intracellular signal transduction.

  19. Signal transduction of the physical environment in the neural differentiation of stem cells

    Science.gov (United States)

    Thompson, Ryan; Chan, Christina

    2016-01-01

    Neural differentiation is largely dependent on extracellular signals within the cell microenvironment. These extracellular signals are mainly in the form of soluble factors that activate intracellular signaling cascades that drive changes in the cell nucleus. However, it is becoming increasingly apparent that the physical microenvironment provides signals that can also influence lineage commitment and very low modulus surfaces has been repeatedly demonstrated to promote neurogenesis. The molecular mechanisms governing mechano-induced neural differentiation are still largely uncharacterized; however, a growing body of evidence indicates that physical stimuli can regulate known signaling cascades and transcription factors involved in neural differentiation. Understanding how the physical environment affects neural differentiation at the molecular level will enable research and design of materials that will eventually enhance neural stem cell (NSC) differentiation, homogeneity and specificity.

  20. Small-Molecule Inhibitors of Cytokine-Mediated STAT1 Signal Transduction In ß-Cells With Improved Aqueous Solubility

    DEFF Research Database (Denmark)

    Scully, Stephen Shane; Tang, Alicia J; Lundh, Morten;

    2013-01-01

    We previously reported the discovery of BRD0476 (1), a small molecule generated by diversity-oriented synthesis that suppresses cytokine-induced ß-cell apoptosis. Herein, we report the synthesis and biological evaluation of 1 and analogs with improved aqueous solubility. By replacing naphthyl wit...... with quinoline moieties, we prepared active analogs with up to a 1400-fold increase in solubility from 1. In addition, we demonstrated that compound 1 and analogs inhibit STAT1 signal transduction induced by IFN-¿....

  1. Methoxychlor enhances degranulation of murine mast cells by regulating FcεRI-mediated signal transduction.

    Science.gov (United States)

    Yasunaga, Sho; Nishi, Kosuke; Nishimoto, Sogo; Sugahara, Takuya

    2015-01-01

    Methoxychlor, an organochlorine insecticide developed to replace DDT (dichlorodiphenyltrichloroethane), has been reported to induce mast cell degranulation and to enhance IgE-mediated allergic responses. However, the mechanisms underlying these effects are not clear. To clarify potential mechanisms, the effects of methoxychlor on degranulation of mast cells were examined. Degranulation responses were evaluated using RBL-2H3 cells and mouse bone marrow-derived mast cells with either the antigen-induced or calcium ionophore-induced stimulation. Phosphorylation of enzymes related to signaling events associated with mast cell degranulation was analyzed by immunoblotting. Effects on vascular permeability in the passive cutaneous anaphylaxis reaction were evaluated following oral administration of methoxychlor to BALB/c mice. The results indicated that methoxychlor caused increased mast cell degranulation in the presence of antigen, whereas it had no effect on calcium ionophore-induced degranulation of RBL-2H3 cells. Immunoblot analyses demonstrated that the phosphorylation level of phosphoinositide 3-kinase (which plays a central role in mast cell signaling) was increased by methoxychlor during antigen-induced degranulation. In addition, methoxychlor activated the signaling pathway via the high-affinity IgE receptor by inducing phosphorylation of Syk and PLCγ1/2, which transfer the signal for degranulation downstream. Lastly, oral administration of methoxychlor exhibited a tendency to promote vascular permeability in passive cutaneous anaphylaxis model mice. Taken together, the results here suggested that methoxychlor enhanced degranulation through FcεRI-mediated signaling and promoted allergenic symptoms involved in mast cell degranulation.

  2. Single molecule narrowfield microscopy of protein-DNA binding dynamics in glucose signal transduction of live yeast cells

    CERN Document Server

    Wollman, Adam J M

    2016-01-01

    Single-molecule narrowfield microscopy is a versatile tool to investigate a diverse range of protein dynamics in live cells and has been extensively used in bacteria. Here, we describe how these methods can be extended to larger eukaryotic, yeast cells, which contain sub-cellular compartments. We describe how to obtain single-molecule microscopy data but also how to analyse these data to track and obtain the stoichiometry of molecular complexes diffusing in the cell. We chose glucose mediated signal transduction of live yeast cells as the system to demonstrate these single-molecule techniques as transcriptional regulation is fundamentally a single molecule problem - a single repressor protein binding a single binding site in the genome can dramatically alter behaviour at the whole cell and population level.

  3. Signal transduction pathways in mast cell granule-mediated endothelial cell activation

    Directory of Open Access Journals (Sweden)

    Luqi Chi

    2003-01-01

    Full Text Available Background: We have previously shown that incubation of human endothelial cells with mast cell granules results in potentiation of lipopolysaccharide-induced production of interleukin-6 and interleukin-8.

  4. Sentra, a database of signal transduction proteins.

    Energy Technology Data Exchange (ETDEWEB)

    Maltsev, N.; Marland, E.; Yu, G. X.; Bhatnagar, S.; Lusk, R.; Mathematics and Computer Science

    2002-01-01

    Sentra (http://www-wit.mcs.anl.gov/sentra) is a database of signal transduction proteins with the emphasis on microbial signal transduction. The database was updated to include classes of signal transduction systems modulated by either phosphorylation or methylation reactions such as PAS proteins and serine/threonine kinases, as well as the classical two-component histidine kinases and methyl-accepting chemotaxis proteins. Currently, Sentra contains signal transduction proteins from 43 completely sequenced prokaryotic genomes as well as sequences from SWISS-PROT and TrEMBL. Signal transduction proteins are annotated with information describing conserved domains, paralogous and orthologous sequences, and conserved chromosomal gene clusters. The newly developed user interface supports flexible search capabilities and extensive visualization of the data.

  5. SENTRA, a database of signal transduction proteins.

    Energy Technology Data Exchange (ETDEWEB)

    D' Souza, M.; Romine, M. F.; Maltsev, N.; Mathematics and Computer Science; PNNL

    2000-01-01

    SENTRA, available via URL http://wit.mcs.anl.gov/WIT2/Sentra/, is a database of proteins associated with microbial signal transduction. The database currently includes the classical two-component signal transduction pathway proteins and methyl-accepting chemotaxis proteins, but will be expanded to also include other classes of signal transduction systems that are modulated by phosphorylation or methylation reactions. Although the majority of database entries are from prokaryotic systems, eukaroytic proteins with bacterial-like signal transduction domains are also included. Currently SENTRA contains signal transduction proteins in 34 complete and almost completely sequenced prokaryotic genomes, as well as sequences from 243 organisms available in public databases (SWISS-PROT and EMBL). The analysis was carried out within the framework of the WIT2 system, which is designed and implemented to support genetic sequence analysis and comparative analysis of sequenced genomes.

  6. A TRPV2–PKA Signaling Module for Transduction of Physical Stimuli in Mast Cells

    Science.gov (United States)

    Stokes, Alexander J.; Shimoda, Lori M.N.; Koblan-Huberson, Murielle; Adra, Chaker N.; Turner, Helen

    2004-01-01

    Cutaneous mast cell responses to physical (thermal, mechanical, or osmotic) stimuli underlie the pathology of physical urticarias. In vitro experiments suggest that mast cells respond directly to these stimuli, implying that a signaling mechanism couples functional responses to physical inputs in mast cells. We asked whether transient receptor potential (vanilloid) (TRPV) cation channels were present and functionally coupled to signaling pathways in mast cells, since expression of this channel subfamily confers sensitivity to thermal, osmotic, and pressure inputs. Transcripts for a range of TRPVs were detected in mast cells, and we report the expression, surface localization, and oligomerization of TRPV2 protein subunits in these cells. We describe the functional coupling of TRPV2 protein to calcium fluxes and proinflammatory degranulation events in mast cells. In addition, we describe a novel protein kinase A (PKA)–dependent signaling module, containing PKA and a putative A kinase adapter protein, Acyl CoA binding domain protein (ACBD)3, that interacts with TRPV2 in mast cells. We propose that regulated phosphorylation by PKA may be a common pathway for TRPV modulation. PMID:15249591

  7. Pancreatic acinar cells: molecular insight from studies of signal-transduction using transgenic animals.

    Science.gov (United States)

    Yule, David I

    2010-11-01

    Pancreatic acinar cells are classical exocrine gland cells. The apical regions of clusters of coupled acinar cells collectively form a lumen which constitutes the blind end of a tube created by ductal cells - a structure reminiscent of a "bunch of grapes". When activated by neural or hormonal secretagogues, pancreatic acinar cells are stimulated to secrete a variety of proteins. These proteins are predominately inactive digestive enzyme precursors called "zymogens". Acinar cell secretion is absolutely dependent on secretagogue-induced increases in intracellular free Ca(2+). The increase in [Ca(2+)](i) has precise temporal and spatial characteristics as a result of the exquisite regulation of the proteins responsible for Ca(2+) release, Ca(2+) influx and Ca(2+) clearance in the acinar cell. This brief review discusses recent studies in which transgenic animal models have been utilized to define in molecular detail the components of the Ca(2+) signaling machinery which contribute to these characteristics.

  8. Endoglin promotes endothelial cell proliferation and TGF-beta/ALK1 signal transduction

    NARCIS (Netherlands)

    Lebrin, F; Goumans, MJ; Jonker, L; Carvalho, RLC; Valdimarsdottir, G; Thorikay, M; Mummery, C; Arthur, HM; ten Dijke, P

    2004-01-01

    Endoglin is a transmembrane accessory receptor for transforming growth factor-beta (TGF-beta) that is predominantly expressed on proliferating endothelial cells in culture and on angiogenic blood vessels in vivo. Endoglin, as well as other TGF-beta signalling components, is essential during angiogen

  9. Two-component signal transduction pathways regulating growth and cell cycle progression in a bacterium: a system-level analysis.

    Directory of Open Access Journals (Sweden)

    Jeffrey M Skerker

    2005-10-01

    Full Text Available Two-component signal transduction systems, comprised of histidine kinases and their response regulator substrates, are the predominant means by which bacteria sense and respond to extracellular signals. These systems allow cells to adapt to prevailing conditions by modifying cellular physiology, including initiating programs of gene expression, catalyzing reactions, or modifying protein-protein interactions. These signaling pathways have also been demonstrated to play a role in coordinating bacterial cell cycle progression and development. Here we report a system-level investigation of two-component pathways in the model organism Caulobacter crescentus. First, by a comprehensive deletion analysis we show that at least 39 of the 106 two-component genes are required for cell cycle progression, growth, or morphogenesis. These include nine genes essential for growth or viability of the organism. We then use a systematic biochemical approach, called phosphotransfer profiling, to map the connectivity of histidine kinases and response regulators. Combining these genetic and biochemical approaches, we identify a new, highly conserved essential signaling pathway from the histidine kinase CenK to the response regulator CenR, which plays a critical role in controlling cell envelope biogenesis and structure. Depletion of either cenK or cenR leads to an unusual, severe blebbing of cell envelope material, whereas constitutive activation of the pathway compromises cell envelope integrity, resulting in cell lysis and death. We propose that the CenK-CenR pathway may be a suitable target for new antibiotic development, given previous successes in targeting the bacterial cell wall. Finally, the ability of our in vitro phosphotransfer profiling method to identify signaling pathways that operate in vivo takes advantage of an observation that histidine kinases are endowed with a global kinetic preference for their cognate response regulators. We propose that this

  10. The Role of Intrinsic Flexibility in Signal Transduction Mediated by the Cell Cycle Regulator, p27Kip1

    Energy Technology Data Exchange (ETDEWEB)

    Galea, Charles A. [St. Jude Children' s Research Hospital; Nourse, Amanda [St. Jude Children' s Research Hospital; Wang, Yuefeng [St. Jude Children' s Research Hospital; Sivakolundu, Sivashankar G. [St. Jude Children' s Research Hospital; Heller, William T [ORNL; Kriwacki, Richard W [University of Tennessee (UT) Health Science Center, Memphis

    2008-02-01

    p27{sup Kip1} (p27), which controls eukaryotic cell division through interactions with cyclin-dependent kinases (Cdks), integrates and transduces promitogenic signals from various nonreceptor tyrosine kinases by orchestrating its own phosphorylation, ubiquitination and degradation. Intrinsic flexibility allows p27 to act as a 'conduit' for sequential signaling mediated by tyrosine and threonine phosphorylation and ubiquitination. While the structural features of the Cdk/cyclin-binding domain of p27 are understood, how the C-terminal regulatory domain coordinates multistep signaling leading to p27 degradation is poorly understood. We show that the 100-residue p27 C-terminal domain is extended and flexible when p27 is bound to Cdk2/cyclin A. We propose that the intrinsic flexibility of p27 provides a molecular basis for the sequential signal transduction conduit that regulates p27 degradation and cell division. Other intrinsically unstructured proteins possessing multiple sites of posttranslational modification may participate in similar signaling conduits.

  11. The biological networks in studying cell signal transduction complexity: The examples of sperm capacitation and of endocannabinoid system

    Science.gov (United States)

    Bernabò, Nicola; Barboni, Barbara; Maccarrone, Mauro

    2014-01-01

    Cellular signal transduction is a complex phenomenon, which plays a central role in cell surviving and adaptation. The great amount of molecular data to date present in literature, together with the adoption of high throughput technologies, on the one hand, made available to scientists an enormous quantity of information, on the other hand, failed to provide a parallel increase in the understanding of biological events. In this context, a new discipline arose, the systems biology, aimed to manage the information with a computational modeling-based approach. In particular, the use of biological networks has allowed the making of huge progress in this field. Here we discuss two possible application of the use of biological networks to explore cell signaling: the study of the architecture of signaling systems that cooperate in determining the acquisition of a complex cellular function (as it is the case of the process of activation of spermatozoa) and the organization of a single specific signaling systems expressed by different cells in different tissues (i.e. the endocannabinoid system). In both the cases we have found that the networks follow a scale free and small world topology, likely due to the evolutionary advantage of robustness against random damages, fastness and specific of information processing, and easy navigability. PMID:25379139

  12. Calcium and signal transduction in plants

    Science.gov (United States)

    Poovaiah, B. W.; Reddy, A. S.

    1993-01-01

    Environmental and hormonal signals control diverse physiological processes in plants. The mechanisms by which plant cells perceive and transduce these signals are poorly understood. Understanding biochemical and molecular events involved in signal transduction pathways has become one of the most active areas of plant research. Research during the last 15 years has established that Ca2+ acts as a messenger in transducing external signals. The evidence in support of Ca2+ as a messenger is unequivocal and fulfills all the requirements of a messenger. The role of Ca2+ becomes even more important because it is the only messenger known so far in plants. Since our last review on the Ca2+ messenger system in 1987, there has been tremendous progress in elucidating various aspects of Ca(2+) -signaling pathways in plants. These include demonstration of signal-induced changes in cytosolic Ca2+, calmodulin and calmodulin-like proteins, identification of different Ca2+ channels, characterization of Ca(2+) -dependent protein kinases (CDPKs) both at the biochemical and molecular levels, evidence for the presence of calmodulin-dependent protein kinases, and increased evidence in support of the role of inositol phospholipids in the Ca(2+) -signaling system. Despite the progress in Ca2+ research in plants, it is still in its infancy and much more needs to be done to understand the precise mechanisms by which Ca2+ regulates a wide variety of physiological processes. The purpose of this review is to summarize some of these recent developments in Ca2+ research as it relates to signal transduction in plants.

  13. Bioinformatics analyses for signal transduction networks

    Institute of Scientific and Technical Information of China (English)

    2008-01-01

    Research in signaling networks contributes to a deeper understanding of organism living activities. With the development of experimental methods in the signal transduction field, more and more mechanisms of signaling pathways have been discovered. This paper introduces such popular bioin-formatics analysis methods for signaling networks as the common mechanism of signaling pathways and database resource on the Internet, summerizes the methods of analyzing the structural properties of networks, including structural Motif finding and automated pathways generation, and discusses the modeling and simulation of signaling networks in detail, as well as the research situation and tendency in this area. Now the investigation of signal transduction is developing from small-scale experiments to large-scale network analysis, and dynamic simulation of networks is closer to the real system. With the investigation going deeper than ever, the bioinformatics analysis of signal transduction would have immense space for development and application.

  14. Sorbitol induces apoptosis of human colorectal cancer cells via p38 MAPK signal transduction.

    Science.gov (United States)

    Lu, Xue; Li, Chun; Wang, Yong-Kun; Jiang, Kun; Gai, Xiao-Dong

    2014-06-01

    Sorbitol has been reported to have anticancer effects in several tumor models, however its effects on colorectal cancer remain elusive. In the present study, the effects of sorbitol on growth inhibition and apoptosis in the colorectal cancer HCT116 cell line were evaluated and its mechanism of action was examined. An MTT assay was utilized to determine the effect of sorbitol on HCT116 cell proliferation at different time points and variable doses. Western blot analysis was used to examine the effect of sorbitol on apoptosis-related protein expression and the p38 MAPK signaling pathway. The results revealed that sorbitol may inhibit the growth of HCT116 cells in a time- and dose-dependent manner. Following treatment with sorbitol for 3 h, western blotting demonstrated cleavage of the caspase-3 zymogen protein and a cleavage product of poly (ADP-ribose) polymerase (PARP), a known substrate of caspase-3, was also evident. During sorbitol-induced apoptosis, the mitochondrial pathway was activated by a dose-dependent increase in Bax expression and cytochrome c release, while the expression of anti-apoptotic protein Bcl-2 was significantly decreased in a dose-dependent manner. The investigation for the downstream signal pathway revealed that sorbitol-induced apoptosis was mediated by an increase in phosphorylated p38 MAPK expression. Overall, the observations from the present study imply that sorbitol causes increased levels of Bax in response to p38 MAPK signaling, which results in the initiation of the mitochondrial death cascade. Therefore, sorbitol is a promising candidate as a potential chemotherapeutic agent for the treatment of colorectal cancer HCT116 cells.

  15. Leptin differentially regulates NPY secretion in hypothalamic cell lines through distinct intracellular signal transduction pathways.

    Science.gov (United States)

    Dhillon, Sandeep S; Belsham, Denise D

    2011-04-11

    Leptin acts as a key peripheral hormone in distinct neurons in the hypothalamus to modulate both reproductive function and energy homeostasis. The control of neuropeptide Y (NPY) secretion is an example of a process that can be differentially regulated by leptin. In order to further understand these distinct modulatory effects, we have used immortalized, neuronal hypothalamic cell lines expressing NPY, mHypoE-38 and mHypoE-46. We found that these cell lines express the endogenous leptin receptor, ObRb, and secrete detectable levels of NPY. We exposed the neurons to 100nM leptin for 1h and determined that the basal levels of NPY in the cell lines were differentially regulated: NPY secretion was inhibited in mHypoE-46 neurons, whereas NPY secretion was induced in the mHypoE-38 neurons. In order to determine the mechanisms involved in the divergent regulation of NPY release, we analyzed the activity of a number of signaling components using phospho-specific antibodies directed towards specific proteins in the MAP kinase, PI3K, and AMPK pathways, among others. We found that leptin activated a different combination of second messengers in each cell line. Importantly, we could link the regulation of NPY secretion to different signaling pathways, AMPK in the mHypoE-46 and both MAPK and PI3K in the mHypoE-38 neurons. This is the first demonstration that leptin can specifically regulate individual NPY neuron secretory responses through distinct signaling pathways.

  16. Activity Dependent Signal Transduction in Skeletal Muscle

    Science.gov (United States)

    Hamilton, Susan L.

    1999-01-01

    The overall goals of this project are: 1) to define the initial signal transduction events whereby the removal of gravitational load from antigravity muscles, such as the soleus, triggers muscle atrophy, and 2) to develop countermeasures to prevent this from happening. Our rationale for this approach is that, if countermeasures can be developed to regulate these early events, we could avoid having to deal with the multiple cascades of events that occur downstream from the initial event. One of our major findings is that hind limb suspension causes an early and sustained increase in intracellular Ca(2+) concentration ([Ca (2+)](sub i)). In most cells the consequences of changes in ([Ca (2+)](sub i))depend on the amplitude, frequency and duration of the Ca(2+) signal and on other factors in the intracellular environment. We propose that muscle remodeling in microgravity represents a change in the balance among several CA(2+) regulated signal transduction pathways, in particular those involving the transcription factors NFAT and NFkB and the pro-apoptotic protein BAD. Other Ca(2+) sensitive pathways involving PKC, ras, rac, and CaM kinase II may also contribute to muscle remodeling.

  17. Signal transduction by the major histocompatibility complex class I molecule

    DEFF Research Database (Denmark)

    Pedersen, Anders Elm; Skov, S; Bregenholt, S;

    1999-01-01

    Ligation of cell surface major histocompatibility class I (MHC-I) proteins by antibodies, or by their native counter receptor, the CD8 molecule, mediates transduction of signals into the cells. MHC-I-mediated signaling can lead to both increased and decreased activity of the MHC-I-expressing cell...

  18. Opposing effects of bile acids deoxycholic acid and ursodeoxycholic acid on signal transduction pathways in oesophageal cancer cells.

    Science.gov (United States)

    Abdel-Latif, Mohamed M; Inoue, Hiroyasu; Reynolds, John V

    2016-09-01

    Ursodeoxycholic acid (UDCA) was reported to reduce bile acid toxicity, but the mechanisms underlying its cytoprotective effects are not fully understood. The aim of the present study was to examine the effects of UDCA on the modulation of deoxycholic acid (DCA)-induced signal transduction in oesophageal cancer cells. Nuclear factor-κB (NF-κB) and activator protein-1 (AP-1) activity was assessed using a gel shift assay. NF-κB activation and translocation was performed using an ELISA-based assay and immunofluorescence analysis. COX-2 expression was analysed by western blotting and COX-2 promoter activity was assessed by luciferase assay. DCA induced NF-κB and AP-1 DNA-binding activities in SKGT-4 and OE33 cells. UDCA pretreatment inhibited DCA-induced NF-κB and AP-1 activation and NF-κB translocation. This inhibitory effect was coupled with a blockade of IκB-α degradation and inhibition of phosphorylation of IKK-α/β and ERK1/2. Moreover, UDCA pretreatment inhibited COX-2 upregulation. Using transient transfection of the COX-2 promoter, UDCA pretreatment abrogated DCA-induced COX-2 promoter activation. In addition, UDCA protected oesophageal cells from the apoptotic effects of deoxycholate. Our findings indicate that UDCA inhibits DCA-induced signalling pathways in oesophageal cancer cells. These data indicate a possible mechanistic role for the chemopreventive actions of UDCA in oesophageal carcinogenesis.

  19. Ca2+ is involved in muscarine-acetylcholine-receptor-mediated acetylcholine signal transduction in guard cells of Vicia faba L.

    Institute of Scientific and Technical Information of China (English)

    MENG Fanxia; MIAO Long; ZHANG Shuqiu; LOU Chenghou

    2004-01-01

    Acetylcholine (ACh) is an important neurochemical transmitter in animals; it also exists in plants and plays a significant role in various kinds of physiological functions in plants. ACh has been known to induce the stomatal opening. By monitoring the changes of cytosolic Ca2+ with fluorescent probe Fluo-3 AM under the confocal microscopy,we found that exogenous ACh increased cytosolic Ca2+ concentration of guard cells of Vicia faba L. Muscarine, an agonist of muscarine acetylcholine receptor (mAChR), could do so as well. In contrast, atropine, the antagonist of mAChR abolished the ability of ACh to increase Ca2+ in guard cells.This mechanism is similar to mAChR in animals. When EGTA was used to chelate Ca2+ or ruthenium red to block Ca2+ released from vacuole respectively, the results showed that the increased cytosolic Ca2+ mainly come from intracellular Ca2+ store. The evidence supports that Ca2+ is involved in guard-cell response to ACh and that Ca2+ signal is coupled to mAChRs in ACh signal transduction in guard cells.

  20. Quantitative phosphoproteomics of murine Fmr1-KO cell lines provides new insights into FMRP-dependent signal transduction mechanisms.

    Science.gov (United States)

    Matic, Katarina; Eninger, Timo; Bardoni, Barbara; Davidovic, Laetitia; Macek, Boris

    2014-10-01

    Fragile X mental retardation protein (FMRP) is an RNA-binding protein that has a major effect on neuronal protein synthesis. Transcriptional silencing of the FMR1 gene leads to loss of FMRP and development of Fragile X syndrome (FXS), the most common known hereditary cause of intellectual impairment and autism. Here we utilize SILAC-based quantitative phosphoproteomics to analyze murine FMR1(-) and FMR1(+) fibroblastic cell lines derived from FMR1-KO embryos to identify proteins and phosphorylation sites dysregulated as a consequence of FMRP loss. We quantify FMRP-related changes in the levels of 5,023 proteins and 6,133 phosphorylation events and map them onto major signal transduction pathways. Our study confirms global downregulation of the MAPK/ERK pathway and decrease in phosphorylation level of ERK1/2 in the absence of FMRP, which is connected to attenuation of long-term potentiation. We detect differential expression of several key proteins from the p53 pathway, pointing to the involvement of p53 signaling in dysregulated cell cycle control in FXS. Finally, we detect differential expression and phosphorylation of proteins involved in pre-mRNA processing and nuclear transport, as well as Wnt and calcium signaling, such as PLC, PKC, NFAT, and cPLA2. We postulate that calcium homeostasis is likely affected in molecular pathogenesis of FXS.

  1. Quantitative phosphoproteomics of murine Fmr1-KO cell lines provides new insights into FMRP-dependent signal transduction mechanisms.

    Science.gov (United States)

    Matic, Katarina; Eninger, Timo; Bardoni, Barbara; Davidovic, Laetitia; Macek, Boris

    2014-10-01

    Fragile X mental retardation protein (FMRP) is an RNA-binding protein that has a major effect on neuronal protein synthesis. Transcriptional silencing of the FMR1 gene leads to loss of FMRP and development of Fragile X syndrome (FXS), the most common known hereditary cause of intellectual impairment and autism. Here we utilize SILAC-based quantitative phosphoproteomics to analyze murine FMR1(-) and FMR1(+) fibroblastic cell lines derived from FMR1-KO embryos to identify proteins and phosphorylation sites dysregulated as a consequence of FMRP loss. We quantify FMRP-related changes in the levels of 5,023 proteins and 6,133 phosphorylation events and map them onto major signal transduction pathways. Our study confirms global downregulation of the MAPK/ERK pathway and decrease in phosphorylation level of ERK1/2 in the absence of FMRP, which is connected to attenuation of long-term potentiation. We detect differential expression of several key proteins from the p53 pathway, pointing to the involvement of p53 signaling in dysregulated cell cycle control in FXS. Finally, we detect differential expression and phosphorylation of proteins involved in pre-mRNA processing and nuclear transport, as well as Wnt and calcium signaling, such as PLC, PKC, NFAT, and cPLA2. We postulate that calcium homeostasis is likely affected in molecular pathogenesis of FXS. PMID:25168779

  2. Low concentration of ethanol induce apoptosis in HepG2 cells: role of various signal transduction pathways

    Directory of Open Access Journals (Sweden)

    Francisco Castaneda, Sigrid Rosin-Steiner

    2006-01-01

    Full Text Available As we previously demonstrated in human hepatocellular carcinoma (HepG2 cells, ethanol at low concentration triggers the Fas apoptotic pathway. However, its role in other intracellular signaling pathways remains unknown. Therefore, the aim of the present study was to evaluate the role of low concentration of ethanol on different intracellular signaling pathways. For this purpose, HepG2 cells were treated with 1 mM ethanol for 10 min and the phosphorylation state of protein kinases was determined. In addition, the mRNA levels of transcription factors and genes associated with the Fas apoptotic pathway were determined. Our data demonstrated that ethanol-induced phosphorylation of protein kinases modulates both anti-apoptotic and pro-apoptotic mechanisms in HepG2 cells. Pro-apoptosis resulted mainly from the strong inhibition of the G-protein couple receptor signaling pathway. Moreover, the signal transduction initiated by ethanol-induced protein kinases phosphorylation lead to increased expression of the transcription factors with subsequent expression of genes associated with the Fas apoptotic pathway (Fas receptor, Fas ligand, FADD and caspase 8. These results indicate that low concentration of ethanol exert their effect by predominant activation of pro-apoptotic events that can be divided in two phases. An early phase characterized by a rapid transient effect on protein kinases phosphorylation, after 10 min exposure, with subsequent increased expression of transcription factors for up to 6 hr. This early phase is followed by a second phase associated with increased gene expression that began after 6 hr and persisted for more than 24 hr. This information provided a novel insight into the mechanisms of action of ethanol (1mM in human hepatocellular carcinoma cells.

  3. MAPK Signal Transduction Pathway Regulation: A Novel Mechanism of Rat HSC-T6 Cell Apoptosis Induced by FUZHENGHUAYU Tablet

    Directory of Open Access Journals (Sweden)

    Qi Wang

    2013-01-01

    Full Text Available FUZHENGHUAYU Tablets have been widely used in the treatment of liver fibrosis in China. Here, we investigate the apoptotic effect of FUZHENGHUAYU Tablet in rat liver stellate cell line HSC-T6. HSC-T6 cells were incubated with control serum or drug serum from rats fed with 0.9% NaCl or FUZHENGHUAYU Tablet, respectively. Cells exposed to drug serum showed higher proportions of early and late apoptotic cells than controls. The mRNA levels of collagens I and III, TGF-β1 and α-SMA were reduced by drug serum compared to control serum. Differentially expressed mRNAs and miRNAs were analyzed by microarray and sequencing, respectively. We identified 334 differentially expressed mRNAs and also 60 GOs and two pathways related to the mRNAs. Seventy-five differentially expressed miRNAs were down-regulated by drug serum and 1963 target genes were predicted. 134 GOs up-regulated in drug serum group were linked to miRNA targets, and drug serum also regulated 43 miRNA signal transduction pathways. Protein levels were evaluated by Western blot. Drug serum down-regulated (phospho-SAPK/JNK/(SAPK/JNK and up-regulated phospho-p38/p38 ratios. The study showed that FUZHENGHUAYU Tablet induced apoptosis in rat HSC-T6 cells possibly in part by activating p38 and inhibiting SAPK/JNK.

  4. Mechanisms of UV-induced signal transduction

    Energy Technology Data Exchange (ETDEWEB)

    Kulms, D.; Schwarz, T. [Univ. Muenster, Muenster (Germany). Ludwing Boltzmann Inst. for Cell Biology and Immunobiology of the Skin

    2002-04-01

    Ultraviolet radiation (UV) causes a variety of biological effects that can be either beneficial or harmful for human health. To exert these effects on a cellular basis, UV uses a variety of signaling pathways. DNA is the major chromophore for UVB. Thus, nuclear DNA damage has been detected to be a major mediator of numerous UVB effects, and experimental reduction of DNA damage is associated with a loss of these effects. On the other hand, UV has been found to utilize molecular components within the cytoplasm or at the cell membrane for signaling. UV can directly activate cell surface receptors, kinases, and transcription factors. The nuclear and extranuclear signaling pathways are generated independently and have been recently recognized to be not mutually exclusive but to contribute to various UV effects in an independent and additive way. Further knowledge of how these signaling pathways relate to each other will certainly increase our understanding of how UV acts as a pathogen. The following review will briefly discuss current aspects of the mechanisms involved in UV-induced signal transduction. (author)

  5. Lipid rafts are required for signal transduction by angiotensin II receptor type 1 in neonatal glomerular mesangial cells

    Energy Technology Data Exchange (ETDEWEB)

    Adebiyi, Adebowale, E-mail: aadebiyi@uthsc.edu; Soni, Hitesh; John, Theresa A.; Yang, Fen

    2014-05-15

    Angiotensin II (ANG-II) receptors (AGTRs) contribute to renal physiology and pathophysiology, but the underlying mechanisms that regulate AGTR function in glomerular mesangium are poorly understood. Here, we show that AGTR1 is the functional AGTR subtype expressed in neonatal pig glomerular mesangial cells (GMCs). Cyclodextrin (CDX)-mediated cholesterol depletion attenuated cell surface AGTR1 protein expression and ANG-II-induced intracellular Ca{sup 2+} ([Ca{sup 2+}]{sub i}) elevation in the cells. The COOH-terminus of porcine AGTR1 contains a caveolin (CAV)-binding motif. However, neonatal GMCs express CAV-1, but not CAV-2 and CAV-3. Colocalization and in situ proximity ligation assay detected an association between endogenous AGTR1 and CAV-1 in the cells. A synthetic peptide corresponding to the CAV-1 scaffolding domain (CSD) sequence also reduced ANG-II-induced [Ca{sup 2+}]{sub i} elevation in the cells. Real-time imaging of cell growth revealed that ANG-II stimulates neonatal GMC proliferation. ANG-II-induced GMC growth was attenuated by EMD 66684, an AGTR1 antagonist; BAPTA, a [Ca{sup 2+}]{sub i} chelator; KN-93, a Ca{sup 2+}/calmodulin-dependent protein kinase II inhibitor; CDX; and a CSD peptide, but not PD 123319, a selective AGTR2 antagonist. Collectively, our data demonstrate [Ca{sup 2+}]{sub i}-dependent proliferative effect of ANG-II and highlight a critical role for lipid raft microdomains in AGTR1-mediated signal transduction in neonatal GMCs. - Highlights: • AGTR1 is the functional AGTR subtype expressed in neonatal mesangial cells. • Endogenous AGTR1 associates with CAV-1 in neonatal mesangial cells. • Lipid raft disruption attenuates cell surface AGTR1 protein expression. • Lipid raft disruption reduces ANG-II-induced [Ca{sup 2+}]{sub i} elevation in neonatal mesangial cells. • Lipid raft disruption inhibits ANG-II-induced neonatal mesangial cell growth.

  6. A therapeutic anti-CD4 monoclonal antibody inhibits T cell receptor signal transduction in mouse autoimmune cardiomyopathy

    Institute of Scientific and Technical Information of China (English)

    WANG Zhao-hui; LIAO Yu-hua; YUAN Jing; ZHANG Li; WANG Min; ZHANG Jing-hui; LIU Zhong-ping; DONG Ji-hua

    2007-01-01

    Background T cell immune abnormalities in patients with dilated cardiomyopathy (DCM) has been intensively studied over the past 10 years. Our previous study has suggested that immunization of mice with the peptides derived from human adenine nucleotide translocator (ANT) result in the production of autoantibodies against the ANT and histopathological changes similar to those in human DCM. The ANT peptides can induce autoimmune cardiomyopathy like DCM in Balb/c mice. In this study we aimed to focus on the molecular mechanism of T cells in the autoimmune cardiomyopathy mouse model by detecting the expression of the two T cell signaling molecules.Methods The ANT peptides were used to cause autoimmune cardiomyopathy in Balb/c mice. Anti-L3T4 or rat anti-mouse IgG was administered to the mice (n=6 in each group) simultaneously immunized with ANT. ELISA analysis was used to detect autoantibodies against the ANT peptides and the percentages of interferon-Y and interleukin-4 producing cells among splenic CD4+ lymphocytes was determined by using flow cytometry analysis. The expression of CD45 in spleen T cells was determined by immunohistochemistry and the mRNAs of T cell signaling molecules were detected by real-time PCR.Results Treatment of ANT immunized Balb/c mice with anti-CD4 mAb caused a reduction in the gene expression of P56lck and Zap-70 and a lower level of CD45 expression by spleen T cells. Aiso, a reverse of the Th1/Th2 ratio that results in the reduced production of antibodies against ANT was found in the anti-CD4 monoclonal antibodies (mAb)group. Whereas irrelevant antibody (rat anti-mouse IgG) did not suppress T cell signaling molecules nor inhibit CD45 expression, and control-antibody mice did not show any significant differences compared with the DCM group.Conclusion The results show that anti-CD4 mAb is a powerful inhibitor of the early initiating events of T cell receptor(TCR) signal transduction in mouse autoimmune dilated cardiomyopathy.

  7. Signal transduction pathways in liver and the influence of hepatitis C virus infection on their activities

    Institute of Scientific and Technical Information of China (English)

    Magdalena M Dabrowska; Anatol Panasiuk; Robert Flisiak

    2009-01-01

    In liver, the most intensively studied transmembrane and intracellular signal transduction pathways are the Janus kinase signal transduction pathway, the mitogen-activated protein kinases signal transduction pathway, the transforming growth factor b signal transduction pathway, the tumor necrosis factor a signal transduction pathway and the recently discovered sphingolipid signal transduction pathway. All of them are activated by many different cytokines and growth factors. They regulate specific cell mechanisms such as hepatocytes proliferation, growth, differentiation, adhesion, apoptosis, and synthesis and degradation of the extracellular matrix. The replication cycle of hepatitis C virus (HCV) is intracellular and requires signal transduction to the nucleus to regulate transcription of its genes. Moreover, HCV itself, by its structural and nonstructural proteins, could influence the activity of the second signal messengers. Thus, the inhibition of the transmembrane and intracellular signal transduction pathways could be a new therapeutic target in chronic hepatitis C treatment.

  8. Thyroxine signal transduction in liver cells involves phospholipase C and phospholipase D activation. Genomic independent action of thyroid hormone

    Directory of Open Access Journals (Sweden)

    Krasilnikova Oksana A

    2001-04-01

    Full Text Available Abstract Background Numerous investigations demonstrate a novel role of thyroid hormone as a modulator of signal transduction. Protein kinase C (PKC is critical to the mechanism by which thyroid hormones potentiate both the antiviral and immunomodulatory actions of IFNγ in different cells and regulate the exchange of signalling phospholipids in hepatocytes. Because nothing is known about accumulation of PKC modulator - diacylglycerol in cells treated with T4, we examined the nongenomic effect of thyroid hormones on DAG formation and phospholipase activation in liver cells. Results The results obtained provide the first demonstration of phospholipase C, phospholipase D and protein kinase C nongenomic activation and diacylglycerol (DAG accumulation by L-T4 in liver cells. The experiments were performed in either the [14C]CH3COOH-labeled rat liver slices or isolated hepatocytes pre-labeled by [14C]oleic acid. L-T4 activates the DAG production in a concentration- and time-dependent manner. DAG formation in stimulated cells is biphasic and short-lived event: there is an initial, rapid rise in DAG concentration and then a slower accumulation that can be sustained for a few minutes. The early phase of L-T4 generated DAG only is accompanied by phosphatidylinositol 4,5-bisphosphate level decrease and inositol 1,4,5-trisphosphate formation while the second phase is abolished by PKC inhibitor l,(5-isoquinolinesulphonyl2methylpiperasine dihydrochloride (H7 and propranolol. The second phase of DAG production is accompanied by free choline release, phosphatidylcholine content drop and phosphatidylethanol (Peth formation. Inhibitor of phospholipase-C-dependent phosphoinositide hydrolysis, neomycin sulfate, reduced the Peth as well as the DAG response to L-T4. Conclusions The present data have indicated the DAG signaling in thyroid hormone-stimulated liver cells. L-thyroxine activates a dual phospholipase pathway in a sequential and synchronized manner

  9. EDITORIAL: Special section on signal transduction Special section on signal transduction

    Science.gov (United States)

    Shvartsman, Stanislav

    2012-08-01

    This special section of Physical Biology focuses on multiple aspects of signal transduction, broadly defined as the study of the mechanisms by which cells communicate with their environment. Mechanisms of cell communication involve detection of incoming signals, which can be chemical, mechanical or electromagnetic, relaying these signals to intracellular processes, such as cytoskeletal networks or gene expression systems, and, ultimately, converting these signals to responses such as cell differentiation or death. Given the multiscale nature of signal transduction systems, they must be studied at multiple levels, from the identities and structures of molecules comprising signal detection and interpretation networks, to the systems-level properties of these networks. The 11 papers in this special section illustrate some of the most exciting aspects of signal transduction research. The first two papers, by Marie-Anne Félix [1] and by Efrat Oron and Natalia Ivanova [2], focus on cell-cell interactions in developing tissues, using vulval patterning in worm and cell fate specification in mammalian embryos as prime examples of emergent cell behaviors. Next come two papers from the groups of Julio Saez-Rodriguez [3] and Kevin Janes [4]. These papers discuss how the causal relationships between multiple components of signaling systems can be inferred using multivariable statistical analysis of empirical data. An authoritative review by Zarnitsyna and Zhu [5] presents a detailed discussion of the sequence of signaling events involved in T-cell triggering. Once the structure and components of the signaling systems are determined, they can be modeled using approaches that have been successful in other physical sciences. As two examples of such approaches, reviews by Rubinstein [6] and Kholodenko [7], present reaction-diffusion models of cell polarization and thermodynamics-based models of gene regulation. An important class of models takes the form of enzymatic networks

  10. Signal transduction pathway(s) in guard cells after prolonged exposure to low vapour pressure deficit

    NARCIS (Netherlands)

    Ali Niaei Fard, S.

    2014-01-01

    Keywords: Abscisic acid, Arabidopsis thaliana, calcium, CYP707As, desiccation, environmental factors, guard cells’ signalling pathway, hydrogen peroxide, natural variation, nitric oxide, photosystem II efficiency, RD29A, relative water content, secondary messengers, stomata, vapour pressure def

  11. Signal transduction and metabolic changes during tumor cell apoptosis following phthalocyanine-sensitized photodynamic therapy

    Science.gov (United States)

    Oleinick, Nancy L.; Agarwal, Munna L.; Berger, Nathan A.; Cheng, Ming-Feng; Chatterjee, Satadel; He, Jin; Kenney, Malcolm E.; Larkin, Hedy E.; Mukhter, Hasan; Rihter, Boris D.; Zaidi, Syed I. A.

    1993-06-01

    Mechanisms of cell death have been explored in cells and tumors treated with photodynamic therapy (PDT). Photosensitizers used for these studies were Photofrin, tetrasulfonated and nonsulfonated aluminum phthalocyanine, and a new silicon phthalocyanine [SiPc(OH)OSi(CH3)2(CH2)3N(CH3)2], referred to as PcIV. In mouse lymphoma L5178Y cells, a dose of PDT sensitized by PcIV which causes a 90% loss of cell survival induces apoptosis (programmed cell death) over a several-hour time course, beginning within 10 minutes of irradiation. Apoptosis is a metabolic process initiated by PDT-induced damage to membranes and triggered by the activation of phospholipases A2 and C and the release of Ca++ from intracellular stores. An endogenous endonuclease is activated and cleaves nuclear DNA in the internucleosomal region of chromatin. Subsequent metabolic events now appear to cause the loss of cellular NAD and ATP, the former a result of the activation of a second nuclear enzyme, poly(ADP-ribose) polymerase, by the endonucleolytically generated DNA strand breaks. Loss of ATP follows upon the loss of NAD needed for energy metabolism. Although the induction of apoptosis is efficiently produced by direct PDT damage to L5178Y cells, we now find that apoptosis is also produced by treatment of certain other lymphoid-derived cells and cells of epithelial origin. Under the limited set of conditions tested, there was no evidence for PDT-induced apoptosis in a fibroblast cell line, in mouse fibrosarcoma RIF-1 and L929 cells, in human adenocarcinoma A549 cells, or in human squamous cell carcinoma cells in culture. The evidence suggests that apoptosis, a form of metabolic cell death, is an important mechanism of tumor ablation in PDT-treated tumors, and that the induction of apoptosis may involve the interaction of direct PDT damage to malignant cells with factors produced by PDT action on vascular and other host cells.

  12. Signal transduction by HLA class II antigens expressed on activated T cells

    DEFF Research Database (Denmark)

    Ødum, Niels; Martin, P J; Schieven, G L;

    1991-01-01

    Human T cells express HLA class II antigens upon activation. Although activated, class II+ T cells can present alloantigens under certain circumstances, the functional role of class II antigens on activated T cells remains largely unknown. Here, we report that cross-linking of HLA-DR molecules ex...

  13. Information flow during gene activation by signaling molecules: ethylene transduction in Arabidopsis cells as a study system

    Directory of Open Access Journals (Sweden)

    Díaz José

    2009-05-01

    Full Text Available Abstract Background We study root cells from the model plant Arabidopsis thaliana and the communication channel conformed by the ethylene signal transduction pathway. A basic equation taken from our previous work relates the probability of expression of the gene ERF1 to the concentration of ethylene. Results The above equation is used to compute the Shannon entropy (H or degree of uncertainty that the genetic machinery has during the decoding of the message encoded by the ethylene specific receptors embedded in the endoplasmic reticulum membrane and transmitted into the nucleus by the ethylene signaling pathway. We show that the amount of information associated with the expression of the master gene ERF1 (Ethylene Response Factor 1 can be computed. Then we examine the system response to sinusoidal input signals with varying frequencies to determine if the cell can distinguish between different regimes of information flow from the environment. Our results demonstrate that the amount of information managed by the root cell can be correlated with the frequency of the input signal. Conclusion The ethylene signaling pathway cuts off very low and very high frequencies, allowing a window of frequency response in which the nucleus reads the incoming message as a sinusoidal input. Out of this window the nucleus reads the input message as an approximately non-varying one. From this frequency response analysis we estimate: a the gain of the system during the synthesis of the protein ERF1 (~-5.6 dB; b the rate of information transfer (0.003 bits during the transport of each new ERF1 molecule into the nucleus and c the time of synthesis of each new ERF1 molecule (~21.3 s. Finally, we demonstrate that in the case of the system of a single master gene (ERF1 and a single slave gene (HLS1, the total Shannon entropy is completely determined by the uncertainty associated with the expression of the master gene. A second proposition shows that the Shannon entropy

  14. Expression of SMAD signal transduction molecules in the pancreas

    DEFF Research Database (Denmark)

    Brorson, Michael; Hougaard, D.; Nielsen, Jens Høiriis;

    2001-01-01

    Members of the TGF-beta superfamily of cytokines have been implicated in pancreatic cancer, pancreatitis and in regulation and differentiation of pancreatic endocrine and exocrine cells. Different TGF-beta members signal through phosphorylation of different signal transduction proteins, which...

  15. DC-ATLAS : a systems biology resource to dissect receptor specific signal transduction in dendritic cells

    NARCIS (Netherlands)

    Cavalieri, D.; Rivero, D.; Beltrame, L.; Buschow, S.I.; Calura, E.; Rizzetto, L.; Gessani, S.; Gauzzi, M.C.; Reith, W.; Baur, A.; Bonaiuti, R.; Brandizi, M.; Filippo, C. De; D'Oro, U.; Draghici, S.; Dunand-Sauthier, I.; Gatti, E.; Granucci, F.; Gundel, M.; Kramer, M.; Kuka, M.; Lanyi, A.; Melief, C.J.; Montfoort, N. van; Ostuni, R.; Pierre, P.; Popovici, R.; Rajnavolgyi, E.; Schierer, S.; Schuler, G.; Soumelis, V.; Splendiani, A.; Stefanini, I.; Torcia, M.G.; Zanoni, I.; Zollinger, R.; Figdor, C.G.; Austyn, J.M.

    2010-01-01

    BACKGROUND: The advent of Systems Biology has been accompanied by the blooming of pathway databases. Currently pathways are defined generically with respect to the organ or cell type where a reaction takes place. The cell type specificity of the reactions is the foundation of immunological research,

  16. Signal transduction profile of chemical sensitisers in dendritic cells: An endpoint to be included in a cell-based in vitro alternative approach to hazard identification?

    International Nuclear Information System (INIS)

    The development of non-animal testing methods for the assessment of skin sensitisation potential is an urgent challenge within the framework of existing and forthcoming legislation. Efforts have been made to replace current animal tests, but so far no alternative methods have been developed. It is widely recognised that alternatives to animal testing cannot be accomplished with a single approach, but rather will require the integration of results obtained from different in vitro and in silico assays. The argument subjacent to the development of in vitro dendritic cell (DC)-based assays is that sensitiser-induced changes in the DC phenotype can be differentiated from those induced by irritants. This assumption is derived from the unique capacity of DC to convert environmental signals encountered at the skin into a receptor expression pattern (MHC class II molecules, co-stimulatory molecules, chemokine receptors) and a soluble mediator release profile that will stimulate T lymphocytes. Since signal transduction cascades precede changes in surface marker expression and cytokine/chemokine secretion, these phenotypic modifications are a consequence of a signal transduction profile that is specifically triggered by sensitisers and not by irritants. A limited number of studies have addressed this subject and the present review attempts to summarise and highlight all of the signalling pathways modulated by skin sensitisers and irritants. Furthermore, we conclude this review by focusing on the most promising strategies suitable for inclusion into a cell-based in vitro alternative approach to hazard identification.

  17. 3D-dynamic visualization of complex molecular cell biology processes : 1-year university students' understanding of visualizations of signal transduction

    OpenAIRE

    Jacobsson, Johan Lars Henrik

    2008-01-01

    This study deals with the use of 3D-dynamic visualizations for teaching complex molecular cell biology concepts. The focus is on signal transduction, which is a concept that constitutes an important part of biological systems. 3D-dynamic visualizations (animations) were produced and shown for a total of 24 students attending a course in molecular cell biology at Karlstad University, Sweden. Data were collected by questionnaires and interviews which were structured around the understandability...

  18. Cell surface receptors for signal transduction and ligand transport - a design principles study

    Energy Technology Data Exchange (ETDEWEB)

    Shankaran, Harish; Resat, Haluk; Wiley, H. S.

    2007-06-01

    Although many different receptors undergo endocytosis, the system-level design principles that govern the evolution of receptor dynamics are far from fully understood. We have constructed a generalized mathematical model to understand how receptor internalization dynamics encodes receptor function and regulation. Parametric analysis of the response of receptor systems to ligand inputs reveals that receptors can be categorized a being: i) avidity-controlled where the response control depends primarily on the extracelluar ligand capture efficiency, ii) consumption-controlled where the ability to internalize surface-bound ligand is the primary control parameter, and iii) dual-sensitivity where both the avidity and consumption parameters are important. We show that the transferrin and low-density lipoprotein receptors are avidity-controlled, the vitellogenin receptor is consumption-controlled and epidermal growth factor receptor is a dual-sensitivity receptor. Significantly, we show that ligand-induced endocytosis is a mechanism to anhance the accuracy of signaling receptors rather than serving to attenuate signaling. Our analysis reveals that the location of a receptor system in the avidity-consumption parameter space can be used to understand both its function and its regulations.

  19. The Mammary Epithelial Cell Secretome and its Regulation by Signal Transduction Pathways

    Energy Technology Data Exchange (ETDEWEB)

    Jacobs, Jon M.; Waters, Katrina M.; Kathmann, Loel E.; Camp, David G.; Wiley, H. S.; Smith, Richard D.; Thrall, Brian D.

    2008-02-01

    Extracellular proteins released by mammary epithelial cells are critical mediators of cell communication, proliferation and organization, yet the actual spectrum of proteins released by any given cell (the secretome) is poorly characterized. To define the set of proteins secreted by human mammary epithelial cells (HMEC), we combined analytical and computational approaches to define a secretome protein set based upon probable biological significance. Analysis of HMEC-conditioned medium by liquid chromatography-mass spectrometry resulted in identification of 889 unique proteins, of which 151 were found to be specifically enriched in the extracellular compartment when compared with a database of proteins expressed in whole HMEC lysates. Additional high mass accuracy analysis revealed 36 proteins whose extracellular abundance increased after treatment with phorbol ester (PMA), a protein kinase C agonist and general secretagogue. Many of the PMA stimulated proteins have been reported to be aberrantly expressed in human cancers and appear to be co-regulated as multigene clusters. By inhibiting PMA-mediated transactivation of the epidermal growth factor receptor (EGFR), a pathway critically required for normal HMEC function, we found that the secretion of specific matrix metalloproteases were also coordinately regulated through EGFR transactivation. This study demonstrates a tiered strategy by which extracellular proteins can be identified and progressively assigned to classes of increasing confidence and regulatory importance.

  20. Signal transduction mechanisms in plants: an overview

    Science.gov (United States)

    Clark, G. B.; Thompson, G. Jr; Roux, S. J.

    2001-01-01

    This article provides an overview on recent advances in some of the basic signalling mechanisms that participate in a wide variety of stimulus-response pathways. The mechanisms include calcium-based signalling, G-protein-mediated-signalling and signalling involving inositol phospholipids, with discussion on the role of protein kinases and phosphatases interspersed. As a further defining feature, the article highlights recent exciting findings on three extracellular components that have not been given coverage in previous reviews of signal transduction in plants, extracellular calmodulin, extracellular ATP, and integrin-like receptors, all of which affect plant growth and development.

  1. Chronic Hyperinsulinism Induced Down-regulation of Insulin Post-Recentor Signaling Transduction in Hep G2 Cells

    Institute of Scientific and Technical Information of China (English)

    2002-01-01

    Summary: To study the regulatory effect of acute and chronic insulin treatment on insulin post-re-ceptor signaling transduction pathway in a human hepatoma cell line (Hep G2), Hep G2 cells wereincubated in the presence or absence of insulin with different concentrations in serum free mediafor 16 h and then stimulated with 100 nmol/L insulin for 1 min. Protein levels of insulin receptorβ-subunit (IRβ), insulin receptor substrate-1 (IRS-1) and p85 subunit of phosphatidylinositol 3-kinase (PI 3-kinase) were determined in total cell lysates by Western-immunoblot. Phosphorylat-ed proteins IRβ, IRS-1 and interaction of PI 3-kinase with IRS-1 were determined by immunopre-cipitation. Results showed that 1-min insulin stimulation rapidly induced tyrosine phosphorylationof IRβ and IRS-l, which in turn, resulting in association of PI 3-kinase with IRS-1. 1-100 nmol/L chronic insulin treatment induced a dose-dependent decrease in the protein level of IRβ and aslight decrease in the protein level of IRS-1. There wass more marked reduction in the phospho-rylation of IRβ, IRS-1, reaching a nadir of 22 % (P<0. 01) and 15 % (P<0. 01) of control lev-els, respectively, after 16 h treatment with 100 nmol/L insulin. The association between IRS-1and PI 3-kinase was decreased by 66 % (P<0. 01). There was no significant change in PI 3-ki-nase protein levels. These data suggest that chronic insulin treatment can induce alterations ofIRβ, IRS-1 and PI 3-kinase three early steps in insulin action, which contributes significantly toinsulin resistance, and may account for desensitization of insulin action.

  2. Action of luteinizing hormone-releasing hormone in rat ovarian cells: Hormone production and signal transduction

    Energy Technology Data Exchange (ETDEWEB)

    Wang, Jian.

    1989-01-01

    The present study was conducted to investigate the hypothesis that the breakdown of membrane phosphoinositides may participate in the actions of luteinizing hormone-releasing hormone (LHRH) on hormone production in rat granulosa cells. In cells prelabeled with ({sup 3}H)inositol or ({sup 3}H)arachidonic acid (AA), treatment with LHRH increased the formation of radiolabeled inositol 1,4,5-trisphosphate (IP{sub 3}) and diacylglycerol (DG), and the release of radiolabeled AA. Since IP{sub 3} induces intracellular Ca{sup 2+} mobilization, changes in the cytosolic free calcium ion concentrations ((Ca{sup 2+})i) induced by LHRH were studied in individual cells using fura-2 microspectrofluorimetry. Alterations in (Ca{sup 2+})i induced by LHRH were rapid and transient, and could be completely blocked by a LHRH antagonist. Sustained perifusion of LHRH resulted in a desensitization of the (Ca{sup 2+})i response to LHRH. LHRH treatment accelerated (Ca{sup 2+})i depletion in the cells perifused with Ca{sup 2+} free medium, indicating the involvement of intracellular Ca{sup 2+} pool(s) in (Ca{sup 2+})i changes. The actions of LHRH on the regulation of progesterone (P{sub 4}) and prostaglandin E{sub 2} (PGE{sub 2}) production were also examined. LHRH increased basal P{sub 4} production and attenuated FSH induced P{sub 4} production. Both basal and FSH stimulated PGE{sub 2} formation were increased by LHRH. Since LHRH also increased the formation of DG that stimulates the activity of protein kinase C, an activator of protein kinase C (12-0-tetradecanolyphorbol-13-acetate: TPA) was used with the Ca{sup 2+} ionophore A23187 and melittin (an activator of phospholipase A{sub 2}) to examine the roles of protein kinase C, Ca{sup 2+} and free AA, respectively, in LHRH action.

  3. Signal transduction in red blood cells of the lizards Ameiva ameiva and Tupinambis merianae (Squamata, Teiidae).

    Science.gov (United States)

    Beraldo, F H; Sartorello, R; Lanari, R D; Garcia, C R

    2001-06-01

    The fluorescent calcium probe, Fluo-3, AM was used to measure the intracellular calcium concentration in red blood cells (RBCs) of the teiid lizards Ameiva ameiva and Tupinambis merianae. The cytosolic [Ca2+] is maintained around 20 nM and the cells contain membrane-bound Ca2+ pools. One pool appears to be identifiable with the endoplasmic reticulum (ER) inasmuch as addition of the sarco-endoplasmic reticulum Ca2+ ATPase, SERCA, inhibitor thapsigargin induces an increase in cytosolic [Ca2+ both in the presence and in the absence of extracellular Ca2+. In addition to the ER, an acidic compartment appears to be involved in Ca2+ storage, as collapse of intracellular pHgradients by monensin, a Na+ -H+ exchanger, and nigericin, a K+ -H+ exchanger, induce the release of Ca2+ from internal pools. A vacuolar H+ pump, sensitive to NBD-Cl and bafilomycin appears to be necessary to load the acidic Ca2+ pools. Finally, the purinergic agonist ATP triggers a rapid and transient increase of [Ca2+]c in the cells from both lizard species, mostly by mobilization of the cation from internal stores. PMID:11352509

  4. Molecular Basis of Mechano-Signal Transduction in Vascular Endothelial Cells

    Science.gov (United States)

    Jo, Hanjoong

    2004-01-01

    Simulated microgravity studies using a random positioning machine (RPM). One RPM machine has been built for us by Fokker Science in Netherland. Using the device, we have developed an in vitro system to examine the effect of simulated microgravity on osteoblastic bone cells. Using this system, we have carried out gene chip studies to determine the gene expression profiles of osteoblasts cultured under simulated microgravity conditions in comparison to static controls. From this study, we have identified numerous genes, some of which are expected ones inducing bone loss, but many of which are unexpected and unknown. These findings are being prepared for publications.

  5. Methylmercury, an environmental electrophile capable of activation and disruption of the Akt/CREB/Bcl-2 signal transduction pathway in SH-SY5Y cells

    Science.gov (United States)

    Unoki, Takamitsu; Abiko, Yumi; Toyama, Takashi; Uehara, Takashi; Tsuboi, Koji; Nishida, Motohiro; Kaji, Toshiyuki; Kumagai, Yoshito

    2016-01-01

    Methylmercury (MeHg) modifies cellular proteins via their thiol groups in a process referred to as “S-mercuration”, potentially resulting in modulation of the cellular signal transduction pathway. We examined whether low-dose MeHg could affect Akt signaling involved in cell survival. Exposure of human neuroblastoma SH-SY5Y cells of up to 2 μM MeHg phosphorylated Akt and its downstream signal molecule CREB, presumably due to inactivation of PTEN through S-mercuration. As a result, the anti-apoptotic protein Bcl-2 was up-regulated by MeHg. The activation of Akt/CREB/Bcl-2 signaling mediated by MeHg was, at least in part, linked to cellular defence because either pretreatment with wortmannin to block PI3K/Akt signaling or knockdown of Bcl-2 enhanced MeHg-mediated cytotoxicity. In contrast, increasing concentrations of MeHg disrupted Akt/CREB/Bcl-2 signaling. This phenomenon was attributed to S-mercuration of CREB through Cys286 rather than Akt. These results suggest that although MeHg is an apoptosis-inducing toxicant, this environmental electrophile is able to activate the cell survival signal transduction pathway at lower concentrations prior to apoptotic cell death. PMID:27357941

  6. Hypergravity signal transduction in HeLa cells with concomitant phosphorylation of proteins immunoprecipitated with anti-microtubule-associated protein antibodies

    Science.gov (United States)

    Kumei, Yasuhiro; Whitson, Peggy A.; Sato, Atsushige; Cintron, Nitza M.

    1991-01-01

    It is shown that hypergravity (35g) stimulates the production of inositol 1,4,5-trisphosphate (IP3) and decreases adenosine 3-prime,5-prime-cyclic monophosphate (cAMP) levels in HeLa cells. It is proposed that IP3 and cAMP may act as second messengers in hypergravity signal transduction. Phosphorylation of microtubule-associated proteins in both the detergent-soluble and -insoluble fractions suggests that cytoskeletal structures may be influenced by gravity.

  7. Signal transduction immunohistochemistry - Methods and protocols

    Directory of Open Access Journals (Sweden)

    CarloAlberto Redi

    2011-11-01

    Full Text Available Alexander E. Kalyuzhny statement that immunohistochemical detection of labile, low abundance and short-lived signal transduction molecules appears to be a very challenging task actually captures the same reader’s feeling. Each of us daily using immunohistochemical protocols to reveal targets either useful for research or diagnostic aims will surely wonder by which tricky techniques it is possible to overcome the preservation and unmasking of those labile antigens involved in signal transduction. Well, by seventheen chapters grouped in five parts Prof. Alexander E. Kalyuzhny is presenting an invaluable technical and methodological source of hints to satisfy our needs: to overcome troubleshottings if we are already in the field or to orientate those entering the field....

  8. Signal transduction by guanine nucleotide binding proteins.

    Science.gov (United States)

    Spiegel, A M

    1987-01-01

    High affinity binding of guanine nucleotides and the ability to hydrolyze bound GTP to GDP are characteristics of an extended family of intracellular proteins. Subsets of this family include cytosolic initiation and elongation factors involved in protein synthesis, and cytoskeletal proteins such as tubulin (Hughes, S.M. (1983) FEBS Lett. 164, 1-8). A distinct subset of guanine nucleotide binding proteins is membrane-associated; members of this subset include the ras gene products (Ellis, R.W. et al. (1981) Nature 292, 506-511) and the heterotrimeric G-proteins (also termed N-proteins) (Gilman, A.G. (1984) Cell 36, 577-579). Substantial evidence indicates that G-proteins act as signal transducers by coupling receptors (R) to effectors (E). A similar function has been suggested but not proven for the ras gene products. Known G-proteins include Gs and Gi, the G-proteins associated with stimulation and inhibition, respectively, of adenylate cyclase; transducin (TD), the G-protein coupling rhodopsin to cGMP phosphodiesterase in rod photoreceptors (Bitensky, M.W. et al. (1981) Curr. Top. Membr. Transp. 15, 237-271; Stryer, L. (1986) Annu. Rev. Neurosci. 9, 87-119), and Go, a G-protein of unknown function that is highly abundant in brain (Sternweis, P.C. and Robishaw, J.D. (1984) J. Biol. Chem. 259, 13806-13813; Neer, E.J. et al. (1984) J. Biol. Chem. 259, 14222-14229). G-proteins also participate in other signal transduction pathways, notably that involving phosphoinositide breakdown. In this review, I highlight recent progress in our understanding of the structure, function, and diversity of G-proteins. PMID:2435586

  9. Signal transduction by growth factor receptors: signaling in an instant

    DEFF Research Database (Denmark)

    Dengjel, Joern; Akimov, Vyacheslav; Blagoev, Blagoy;

    2007-01-01

    -out by mass spectrometry-based proteomics has allowed exciting views on the very early events in signal transduction. Activation profiles of regulated phosphorylation sites on epidermal growth factor receptor and downstream signal transducers showed different kinetics within the first ten seconds...

  10. [6]-Gingerol Prevents Disassembly of Cell Junctions and Activities of MMPs in Invasive Human Pancreas Cancer Cells through ERK/NF-κB/Snail Signal Transduction Pathway

    Directory of Open Access Journals (Sweden)

    Sung Ok Kim

    2013-01-01

    Full Text Available To study the effects of [6]-gingerol, a ginger phytochemical, on tight junction (TJ molecules, we investigated TJ tightening and signal transduction pathways in human pancreatic duct cell-derived cancer cell line PANC-1. The following methods were utilized: MTT assay to determine cytotoxicity; zymography to examine matrix metalloproteinase (MMP activities; transepithelial electrical resistance (TER and paracellular flux for TJ measurement; RT-PCR and immunoblotting for proteins related to TJ and invasion; and EMSA for NF-κB activity in PANC-1 cells. Results revealed that TER significantly increased and claudin 4 and MMP-9 decreased compared to those of the control. TJ protein levels, including zonula occludens (ZO- 1, occludin, and E-cadherin, increased in [6]-gingerol-treated cells, which correlated with a decrease in paracellular flux and MMP activity. Furthermore, NF-κB/Snail nuclear translocation was suppressed via downregulation of the extracellular signal-regulated kinase (ERK pathway in response to [6]-gingerol treatment. Moreover, treatment with U0126, an ERK inhibitor, completely blocked NF-κB activity. In conclusion, these findings demonstrate that [6]-gingerol regulates TJ-related proteins and suppresses invasion and metastasis through NF-κB/Snail inhibition via inhibition of the ERK pathway. Therefore, [6]-gingerol may suppress the invasive activity of PANC-1 cells.

  11. Analysis of signal transduction in brain cells using molecular signal microscope; Bunshi jiho kenbikyo wo mochiita nousaibou no joho henkan kiko no kaiseki

    Energy Technology Data Exchange (ETDEWEB)

    Kawato, Suguru [The University of Tokyo, Tokyo (Japan). Dept. of Biophysics and Life Sciences

    1999-12-16

    We analyzed the signal transduction in brain neurons by real-time imaging of Ca/NO signals using the Molecular Signal Microscope. We also analyzed synthesis and action of neurosteroids in the hippocampus. We discovered steroid synthesis machinery containing cytochrome P 450 scc in hippocampal neurons. We found that pregnenolone sulfate acutely potentiated NMDA receptor-mediated Ca conductivity in hippocampal neurons. We also found that stress steroid corticosterone acutely prolonged NMDA receptor-mediated Ca{sup 2+} influx, resulting in Ca-induced neuro-toxicity. (author)

  12. Host Signal Transduction and Protein Kinases Implicated in Legionella Infection

    OpenAIRE

    Hempstead, Andrew D.; Isberg, Ralph R.

    2013-01-01

    Modulation of the phosphorylation status of proteins by both kinases and phosphatases plays an important role in cellular signal transduction. Challenge of host cells by Legionella pneumophila manipulates the phosphorylation state of multiple host factors. These changes play roles in bacterial uptake, vacuole modification, cellular survival, and the immune response. In addition to modification by host cell kinases in response to the bacterium, L. pneumophila translocates bacterial kinases int...

  13. Role of the phosphoinositide signal transduction pathway in the endometrium

    Institute of Scientific and Technical Information of China (English)

    Vincenza Rita Lo Vasco

    2012-01-01

    The regulation of calcium concentration triggers physiological events in all cell types. Unregulated elevation in calcium concentrations is often cytotoxic.In fact, uncontrolled calcium levels alter proteins’ function, apoptosis regulation, as well as proliferation, secretion and contraction.Calcium levels are tightly regulated.A great interest was paid to signal transduction pathways for their role in mammalian reproduction.The role of phosphoinositide(PI) signal transduction pathway and related phosphoinositide-specific phospholipaseC(PI-PLC) enzymes in the regulation of calcium levels was actively studied and characterized.However, the role of PI signaling andPI-PLC enzymes in the endometrium is far to be completely highlighted.In the present review the role ofPI, the expression of selectedPI-PLC enzymes and the crosstalk with further signaling systems in the endometrium will be discussed.

  14. Protein phosphorylation and its role in archaeal signal transduction.

    Science.gov (United States)

    Esser, Dominik; Hoffmann, Lena; Pham, Trong Khoa; Bräsen, Christopher; Qiu, Wen; Wright, Phillip C; Albers, Sonja-Verena; Siebers, Bettina

    2016-09-01

    Reversible protein phosphorylation is the main mechanism of signal transduction that enables cells to rapidly respond to environmental changes by controlling the functional properties of proteins in response to external stimuli. However, whereas signal transduction is well studied in Eukaryotes and Bacteria, the knowledge in Archaea is still rather scarce. Archaea are special with regard to protein phosphorylation, due to the fact that the two best studied phyla, the Euryarchaeota and Crenarchaeaota, seem to exhibit fundamental differences in regulatory systems. Euryarchaeota (e.g. halophiles, methanogens, thermophiles), like Bacteria and Eukaryotes, rely on bacterial-type two-component signal transduction systems (phosphorylation on His and Asp), as well as on the protein phosphorylation on Ser, Thr and Tyr by Hanks-type protein kinases. Instead, Crenarchaeota (e.g. acidophiles and (hyper)thermophiles) only depend on Hanks-type protein phosphorylation. In this review, the current knowledge of reversible protein phosphorylation in Archaea is presented. It combines results from identified phosphoproteins, biochemical characterization of protein kinases and protein phosphatases as well as target enzymes and first insights into archaeal signal transduction by biochemical, genetic and polyomic studies.

  15. Protein phosphorylation and its role in archaeal signal transduction

    Science.gov (United States)

    Esser, Dominik; Hoffmann, Lena; Pham, Trong Khoa; Bräsen, Christopher; Qiu, Wen; Wright, Phillip C.; Albers, Sonja-Verena; Siebers, Bettina

    2016-01-01

    Reversible protein phosphorylation is the main mechanism of signal transduction that enables cells to rapidly respond to environmental changes by controlling the functional properties of proteins in response to external stimuli. However, whereas signal transduction is well studied in Eukaryotes and Bacteria, the knowledge in Archaea is still rather scarce. Archaea are special with regard to protein phosphorylation, due to the fact that the two best studied phyla, the Euryarchaeota and Crenarchaeaota, seem to exhibit fundamental differences in regulatory systems. Euryarchaeota (e.g. halophiles, methanogens, thermophiles), like Bacteria and Eukaryotes, rely on bacterial-type two-component signal transduction systems (phosphorylation on His and Asp), as well as on the protein phosphorylation on Ser, Thr and Tyr by Hanks-type protein kinases. Instead, Crenarchaeota (e.g. acidophiles and (hyper)thermophiles) only depend on Hanks-type protein phosphorylation. In this review, the current knowledge of reversible protein phosphorylation in Archaea is presented. It combines results from identified phosphoproteins, biochemical characterization of protein kinases and protein phosphatases as well as target enzymes and first insights into archaeal signal transduction by biochemical, genetic and polyomic studies. PMID:27476079

  16. Effects of potassium channel on shear stress - induced signal transduction in vascular endothelial cells%K离子通道在剪切力诱导血管内皮细胞信号转导中的作用

    Institute of Scientific and Technical Information of China (English)

    胡金麟

    1999-01-01

    Fluid shear stress play an important role in many physiological and pathophysiological processes of cardiovascular system. Shear stress - induced signal transduction throughout the vascular endothelial cell includes ion channels,G- protein linked receptors, tyrosine kinase receptors and integrins. The one impossible pathway of shear stress - induced signal transduction was biochemical reaction through second messenger, activating protein kinases and cytosolic transcription factors, and then regulating gene transcription . The other pathway was cytoskeletal system. This article reviewed the cellular and molecular mechanism of potassium channel signal transduction resulting from shear stress.

  17. Effects of microgravity environment on intracellular signal transduction pathways

    Directory of Open Access Journals (Sweden)

    De CHANG

    2012-09-01

    Full Text Available Microgravity environment is a stress and extracellular signal that affects cellular morphology and function through signal transduction system, thus leading to certain biological effect. At present, many signaling pathways have been reported to be involved in the regulation of cell function under microgravity environment, such as NF-κB signaling pathway, Notch signaling pathway, MAPK signaling pathway, HSP signaling pathway and so on, and these reports have laid a foundation for the molecular studies of cytolergy under outer space environment. The recent progress in the researches on intracellular signaling pathways affected by microgravity is herewith reviewed in present paper in the hope of providing references for understanding the cell activity in space environment, and to find the ways to alleviate the harmful effects caused by the microgravity environment.

  18. Participation of intracellular signal transduction in the radio-adaptive response induced by low-dose X-irradiation in human embryonic cells

    Energy Technology Data Exchange (ETDEWEB)

    Ishii, Keiichiro; Hoshi, Yuko; Iwasaki, Toshiyasu [Central Research Inst. of Electric Power Industry, Komae, Tokyo (Japan). Komae Research Lab.; Watanabe, Masami

    1996-11-01

    To elucidate the induction mechanism of radio-adaptive response in normal cells, we searched the literatures of the intracellular signal transduction. Furthermore, we examined the induction of radio-adaptive response with or without inhibitors of several kinds of protein kinase. The major results obtained were as follows; (1) According to the literature survey it is revealed that there are 4 intracellular signal transduction pathways which are possibly involved in the induction of radio-adaptive response: pathways depending on cAMP, calcium, cGMP, or protein-tyrosine kinase. (2) Addition of either inhibitor of protein-tyrosine kinase or protein kinase C to the cell culture medium during the low-dose X-irradiation inhibited the induction of radio-adaptive response. However, the addition of inhibitor of cAMP-dependent protein kinase, cGMP-dependent protein kinase, or Ca{sup 2+}-calmodulin kinase II failed to inhibit the induction of radio-adaptive response. (3) These results suggest that the signal induced in cells by low-dose X-irradiation was transduced from protein-tyrosine kinase to protein kinase C via either pathway of phosphatidylinositol 3-kinase or splitting of profilin binding phosphatidylinositol 4,5-bisphosphate. (author)

  19. FASEB summer research conference on signal transduction in plants. Final report, June 16, 1996--June 21, 1996

    Energy Technology Data Exchange (ETDEWEB)

    Lomax, T.L.; Quatrano, R.S.

    1996-12-31

    This is the program from the second FASEB conference on Signal Transduction in Plants. Topic areas included the following: environmental signaling; perception and transduction of light signals; signaling in plant microbe interactions; signaling in plant pathogen interactions; cell, cell communication; cytoskeleton, plasma membrane, and cellwall continuum; signaling molecules in plant growth and development I and II. A list of participants is included.

  20. Erythropoietin suppresses epithelial to mesenchymal transition and intercepts Smad signal transduction through a MEK-dependent mechanism in pig kidney (LLC-PK1) cell lines

    Energy Technology Data Exchange (ETDEWEB)

    Chen, Chien-Liang; Chou, Kang-Ju; Lee, Po-Tsang [Division of Nephrology, Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan (China); Department of Medicine, National Yang-Ming University School of Medicine, Taipei, Taiwan (China); Chen, Ying-Shou; Chang, Tsu-Yuan; Hsu, Chih-Yang; Huang, Wei-Chieh [Division of Nephrology, Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan (China); Chung, Hsiao-Min [Division of Nephrology, Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan (China); Department of Medicine, National Yang-Ming University School of Medicine, Taipei, Taiwan (China); Fang, Hua-Chang, E-mail: hcfang@isca.vghks.gov.tw [Division of Nephrology, Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan (China); Department of Medicine, National Yang-Ming University School of Medicine, Taipei, Taiwan (China)

    2010-04-15

    Purpose: Tumor growth factor-{beta}1 (TGF-{beta}1) plays a pivotal role in processes like kidney epithelial-mesenchymal transition (EMT) and interstitial fibrosis, which correlate well with progression of renal disease. Little is known about underlying mechanisms that regulate EMT. Based on the anatomical relationship between erythropoietin (EPO)-producing interstitial fibroblasts and adjacent tubular cells, we investigated the role of EPO in TGF-{beta}1-mediated EMT and fibrosis in kidney injury. Methods: We examined apoptosis and EMT in TGF-{beta}1-treated LLC-PK1 cells in the presence or absence of EPO. We examined the effect of EPO on TGF-{beta}1-mediated Smad signaling. Apoptosis and cell proliferation were assessed with flow cytometry and hemocytometry. We used Western blotting and indirect immunofluorescence to evaluate expression levels of TGF-{beta}1 signal pathway proteins and EMT markers. Results: We demonstrated that ZVAD-FMK (a caspase inhibitor) inhibited TGF-{beta}1-induced apoptosis but did not inhibit EMT. In contrast, EPO reversed TGF-{beta}1-mediated apoptosis and also partially inhibited TGF-{beta}1-mediated EMT. We showed that EPO treatment suppressed TGF-{beta}1-mediated signaling by inhibiting the phosphorylation and nuclear translocation of Smad 3. Inhibition of mitogen-activated protein kinase kinase 1 (MEK 1) either directly with PD98059 or with MEK 1 siRNA resulted in inhibition of EPO-mediated suppression of EMT and Smad signal transduction in TGF-{beta}1-treated cells. Conclusions: EPO inhibited apoptosis and EMT in TGF-{beta}1-treated LLC-PK1 cells. This effect of EPO was partially mediated by a mitogen-activated protein kinase-dependent inhibition of Smad signal transduction.

  1. Effect of cigarette smoke extract on lipopolysaccha-ride-activated mitogen-activated protein kinase signal transduction pathway in cultured cells

    Institute of Scientific and Technical Information of China (English)

    LI Wen; XU Yong-jian; SHEN Hua-hao

    2007-01-01

    Background Lipopolysaccharide (LPS) forms outer membrane of the wall of Gram-negative cells. LPS can directly cause damage to epithelia of respiratory tract and is the major factor responsible for the chronic inflammation of respiratory passage. The mitogen-activated protein kinase (MAPK) signal transduction pathway of the airway epithelia is intimately associated with the action of LPS. The chronic inflammation of respiratory tract and smoking are interrelated and entwined in the development and progression of chronic lung diseases. This study was designed to examine the effects of cigarette smoke extract (CSE) and LPS on MAPK signal transduction pathway in order to further understand the roles CSE and LPS play in chronic lung inflammation.Methods Cultured primary human epithelial cells of airway were divided into four groups according to the stimulants used: blank control group, LPS-stimulation group, CSE-stimulation group and CSE plus LPS group. Western blotting was employed for the detection of phosphorylation level of extracellular-signal-regulated-kinase (ERK1/2), p38 MAPK and c-Jun N-terminal kinase (JNK). The expression of cytokines of MAPK transduction pathway (granulocyte-macrophage colony stimulating factor (GM-CSF) and mRNA of IL-8) in the primary epithelial cells of respiratory tract was also determined.Results Western blotting revealed that the phosphorylation levels of ERK1/2, p38 MAPK and JNK were low and 2 hours after the LPS stimulation, the phosphorylation of ERK1/2, p38 MAPK and JNK were all increased. There was a significant difference in the phosphorylation between the LPS-stimulation group and blank control group (P<0.05); no significant difference was found between CSE-stimulation group and blank control group (P>0.05); there was a significant difference between CSE + LPS group and blank control group and between CSE + LPS group and LPS group (P<0.05). The phosphorylation of CSE-LPS group was higher than that of blank control group but

  2. Striatal Signal Transduction and Drug Addiction

    Science.gov (United States)

    Philibin, Scott D.; Hernandez, Adan; Self, David W.; Bibb, James A.

    2011-01-01

    Drug addiction is a severe neuropsychiatric disorder characterized by loss of control over motivated behavior. The need for effective treatments mandates a greater understanding of the causes and identification of new therapeutic targets for drug development. Drugs of abuse subjugate normal reward-related behavior to uncontrollable drug-seeking and -taking. Contributions of brain reward circuitry are being mapped with increasing precision. The role of synaptic plasticity in addiction and underlying molecular mechanisms contributing to the formation of the addicted state are being delineated. Thus we may now consider the role of striatal signal transduction in addiction from a more integrative neurobiological perspective. Drugs of abuse alter dopaminergic and glutamatergic neurotransmission in medium spiny neurons of the striatum. Dopamine receptors important for reward serve as principle targets of drugs abuse, which interact with glutamate receptor signaling critical for reward learning. Complex networks of intracellular signal transduction mechanisms underlying these receptors are strongly stimulated by addictive drugs. Through these mechanisms, repeated drug exposure alters functional and structural neuroplasticity, resulting in transition to the addicted biological state and behavioral outcomes that typify addiction. Ca2+ and cAMP represent key second messengers that initiate signaling cascades, which regulate synaptic strength and neuronal excitability. Protein phosphorylation and dephosphorylation are fundamental mechanisms underlying synaptic plasticity that are dysregulated by drugs of abuse. Increased understanding of the regulatory mechanisms by which protein kinases and phosphatases exert their effects during normal reward learning and the addiction process may lead to novel targets and pharmacotherapeutics with increased efficacy in promoting abstinence and decreased side effects, such as interference with natural reward, for drug addiction. PMID

  3. Cellular Prion Protein and Caveolin-1 Interaction in a Neuronal Cell Line Precedes Fyn/Erk 1/2 Signal Transduction

    Directory of Open Access Journals (Sweden)

    Mattia Toni

    2006-01-01

    Full Text Available It has been reported that cellular prion protein (PrPc is enriched in caveolae or caveolae-like domains with caveolin-1 (Cav-1 participating to signal transduction events by Fyn kinase recruitment. By using the Glutathione-S-transferase (GST-fusion proteins assay, we observed that PrPc strongly interacts in vitro with Cav-1. Thus, we ascertained the PrPc caveolar localization in a hypothalamic neuronal cell line (GN11, by confocal microscopy analysis, flotation on density gradient, and coimmunoprecipitation experiments. Following the anti-PrPc antibody-mediated stimulation of live GN11 cells, we observed that PrPc clustered on plasma membrane domains rich in Cav-1 in which Fyn kinase converged to be activated. After these events, a signaling cascade through p42/44 MAP kinase (Erk 1/2 was triggered, suggesting that following translocations from rafts to caveolae or caveolae-like domains PrPc could interact with Cav-1 and induce signal transduction events.

  4. Cell signaling review series

    Institute of Scientific and Technical Information of China (English)

    Aiming Lin; Zhenggang Liu

    2008-01-01

    @@ Signal transduction is pivotal for many, if not all, fundamental cellular functions including proliferation, differentiation, transformation and programmed cell death. Deregulation of cell signaling may result in certain types of cancers and other human diseases.

  5. Roles of lipid turnover in transmembrane signal transduction.

    Science.gov (United States)

    Ganong, B R

    1991-11-01

    Cells of higher organisms respond to external stimuli with a cascade of intracellular biochemical events initiated by binding of a hormone, growth factor, or neurotransmitter to a specific cell surface receptor. Previously well-characterized signal transduction pathways involve cyclic nucleotides as intracellular second messengers. Over the past decade, increasing attention has been focused on other signaling pathways in which membrane lipids serve as second messengers or their precursors. This review describes current understanding of these pathways and points to recent discoveries likely to open new frontiers in the coming decade.

  6. Effect of mitogen-activated protein kinase signal transduction pathway on multidrug resistance induced by vincristine in gastric cancer cell line MGC803

    Institute of Scientific and Technical Information of China (English)

    Bo Chen; Feng Jin; Ping Lu; Xiang-Lan Lu; Ping-Ping Wang; Yun-Peng Liu; Fan Yao; Shu-Bao Wang

    2004-01-01

    AIM: To investigate the correlation between mitogenactivated protein kinase (MAPK) signal transduction pathway and multidrug resistance (MDR) in MGC803 cells. METHODS: Western blot was used to analyze the expression of MDR associated gene in transient vincristine (VCR) induced MGC803 cells, which were treated with or without the specific inhibitor of MAPK, PD098059. Morphologic analysis of the cells treated by VCR with or without PD098059 was determined by Wright-Giemsa staining. The cell cycle analysis was performed by using flow cytometric assay and the drug sensitivity of MGC803 cells which were exposed to VCR with or without PD098059 was tested by using MTT assay. RESULTS: Transient exposure to VCR induced P-gp but not MRP1 or GST-π expression in MGC803 cells and the expression of P-gp was inhibited by PD098059. Apoptotic bodies were found in the cells treated with VCR or VCR+PD098059. FCM results indicated that more MGC803 cells showed apoptotic phenotype when treated by VCR and PD098059 (rate: 3L.23%) than treated by VCR only (rate:18.42%) (P<0.05). The ICs0 (284±13.2 μg/L) of MGC803 cells pretreated with VCR was 2.24-fold as that of negative control group (127±17.6 μg/L) and 1.48-fold as that of the group treated with PD098059 (191±27.9 μg/L). CONCLUSION: This study shows that the expression of P-gp can be induced by transient exposure to VCR and this induction can be prevented by PD098059, which can block the activity of MAPK. MAPK signal transduction pathway may play some roles in modulating MDR1 expression in gastric cancer.

  7. Nonequilibrium phase transitions in biomolecular signal transduction

    Science.gov (United States)

    Smith, Eric; Krishnamurthy, Supriya; Fontana, Walter; Krakauer, David

    2011-11-01

    We study a mechanism for reliable switching in biomolecular signal-transduction cascades. Steady bistable states are created by system-size cooperative effects in populations of proteins, in spite of the fact that the phosphorylation-state transitions of any molecule, by means of which the switch is implemented, are highly stochastic. The emergence of switching is a nonequilibrium phase transition in an energetically driven, dissipative system described by a master equation. We use operator and functional integral methods from reaction-diffusion theory to solve for the phase structure, noise spectrum, and escape trajectories and first-passage times of a class of minimal models of switches, showing how all critical properties for switch behavior can be computed within a unified framework.

  8. Effects of TNF-α on the expression of monocyte chemoattractant protein-1 and the corresponding signal transduction pathway in dental follicle cells

    Directory of Open Access Journals (Sweden)

    Ying-chun BI

    2011-02-01

    Full Text Available Objective To study the effect of different concentration of tumor necrosis factor-α(TNF-α on the expression of monocyte chemoattractant protein-1(MCP-1 and the corresponding signal transduction pathway in human dental follicle cells.Methods The 5th passage of human dental follicle cells were co-incubated with 0(control group,5,10,25,50 and 100 ng/ml TNF-α,respectively,for 6 hours.The contents of MCP-1 in the supernatant were measured by using sandwich ELISA,and the expression of MCP-1 mRNA was determined by reverses transcription polymerase chain reaction(RT-PCR.Furthermore,to determine the corresponding signal transduction pathway,the 5th passage of human dental follicle cells were incubated with 25 μmol/L SB203580 to inhibit p38 mitogen-activated protein kinase(p38MARK,with 50 μmol/L PD98059 to inhibit extracellular signal-regulated kinases(ERK,and with 15 μmol/L SP600125 to inhibit c-Jun N-terminal kinases(JNK for 30min,then incubated with TNF-α(10ng/ml for 6h.MCP-1 mRNA was detected by RT-PCR.Results The results of ELISA revealed that 10-100 ng/ml of TNF-α enhanced MCP-1 secretion(P < 0.05 compared to that in human dental follicle cells without TNF-α treatment.Cells treated with 10-50 ng/ml of TNF-α showed a significant increase of MCP-1 mRNA expression(P < 0.05,and the action was inhibited by SP600125,which was the special inhibitor of c-Jun N-terminal kinase(JNK.Conclusion TNF-α may enhance MCP-1 gene expression and secretion in human dental follicle cells,and the activation of JNK signal transduction pathway is required in this process.

  9. The role of a cell surface inhibitor in early signal transduction associated with the regulation of cell division and differentiation

    Science.gov (United States)

    Johnson, T. C.; Enebo, D. J.; Moos, P. J.; Fattaey, H. K.; Spooner, B. S. (Principal Investigator)

    1992-01-01

    Serum stimulation of quiescent human fibroblast cultures resulted in a hyperphosphorylation of the nuclear retinoblastoma gene susceptibility product (RB). However, serum stimulation in the presence of 9 x 10(-8) M of a purified bovine sialoglycopeptide (SGP) cell surface inhibitor abrogated the hyperphosphorylation of the RB protein and the subsequent progression of cells through the mitotic cycle. The experimental results suggest that the SGP mediated its cell cycle arrest at a site in the cell cycle that was at the time of RB phosphorylation or somewhat upstream of the modification of this regulatory protein of cell division. Both cells serum-deprived and serum stimulated in the presence of the SGP displayed only a hypophosphorylated RB protein, consistent with the SGP-mediated cell cycle arrest point being near the G1/S interface.

  10. Growth inhibition and apoptosis in cancer cells induced by polyphenolic compounds of Acacia hydaspica: Involvement of multiple signal transduction pathways

    Science.gov (United States)

    Afsar, Tayyaba; Trembley, Janeen H.; Salomon, Christine E.; Razak, Suhail; Khan, Muhammad Rashid; Ahmed, Khalil

    2016-01-01

    Acacia hydaspica R. Parker is known for its medicinal uses in multiple ailments. In this study, we performed bioassay-guided fractionation of cytotoxic compounds from A. hydaspica and investigated their effects on growth and signaling activity in prostate and breast cancer cell lines. Four active polyphenolic compounds were identified as 7-O-galloyl catechin (GC), catechin (C), methyl gallate (MG), and catechin-3-O-gallate (CG). The four compounds inhibited prostate cancer PC-3 cell growth in a dose-dependent manner, whereas CG and MG inhibited breast cancer MDA-MB-231 cell growth. All tested compounds inhibited cell survival and colony growth in both cell lines, and there was evidence of chromatin condensation, cell shrinkage and apoptotic bodies. Further, acridine orange, ethidium bromide, propidium iodide and DAPI staining demonstrated that cell death occurred partly via apoptosis in both PC-3 and MDA-MB-231 cells. In PC-3 cells treatment repressed the expression of anti-apoptotic molecules Bcl-2, Bcl-xL and survivin, coupled with down-regulation of signaling pathways AKT, NFκB, ERK1/2 and JAK/STAT. In MDA-MB-231 cells, treatment induced reduction of CK2α, Bcl-xL, survivin and xIAP protein expression along with suppression of NFκB, JAK/STAT and PI3K pathways. Our findings suggest that certain polyphenolic compounds derived from A. hydaspica may be promising chemopreventive/therapeutic candidates against cancer. PMID:26975752

  11. The Membrane and Lipids as Integral Participants in Signal Transduction: Lipid Signal Transduction for the Non-Lipid Biochemist

    Science.gov (United States)

    Eyster, Kathleen M.

    2007-01-01

    Reviews of signal transduction have often focused on the cascades of protein kinases and protein phosphatases and their cytoplasmic substrates that become activated in response to extracellular signals. Lipids, lipid kinases, and lipid phosphatases have not received the same amount of attention as proteins in studies of signal transduction.…

  12. Association of reactive oxygen species-mediated signal transduction with in vitro apoptosis sensitivity in chronic lymphocytic leukemia B cells.

    Directory of Open Access Journals (Sweden)

    Adam L Palazzo

    Full Text Available BACKGROUND: Chronic lymphocytic leukemia (CLL is a B cell malignancy with a variable clinical course and unpredictable response to therapeutic agents. Single cell network profiling (SCNP utilizing flow cytometry measures alterations in signaling biology in the context of molecular changes occurring in malignancies. In this study SCNP was used to identify proteomic profiles associated with in vitro apoptotic responsiveness of CLL B cells to fludarabine, as a basis for ultimately linking these with clinical outcome. METHODOLOGY/PRINCIPAL FINDING: SCNP was used to quantify modulated-signaling of B cell receptor (BCR network proteins and in vitro F-ara-A mediated apoptosis in 23 CLL samples. Of the modulators studied the reactive oxygen species, hydrogen peroxide (H₂O₂, a known intracellular second messenger and a general tyrosine phosphatase inhibitor stratified CLL samples into two sub-groups based on the percentage of B cells in a CLL sample with increased phosphorylation of BCR network proteins. Separately, in the same patient samples, in vitro exposure to F-ara-A also identified two sub-groups with B cells showing competence or refractoriness to apoptotic induction. Statistical analysis showed that in vitro F-ara-A apoptotic proficiency was highly associated with the proficiency of CLL B cells to undergo H₂O₂-augmented signaling. CONCLUSIONS/SIGNIFICANCE: This linkage in CLL B cells among the mechanisms governing chemotherapy-induced apoptosis increased signaling of BCR network proteins and a likely role of phosphatase activity suggests a means of stratifying patients for their response to F-ara-A based regimens. Future studies will examine the clinical applicability of these findings and also the utility of this approach in relating mechanism to function of therapeutic agents.

  13. The Role of Cgrp-Receptor Component Protein (Rcp in Cgrp-Mediated Signal Transduction

    Directory of Open Access Journals (Sweden)

    M. A. Prado

    2001-01-01

    Full Text Available The calcitonin gene-related peptide (CGRP-receptor component protein (RCP is a 17-kDa intracellular peripheral membrane protein required for signal transduction at CGRP receptors. To determine the role of RCP in CGRP-mediated signal transduction, RCP was depleted from NIH3T3 cells using antisense strategy. Loss of RCP protein correlated with loss of cAMP production by CGRP in the antisense cells. In contrast, loss of RCP had no effect on CGRP-mediated binding; therefore RCP is not acting as a chaperone for the CGRP receptor. Instead, RCP is a novel signal transduction molecule that couples the CGRP receptor to the cellular signal transduction machinery. RCP thus represents a prototype for a new class of signal transduction proteins that are required for regulation of G protein-coupled receptors.

  14. Tamarind Seed Xyloglucans Promote Proliferation and Migration of Human Skin Cells through Internalization via Stimulation of Proproliferative Signal Transduction Pathways

    Directory of Open Access Journals (Sweden)

    W. Nie

    2013-01-01

    Full Text Available Xyloglucans (XGs of Tamarindus indica L. Fabaceae are used as drug vehicles or as ingredients of cosmetics. Two xyloglucans were extracted from T. indica seed with cold water (TSw and copper complex precipitation (TSc. Both were analyzed in regard to composition and influence on cell viability, proliferation, cell cycle progression, migration, MAPK phosphorylation, and gene expression of human skin keratinocytes (NHEK and HaCaT and fibroblasts (NHDF in vitro. TSw and TSc differed in molecular weight, rhamnose content, and ratios of xylose, arabinose, galactose, and glucose. Both XGs improved keratinocytes and fibroblast proliferation, promoted the cell cycle, and stimulated migration and intracellular enzyme activity of NHDF after endosomal uptake. Only TSw significantly enhanced HaCaT migration and extracellular enzyme activity of NHDF and HaCaT. TSw and TSc predominantly enhanced the phosphorylation of molecules that referred to Erk signaling in NHEK. In NHDF parts of the integrin signaling and SAPK/JNK pathway were affected. Independent of cell type TSw marginally regulated the expression of genes, which referred to membrane proteins, cytoskeleton, cytokine signaling, and ECM as well as to processes of metabolism and transcription. Results show that T. indica xyloglucans promote skin regeneration by a direct influence on cell proliferation and migration.

  15. Tamarind Seed Xyloglucans Promote Proliferation and Migration of Human Skin Cells through Internalization via Stimulation of Proproliferative Signal Transduction Pathways.

    Science.gov (United States)

    Nie, W; Deters, A M

    2013-01-01

    Xyloglucans (XGs) of Tamarindus indica L. Fabaceae are used as drug vehicles or as ingredients of cosmetics. Two xyloglucans were extracted from T. indica seed with cold water (TSw) and copper complex precipitation (TSc). Both were analyzed in regard to composition and influence on cell viability, proliferation, cell cycle progression, migration, MAPK phosphorylation, and gene expression of human skin keratinocytes (NHEK and HaCaT) and fibroblasts (NHDF) in vitro. TSw and TSc differed in molecular weight, rhamnose content, and ratios of xylose, arabinose, galactose, and glucose. Both XGs improved keratinocytes and fibroblast proliferation, promoted the cell cycle, and stimulated migration and intracellular enzyme activity of NHDF after endosomal uptake. Only TSw significantly enhanced HaCaT migration and extracellular enzyme activity of NHDF and HaCaT. TSw and TSc predominantly enhanced the phosphorylation of molecules that referred to Erk signaling in NHEK. In NHDF parts of the integrin signaling and SAPK/JNK pathway were affected. Independent of cell type TSw marginally regulated the expression of genes, which referred to membrane proteins, cytoskeleton, cytokine signaling, and ECM as well as to processes of metabolism and transcription. Results show that T. indica xyloglucans promote skin regeneration by a direct influence on cell proliferation and migration.

  16. Tamarind Seed Xyloglucans Promote Proliferation and Migration of Human Skin Cells through Internalization via Stimulation of Proproliferative Signal Transduction Pathways.

    Science.gov (United States)

    Nie, W; Deters, A M

    2013-01-01

    Xyloglucans (XGs) of Tamarindus indica L. Fabaceae are used as drug vehicles or as ingredients of cosmetics. Two xyloglucans were extracted from T. indica seed with cold water (TSw) and copper complex precipitation (TSc). Both were analyzed in regard to composition and influence on cell viability, proliferation, cell cycle progression, migration, MAPK phosphorylation, and gene expression of human skin keratinocytes (NHEK and HaCaT) and fibroblasts (NHDF) in vitro. TSw and TSc differed in molecular weight, rhamnose content, and ratios of xylose, arabinose, galactose, and glucose. Both XGs improved keratinocytes and fibroblast proliferation, promoted the cell cycle, and stimulated migration and intracellular enzyme activity of NHDF after endosomal uptake. Only TSw significantly enhanced HaCaT migration and extracellular enzyme activity of NHDF and HaCaT. TSw and TSc predominantly enhanced the phosphorylation of molecules that referred to Erk signaling in NHEK. In NHDF parts of the integrin signaling and SAPK/JNK pathway were affected. Independent of cell type TSw marginally regulated the expression of genes, which referred to membrane proteins, cytoskeleton, cytokine signaling, and ECM as well as to processes of metabolism and transcription. Results show that T. indica xyloglucans promote skin regeneration by a direct influence on cell proliferation and migration. PMID:24106497

  17. The Na+/H+ exchanger NHE1 in stress-induced signal transduction: implications for cell proliferation and cell death

    DEFF Research Database (Denmark)

    Pedersen, Stine Falsig

    2006-01-01

    The ubiquitous plasma membrane Na+/H+ exchanger NHE1 is highly conserved across vertebrate species and is extensively characterized as a major membrane transport mechanism in the regulation of cellular pH and volume. In recent years, the understanding of the role of NHE1 in regulating cell functi...

  18. Involvement of phospholipase D-related signal transduction in chemical-induced programmed cell death in tomato cell cultures

    NARCIS (Netherlands)

    Iakimova, E.T.; Michaeli, R.; Woltering, E.J.

    2013-01-01

    Phospholipase D (PLD) and its product phosphatidic acid (PA) are incorporated in a complex metabolic network in which the individual PLD isoforms are suggested to regulate specific developmental and stress responses, including plant programmed cell death (PCD). Despite the accumulating knowledge, th

  19. Involvement of M3 Cholinergic Receptor Signal Transduction Pathway in Regulation of the Expression of Chemokine MOB-1, MCP-1 Genes in Pancreatic Acinar Cells

    Institute of Scientific and Technical Information of China (English)

    郑海; 陈道达; 张景輝; 田原

    2004-01-01

    Whether M3 cholinergic receptor signal transduction pathway is involved in regulation of the activation of NF-κB and the expression of chemokine MOB-1, MCP-1genes in pancreatic acinar cells was investigated. Rat pancreatic acinar cells were isolated, cultured and treated with carbachol, atropine and PDTC in vitro. The MOB-1 and MCP-1 mRNA expression was detected by using RT-PCR. The activation of NF-κB was monitored by using electrophoretic mobility shift assay.The results showed that as compared with control group, M3 cholinergic receptor agonist (103mol/L, 104-4ol/L carbachol) could induce a concentration-dependent and time-dependent increase in the expression of MOB-1, MCP-1 mRNA in pancreatic acinar cells. After treatment with 10 -3mol/L carbachol for 2 h, the expression of MOB-1, MCP-1 mRNA was strongest. The activity of NF-κB in pancreatic acinar cells was significantly increased (P<0.01) after treated with M3 cholinergic receptor agonist (10-3 mol/L carbachol) in vitro for 30 min. Either M3 cholinergic receptor antagonist (10-5 mol/L atropine) or NF-κB inhibitor (10-2 mol/L PDTC) could obviously inhibit the activation of NF-κB and the chemokine MOB-1, MCP-1 mRNA expression induced by carbachol (P <0.05). This inhibitory effect was significantly increased by atropine plus PDTC (P<0.01). The results of these studies indicated that M3 cholinergic receptor signal transduction pathway was likely involved in regulation of the expression of chemokine MOB-1 and MCP-1genes in pancreatic acinar cells in vitro through the activation of NF-κB.

  20. The Role of Matrine and Mitogen-Ativated Protein Kinase/Extracellular Signal-Regulated Kinase Signal Transduction in the Inhibition of the Proliferation and Migration of Human Umbilical Veins Endothelial Cells Induced by Lung Cancer cells

    Directory of Open Access Journals (Sweden)

    Ming BAI

    2009-07-01

    Full Text Available Background and objective Matrine, one of the major alkaloid components of the traditional Chinese medicine Sophora roots, has a wide range of pharmacological effects including anti-inflammatory activities, growth inhibition and induction of cell differentiation and apoptosis. Motigen-activated protein kinase (MAPK/extracellular signal-regulated kinase (ERK has found to be a crucial signaling pathway in endothelial cells. The aim of this study is to investigate the role of Matrine and MAPK/ERK signal transduction in the inhibition of the proliferation and migration of human umbilical veins endothelial cells (HUVECs induced by lung cancer cells. Methods HUVECs were cultured with A549CM. Mat or PD98059 (i.e PD, specific inhibitor of MAPK/ERK, was added into the A549CM. The proliferation of the HUVECs was measured by cell counting. The migration of the HUVECs was observed by wound healing assay. The expression levels of ERK and p-ERK protein were detected by Western Blot analysis. Results On 24 hours after intervention, the A549CM significantly stimulated the proliferation, migration and expression of p-ERK of HUVECs. Compared with the A549CM group, Mat significantly inhibited the proliferation, migration and p-ERK expression of HUVECs induced by A549CM. While PD only decreased the proliferation and p-ERK expression of HUVECs induced by A549CM. PD had no effect in the migration of HUVECs. Conclusion The results demonstrated that Mat and PD98059 can effectively decrease proliferation and expression of p-ERK of HUVECs induced by A549CM. Furthermore Mat can also inhibit migration of HUVECs induced by A549CM that did not changed by PD98059. These data implied that suppressing MAPK/ERK signal transduction may play the crucial role in resisting lung cacinoma angiogenesis with Mat.

  1. Signal transduction and downregulation of C-MET in HGF stimulated low and highly metastatic human osteosarcoma cells

    Energy Technology Data Exchange (ETDEWEB)

    Husmann, Knut, E-mail: khusmann@research.balgrist.ch [Laboratory for Orthopedic Research, Department of Orthopedics, Balgrist University Hospital, University of Zurich, Zurich (Switzerland); Ducommun, Pascal [Laboratory for Orthopedic Research, Department of Orthopedics, Balgrist University Hospital, University of Zurich, Zurich (Switzerland); Division of Plastic Surgery and Hand Surgery, Department of Surgery, University Hospital Zurich, Zurich (Switzerland); Sabile, Adam A.; Pedersen, Else-Marie; Born, Walter; Fuchs, Bruno [Laboratory for Orthopedic Research, Department of Orthopedics, Balgrist University Hospital, University of Zurich, Zurich (Switzerland)

    2015-09-04

    The poor outcome of osteosarcoma (OS), particularly in patients with metastatic disease and a five-year survival rate of only 20%, asks for more effective therapeutic strategies targeting malignancy-promoting mechanisms. Dysregulation of C-MET, its ligand hepatocyte growth factor (HGF) and the fusion oncogene product TPR-MET, first identified in human MNNG-HOS OS cells, have been described as cancer-causing factors in human cancers. Here, the expression of these molecules at the mRNA and the protein level and of HGF-stimulated signaling and downregulation of C-MET was compared in the parental low metastatic HOS and MG63 cell lines and the respective highly metastatic MNNG-HOS and 143B and the MG63-M6 and MG63-M8 sublines. Interestingly, expression of TPR-MET was only observed in MNNG-HOS cells. HGF stimulated the phosphorylation of Akt and Erk1/2 in all cell lines investigated, but phospho-Stat3 remained at basal levels. Downregulation of HGF-stimulated Akt and Erk1/2 phosphorylation was much faster in the HGF expressing MG63-M8 cells than in HOS cells. Degradation of HGF-activated C-MET occurred predominantly through the proteasomal and to a lesser extent the lysosomal pathway in the cell lines investigated. Thus, HGF-stimulated Akt and Erk1/2 signaling as well as proteasomal degradation of HGF activated C-MET are potential therapeutic targets in OS. - Highlights: • Expression of TPR-MET was only observed in MNNG-HOS cells. • HGF stimulated the phosphorylation of Akt and Erk1/2 but not of Stat3 in osteosarcoma cell lines. • Degradation of HGF-activated C-MET occurred predominantly through the proteasomal pathway.

  2. SELF-ADAPTIVE CONTROLS OF A COMPLEX CELLULAR SIGNALING TRANSDUCTION SYSTEM

    Institute of Scientific and Technical Information of China (English)

    LI Hong; ZHOU Zhiyuan; DAI Rongyang; LUO Bo; ZHENG Xiaoli; YANG Wenli; HE Tao; WU Minglu

    2004-01-01

    In cells, the interactions of distinct signaling transduction pathways originating from cross-talkings between signaling molecules give rise to the formation of signaling transduction networks, which contributes to the changes (emergency) of kinetic behaviors of signaling system compared with single molecule or pathway. Depending on the known experimental data, we have constructed a model for complex cellular signaling transduction system, which is derived from signaling transduction of epidermal growth factor receptor in neuron. By the computational simulating methods, the self-adaptive controls of this system have been investigated. We find that this model exhibits a relatively stable selfadaptive system, especially to over-stimulation of agonist, and the amplitude and duration of signaling intermediates in it could be controlled by multiple self-adaptive effects, such as "signal scattering", "positive feedback", "negative feedback" and "B-Raf shunt". Our results provide an approach to understanding the dynamic behaviors of complex biological systems.

  3. Involvement of formyl peptide receptors in receptor for advanced glycation end products (RAGE - and amyloid beta 1-42-induced signal transduction in glial cells

    Directory of Open Access Journals (Sweden)

    Slowik Alexander

    2012-11-01

    Full Text Available Abstract Background Recent studies suggest that the chemotactic G-protein-coupled-receptor (GPCR formyl-peptide-receptor-like-1 (FPRL1 and the receptor-for-advanced-glycation-end-products (RAGE play an important role in the inflammatory response involved in neurodegenerative disorders such as Alzheimer’s disease (AD. Therefore, the expression and co-localisation of mouse formyl peptide receptor (mFPR 1 and 2 as well as RAGE in an APP/PS1 transgenic mouse model using immunofluorescence and real-time RT-PCR were analysed. The involvement of rat or human FPR1/FPRL1 (corresponds to mFPR1/2 and RAGE in amyloid-β 1–42 (Aβ1-42-induced signalling were investigated by extracellular signal regulated kinase 1/2 (ERK1/2 phosphorylation. Furthermore, the cAMP level in primary rat glial cells (microglia and astrocytes and transfected HEK 293 cells was measured. Formyl peptide receptors and RAGE were inhibited by a small synthetic antagonist WRW4 and an inactive receptor variant delta-RAGE, lacking the intracytoplasmatic domains. Results We demonstrated a strong increase of mFPR1/2 and RAGE expression in the cortex and hippocampus of APP/PS1 transgenic mice co-localised to the glial cells. In addition, the Aβ1-42-induced signal transduction is dependant on FPRL1, but also on FPR1. For the first time, we have shown a functional interaction between FPRL1/FPR1 and RAGE in RAGE ligands S100B- or AGE-mediated signalling by ERK1/2 phosphorylation and cAMP level measurement. In addition a possible physical interaction between FPRL1 as well as FPR1 and RAGE was shown with co-immunoprecipitation and fluorescence microscopy. Conclusions The results suggest that both formyl peptide receptors play an essential role in Aβ1-42-induced signal transduction in glial cells. The interaction with RAGE could explain the broad ligand spectrum of formyl peptide receptors and their important role for inflammation and the host defence against infections.

  4. BowTieBuilder: modeling signal transduction pathways

    Directory of Open Access Journals (Sweden)

    Schröder Adrian

    2009-06-01

    Full Text Available Abstract Background Sensory proteins react to changing environmental conditions by transducing signals into the cell. These signals are integrated into core proteins that activate downstream target proteins such as transcription factors (TFs. This structure is referred to as a bow tie, and allows cells to respond appropriately to complex environmental conditions. Understanding this cellular processing of information, from sensory proteins (e.g., cell-surface proteins to target proteins (e.g., TFs is important, yet for many processes the signaling pathways remain unknown. Results Here, we present BowTieBuilder for inferring signal transduction pathways from multiple source and target proteins. Given protein-protein interaction (PPI data signaling pathways are assembled without knowledge of the intermediate signaling proteins while maximizing the overall probability of the pathway. To assess the inference quality, BowTieBuilder and three alternative heuristics are applied to several pathways, and the resulting pathways are compared to reference pathways taken from KEGG. In addition, BowTieBuilder is used to infer a signaling pathway of the innate immune response in humans and a signaling pathway that potentially regulates an underlying gene regulatory network. Conclusion We show that BowTieBuilder, given multiple source and/or target proteins, infers pathways with satisfactory recall and precision rates and detects the core proteins of each pathway.

  5. Model of the initiation of signal transduction by ligands in a cell culture: Simulation of molecules near a plane membrane comprising receptors

    Science.gov (United States)

    Plante, Ianik; Cucinotta, Francis A.

    2011-11-01

    Cell communication is a key mechanism in tissue responses to radiation. Several molecules are implicated in radiation-induced signaling between cells, but their contributions to radiation risk are poorly understood. Meanwhile, Green's functions for diffusion-influenced reactions have appeared in the literature, which are applied to describe the diffusion of molecules near a plane membrane comprising bound receptors with the possibility of reversible binding of a ligand and activation of signal transduction proteins by the ligand-receptor complex. We have developed Brownian dynamics algorithms to simulate particle histories in this system which can accurately reproduce the theoretical distribution of distances of a ligand from the membrane, the number of reversibly bound particles, and the number of receptor complexes activating signaling proteins as a function of time, regardless of the number of time steps used for the simulation. These simulations will be of great importance to model interactions at low doses where stochastic effects induced by a small number of molecules or interactions come into play.

  6. Modelling protein functional domains in signal transduction using Maude

    Science.gov (United States)

    Sriram, M. G.

    2003-01-01

    Modelling of protein-protein interactions in signal transduction is receiving increased attention in computational biology. This paper describes recent research in the application of Maude, a symbolic language founded on rewriting logic, to the modelling of functional domains within signalling proteins. Protein functional domains (PFDs) are a critical focus of modern signal transduction research. In general, Maude models can simulate biological signalling networks and produce specific testable hypotheses at various levels of abstraction. Developing symbolic models of signalling proteins containing functional domains is important because of the potential to generate analyses of complex signalling networks based on structure-function relationships.

  7. Genetic analysis of gravity signal transduction in roots

    Science.gov (United States)

    Masson, Patrick; Strohm, Allison; Baldwin, Katherine

    To grow downward into the soil, roots use gravity as a guide. Specialized cells, named stato-cytes, enable this directional growth response by perceiving gravity. Located in the columella region of the cap, these cells sense a reorientation of the root within the gravity field through the sedimentation of, and/or tension/pressure exerted by, dense amyloplasts. This process trig-gers a gravity signal transduction pathway that leads to a fast alkalinization of the cytoplasm and a change in the distribution of the plasma membrane-associated auxin-efflux carrier PIN3. The latter protein is uniformly distributed within the plasma membrane on all sides of the cell in vertically oriented roots. However, it quickly accumulates at the bottom side upon gravis-timulation. This process correlates with a preferential transport of auxin to the bottom side of the root cap, resulting in a lateral gradient across the tip. This gradient is then transported to the elongation zone where it promotes differential cellular elongation, resulting in downward curvature. We isolated mutations that affect gravity signal transduction at a step that pre-cedes cytoplasmic alkalinization and/or PIN3 relocalization and lateral auxin transport across the cap. arg1 and arl2 mutations identify a common genetic pathway that is needed for all three gravity-induced processes in the cap statocytes, indicating these genes function early in the pathway. On the other hand, adk1 affects gravity-induced PIN3 relocalization and lateral auxin transport, but it does not interfere with cytoplasmic alkalinization. ARG1 and ARL2 encode J-domain proteins that are associated with membranes of the vesicular trafficking path-way whereas ADK1 encodes adenosine kinase, an enzyme that converts adenosine derived from nucleic acid metabolism and the AdoMet cycle into AMP, thereby alleviating feedback inhibi-tion of this important methyl-donor cycle. Because mutations in ARG1 (and ARL2) do not completely eliminate

  8. Inhibition of Grb2-mediated activation of MAPK signal transduction suppresses NOR1/CB1954-induced cytotoxicity in the HepG2 cell line.

    Science.gov (United States)

    Gui, Rong; Li, Dengqing; Qi, Guannan; Suhad, Ali; Nie, Xinmin

    2012-09-01

    The nitroreductase oxidored-nitro domain containing protein 1 (NOR1) gene may be involved in the chemical carcinogenesis of hepatic cancer and nasopharyngeal carcinoma (NPC). We have previously demonstrated that NOR1 overexpression is capable of converting the monofunctional alkylating agent 5-(aziridin-1-yl)-2,4-dinitrobenzamide (CB1954) into a toxic form by reducing the 4-nitro group of CB1954. Toxic CB1954 is able to enhance cell killing in the NPC cell line CNE1; however, the underlying mechanisms remain unknown. Using cDNA microarrays and quantitative real-time PCR, we previously discovered that NOR1 increases the expression of growth factor receptor-bound protein 2 (Grb2) mRNA by 4.8-fold in the human hepatocellular carcinoma cell line HepG2. In the present study, we revealed that NOR1 increased Grb2 protein expression by 3-fold in HepG2 cells. Additionally, we demonstrated that NOR1 enhanced CB1954-induced cell killing in HepG2 cells, and cell cytotoxicity was inhibited with the tyrosine kinase inhibitor genistein, or by stable transfection of Grb2 small hairpin RNA (shRNA) pU6(+27)-shGrb2 to silence the expression of Grb2. Western blot analysis revealed that Grb2 downregulation may reduce the activity of the mitogen-activated protein kinase (MAPK). Inhibiting the activation of MAPK using the methyl ethyl ketone (MEK) inhibtor PD98059 suppressed CB1954-induced cell killing. These results suggested that the NOR1 gene enhances CB1954-mediated cell cytotoxicity through the upregulation of Grb2 expression and the activation of MAPK signal transduction in the HepG2 cell line. PMID:23741254

  9. Characterization of cell surface and extracellular matrix remodeling of Azospirillum brasilense chemotaxis-like 1 signal transduction pathway mutants by atomic force microscopy.

    Science.gov (United States)

    Edwards, Amanda Nicole; Siuti, Piro; Bible, Amber N; Alexandre, Gladys; Retterer, Scott T; Doktycz, Mitchel J; Morrell-Falvey, Jennifer L

    2011-01-01

    To compete in complex microbial communities, bacteria must sense environmental changes and adjust cellular functions for optimal growth. Chemotaxis-like signal transduction pathways are implicated in the regulation of multiple behaviors in response to changes in the environment, including motility patterns, exopolysaccharide production, and cell-to-cell interactions. In Azospirillum brasilense, cell surface properties, including exopolysaccharide production, are thought to play a direct role in promoting flocculation. Recently, the Che1 chemotaxis-like pathway from A. brasilense was shown to modulate flocculation, suggesting an associated modulation of cell surface properties. Using atomic force microscopy, distinct changes in the surface morphology of flocculating A. brasilense Che1 mutant strains were detected. Whereas the wild-type strain produces a smooth mucosal extracellular matrix after 24 h, the flocculating Che1 mutant strains produce distinctive extracellular fibril structures. Further analyses using flocculation inhibition, lectin-binding assays, and comparison of lipopolysaccharides profiles suggest that the extracellular matrix differs between the cheA1 and the cheY1 mutants, despite an apparent similarity in the macroscopic floc structures. Collectively, these data indicate that disruption of the Che1 pathway is correlated with distinctive changes in the extracellular matrix, which likely result from changes in surface polysaccharides structure and/or composition.

  10. Characterization of cell surface and extracellular matrix remodeling of Azospirillum brasilense chemotaxis-like 1 signal transduction pathway mutants by atomic force microscopy

    Energy Technology Data Exchange (ETDEWEB)

    Doktycz, Mitchel John [ORNL; Morrell-Falvey, Jennifer L [ORNL

    2011-01-01

    To compete in complex microbial communities, bacteria must sense environmental changes and adjust cellular functions for optimal growth. Chemotaxis-like signal transduction pathways are implicated in the regulation of multiple behaviors in response to changes in the environment, including motility patterns, exopolysaccharide production, and cell-to-cell interactions. In Azospirillum brasilense, cell surface properties, including exopolysaccharide production, are thought to play a direct role in promoting flocculation. Recently, the Che1 chemotaxis-like pathway from A. brasilense was shown to modulate flocculation, suggesting an associated modulation of cell surface properties. Using atomic force microscopy, distinct changes in the surface morphology of flocculating A. brasilense Che1 mutant strains were detected. Whereas the wild-type strain produces a smooth mucosal extracellular matrix after 24 h, the flocculating Che1 mutant strains produce distinctive extracellular fibril structures. Further analyses using flocculation inhibition, lectin-binding assays, and comparison of lipopolysaccharides profiles suggest that the extracellular matrix differs between the cheA1 and the cheY1 mutants, despite an apparent similarity in the macroscopic floc structures. Collectively, these data indicate that disruption of the Che1 pathway is correlated with distinctive changes in the extracellular matrix, which likely result from changes in surface polysaccharides structure and/or composition.

  11. Signal transduction by HLA-DR is mediated by tyrosine kinase(s) and regulated by CD45 in activated T cells

    DEFF Research Database (Denmark)

    Odum, Niels; Martin, P J; Schieven, G L;

    1991-01-01

    , but the inhibitory effect of CD45 dominated over the enhancing effect of CD4. These data indicate that PTK activation is obligatory for DR-induced (Ca2+)i responses, suggesting a linkage between these pathways in class II signal transduction. This conclusion is consistent with our observation that in activated human...

  12. Genetic Analysis of Gravity Signal Transduction in Arabidopsis Roots

    Science.gov (United States)

    Masson, Patrick; Strohm, Allison; Barker, Richard; Su, Shih-Heng

    Like most other plant organs, roots use gravity as a directional guide for growth. Specialized cells within the columella region of the root cap (the statocytes) sense the direction of gravity through the sedimentation of starch-filled plastids (amyloplasts). Amyloplast movement and/or pressure on sensitive membranes triggers a gravity signal transduction pathway within these cells, which leads to a fast transcytotic relocalization of plasma-membrane associated auxin-efflux carrier proteins of the PIN family (PIN3 and PIN7) toward the bottom membrane. This leads to a polar transport of auxin toward the bottom flank of the cap. The resulting lateral auxin gradient is then transmitted toward the elongation zones where it triggers a curvature that ultimately leads to a restoration of vertical downward growth. Our laboratory is using strategies derived from genetics and systems biology to elucidate the molecular mechanisms that modulate gravity sensing and signal transduction in the columella cells of the root cap. Our previous research uncovered two J-domain-containing proteins, ARG1 and ARL2, as contributing to this process. Mutations in the corresponding paralogous genes led to alterations of root and hypocotyl gravitropism accompanied by an inability for the statocytes to develop a cytoplasmic alkalinization, relocalize PIN3, and transport auxin laterally, in response to gravistimulation. Both proteins are associated peripherally to membranes belonging to various compartments of the vesicular trafficking pathway, potentially modulating the trafficking of defined proteins between plasma membrane and endosomes. MAR1 and MAR2, on the other end, are distinct proteins of the plastidic outer envelope protein import TOC complex (the transmembrane channel TOC75 and the receptor TOC132, respectively). Mutations in the corresponding genes enhance the gravitropic defects of arg1. Using transformation-rescue experiments with truncated versions of TOC132 (MAR2), we have shown

  13. Importin β1 mediates nuclear factor-κB signal transduction into the nuclei of myeloma cells and affects their proliferation and apoptosis.

    Science.gov (United States)

    Yan, Wenqing; Li, Rong; He, Jie; Du, Juan; Hou, Jian

    2015-04-01

    Multiple myeloma (MM) is a plasma cell neoplasm that is currently incurable. The activation of nuclear factor-κB (NF-κB) signalling plays a crucial role in the immortalisation of MM cells. As the most important transcription factor of the canonical NF-κB pathway, the p50/p65 heterodimer requires transportation into the nucleus for its successful signal transduction. Importin β1 is the key transport receptor that mediates p50/p65 nuclear import. Currently, it remains unclear whether the regulation of importin β1 function affects the biological behaviour of MM cells. In the present study, we investigated the changes in p65 translocation and the proliferation and apoptosis of MM cells after treatment with small interfering RNA (siRNA) or an importin β1 inhibitor. The underlying mechanisms were also investigated. We found importin β1 over-expression and the excessive nuclear transport of p65 in myeloma cells. Confocal laser scanning microscopy and Western blot analysis results indicated that p65 nuclear transport was blocked after inhibiting importin β1 expression with siRNA and the importin β1-specific inhibitor importazole (IPZ). Importantly, electronic mobility shift assay results also verified that p65 nuclear transport was dramatically reduced. Moreover, the expression of the NF-κB signalling target genes involved in MM cell apoptosis, such as BCL-2, c-IAP1 and XIAP, were markedly reduced, as demonstrated by the RT-PCR results. Furthermore, the proliferation of MM cells was inhibited, as demonstrated by MTT assay results, and the MM cell apoptosis rate was higher, as demonstrated by the annexin V/propidium iodide (PI) double-staining assay results. Additionally, the percentage of S phase cells in the myeloma cell lines treated with IPZ was dramatically reduced. In conclusion, our results clearly show that importin β1 mediates the translocation of NF-κB into the nuclei of myeloma cells, thereby regulating proliferation and blocking apoptosis, which

  14. Human hematopoietic cell culture, transduction, and analyses

    DEFF Research Database (Denmark)

    Bonde, Jesper; Wirthlin, Louisa; Kohn, Donald B;

    2008-01-01

    This unit provides methods for introducing genes into human hematopoietic progenitor cells. The Basic Protocol describes isolation of CD34(+) cells, transduction of these cells with a retroviral vector on fibronectin-coated plates, assaying the efficiency of transduction, and establishing long......-term cultures. Support protocols describe methods for maintenance of vector-producing fibroblasts (VPF) and supernatant collection from these cells, screening medium components for the ability to support hematopoietic cell growth, and establishing colonies from long-term cultures. Other protocols provide PCR...

  15. Characterization of Cell Surface and EPS Remodeling of Azospirillum brasilense Chemotaxis-like 1 Signal Transduction Pathway mutants by Atomic Force Microscopy

    Energy Technology Data Exchange (ETDEWEB)

    Billings, Amanda N [ORNL; Siuti, Piro [ORNL; Bible, Amber [University of Tennessee, Knoxville (UTK); Alexandre, Gladys [University of Tennessee, Knoxville (UTK); Retterer, Scott T [ORNL; Doktycz, Mitchel John [ORNL; Morrell-Falvey, Jennifer L [ORNL

    2011-01-01

    To compete in complex microbial communities, bacteria must quickly sense environmental changes and adjust cellular functions for optimal growth. Chemotaxis-like signal transduction pathways are implicated in the modulation of multiple cellular responses, including motility, EPS production, and cell-to-cell interactions. Recently, the Che1 chemotaxis-like pathway from Azospirillum brasilense was shown to modulate flocculation. In A. brasilense, cell surface properties, including EPS production, are thought to play a direct role in promoting flocculation. Using atomic force microscopy (AFM), we have detected distinct changes in the surface morphology of flocculating A. brasilense Che1 mutant strains that are absent in the wild type strain. Whereas the wild type strain produces a smooth mucosal extracellular matrix, the flocculating Che1 mutant strains produce distinctive extracellular fibril structures. Further analyses using flocculation inhibition and lectin-binding assays suggest that the composition of EPS components in the extracellular matrix differs between the cheA1 and cheY1 mutants, despite an apparent similarity in the macroscopic floc structures. Collectively, these data indicate that mutations in the Che1 pathway that result in increased flocculation are correlated with distinctive changes in the extracellular matrix structure produced by the mutants, including likely changes in the EPS structure and/or composition.

  16. Analysis of the gravitaxis signal transduction chain in Euglena gracilis

    Science.gov (United States)

    Nasir, Adeel

    Abstract Euglena gracilis is a photosynthetic, eukaryotic flagellate. It can adapt autotrophic and heterotrophic mode of growth and respond to different stimuli, this makes it an organism of choice for different research disciplines. It swims to reach a suitable niche by employing different stimuli such as oxygen, light, gravity and different chemicals. Among these stimuli light and gravity are the most important. Phototaxis (locomotion under light stimulus) and gravitaxis (locomotion under gravity stimulus) synergistically help cells to attain an optimal niche in the environment. However, in the complete absence of light or under scarcity of detectable light, cells can totally depend on gravity to find its swimming path. Therefore gravity has certain advantages over other stimuli.Unlike phototatic signal transduction chain of Euglena gracilis no clear primary gravity receptor has been identified in Euglena cells so far. However, there are some convincing evidence that TRP like channels act as a primary gravity receptor in Euglena gracilis.Use of different inhibitors gave rise to the involvement of protein kinase and calmodulin proteins in signal transduction chain of Euglena gracilis. Recently, specific calmodulin (Calmodulin 2) and protein kinase (PKA) have been identified as potential candidates of gravitactic signal transduction chain. Further characterization and investigation of these candidates was required. Therefore a combination of biochemical and genetic techniques was employed to localize proteins in cells and also to find interacting partners. For localization studies, specific antibodies were raised and characterized. Specificity of antibodies was validated by knockdown mutants, Invitro-translated proteins and heterologously expressed proteins. Cell fractionation studies, involving separation of the cell body and flagella for western blot analysis and confocal immunofluorescence studies were performed for subcellular localization. In order to find

  17. In search of cellular control: signal transduction in context

    Science.gov (United States)

    Ingber, D.

    1998-01-01

    The field of molecular cell biology has experienced enormous advances over the last century by reducing the complexity of living cells into simpler molecular components and binding interactions that are amenable to rigorous biochemical analysis. However, as our tools become more powerful, there is a tendency to define mechanisms by what we can measure. The field is currently dominated by efforts to identify the key molecules and sequences that mediate the function of critical receptors, signal transducers, and molecular switches. Unfortunately, these conventional experimental approaches ignore the importance of supramolecular control mechanisms that play a critical role in cellular regulation. Thus, the significance of individual molecular constituents cannot be fully understood when studied in isolation because their function may vary depending on their context within the structural complexity of the living cell. These higher-order regulatory mechanisms are based on the cell's use of a form of solid-state biochemistry in which molecular components that mediate biochemical processing and signal transduction are immobilized on insoluble cytoskeletal scaffolds in the cytoplasm and nucleus. Key to the understanding of this form of cellular regulation is the realization that chemistry is structure and hence, recognition of the the importance of architecture and mechanics for signal integration and biochemical control. Recent work that has unified chemical and mechanical signaling pathways provides a glimpse of how this form of higher-order cellular control may function and where paths may lie in the future.

  18. Physalis peruviana extract induces apoptosis in human Hep G2 cells through CD95/CD95L system and the mitochondrial signaling transduction pathway.

    Science.gov (United States)

    Wu, Shu-Jing; Ng, Lean-Teik; Lin, Doung-Liang; Huang, Shan-Ney; Wang, Shyh-Shyan; Lin, Chun-Ching

    2004-11-25

    Physalis species is a popular folk medicine used for treating cancer, leukemia, hepatitis and other diseases. Studies have shown that the ethanol extract of Physalis peruviana (EEPP) inhibits growth and induces apoptotic death of human Hep G2 cells in culture, whereas proliferation of the mouse BALB/C normal liver cells was not affected. In this study, we performed detailed studies to define the molecular mechanism of EEPP-induced apoptosis in Hep G2 cells. The results further confirmed that EEPP inhibited cell proliferation in a dose- and time-dependent manner. At 50 microg/ml, EEPP significantly increased the accumulation of the sub-G1 peak (hypoploid) and the portion of apoptotic annexin V positive cells. EEPP was found to trigger apoptosis through the release of cytochrome c, Smac/DIABLO and Omi/HtrA2 from mitochondria to cytosol and consequently resulted in caspase-3 activation. Pre-treatment with a general caspase inhibitor (z-VAD-fmk) prevented cytochrome c release. After 48 h of EEPP treatment, the apoptosis of Hep G2 cells was found to associate with an elevated p53, and CD95 and CD95L proteins expression. Furthermore, a marked down-regulation of the expression of the Bcl-2, Bcl-XL and XIAP, and up-regulation of the Bax and Bad proteins were noted. Taken together, the present results suggest that EEPP-induced Hep G2 cell apoptosis was possibly mediated through the CD95/CD95L system and the mitochondrial signaling transduction pathway. PMID:15488639

  19. Prolactin receptor and signal transduction to milk protein genes

    Energy Technology Data Exchange (ETDEWEB)

    Djiane, J.; Daniel, N.; Bignon, C. [Unite d`Endocrinologie Moleculaire, Jouy en Josas (France)] [and others

    1994-06-01

    After cloning of the mammary gland prolactin (PRL) receptor cDNA, a functional assay was established using co-transfection of PRL receptor cDNA together with a milk protein promoter/chloramphenicol acetyl transferase (CAT) construct in Chinese hamster ovary (CHO) cells. Different mutants of the PRL receptor were tested in this CAT assay to delimit the domains in the receptor necessary for signal transduction to milk protein genes. In CHO cells stably transfected with PRL receptor cDNA, high numbers of PRL receptor are expressed. By metabolic labeling and immunoprecipitation, expressed PRL receptor was identified as a single species of 100 kDa. Using these cells, we analyzed the effects of PRL on intracellular free Ca{sup ++} concentration. PRL stimulates Ca{sup ++} entry and induces secondary Ca{sup ++} mobilization. The entry of Ca{sup ++} is a result of an increase in K{sup +} conductance that hyperpolarizes the membranes. We have also analyzed tyrosine phosphorylation induced by PRL. In CHO cells stably transfected with PRL receptor cDNA, PRL induced a very rapid and transient tyrosine phosphorylation of a 100-kDa protein which is most probably the PRL receptor. The same finding was obtained in mammary membranes after PRL injection to lactating rabbits. Whereas tyrosine kinase inhibitors genistein and lavendustin were without effect, PRL stimulation of milk protein gene promoters was partially inhibited by 2 {mu}M herbimycin in CHO cells co-transfected with PRL receptor cDNA and the {Beta} lactoglobulin CAT construct. Taken together these observations indicate that the cytoplasmic domain of the PRL receptor interacts with one or several tyrosine kinases, which may represent early postreceptor events necessary for PRL signal transduction to milk protein genes. 14 refs., 4 figs.

  20. Yeast Ca(2+)-signal transduction inhibitors isolated from Dominican amber prevent the degranulation of RBL-2H3 cells through the inhibition of Ca(2+)-influx.

    Science.gov (United States)

    Abe, Tomomi; Kobayashi, Miki; Okawa, Yusuke; Inui, Tomoki; Yoshida, Jun; Higashio, Hironori; Shinden, Hisao; Uesugi, Shota; Koshino, Hiroyuki; Kimura, Ken-Ichi

    2016-09-01

    A new norlabdane compound, named kujigamberol has previously been isolated from Kuji amber (but not from Baltic amber) by activity guided fractionation. However, there has been no study of biological compounds in Dominican amber. Biological activities were examined using the hypersensitive mutant yeast (zds1Δ erg3Δ pdr1Δ pdr3Δ) with respect to Ca(2+)-signal transduction, enzymes and rat basophilic leukemia (RBL)-2H3 cells. The structures were elucidated on the basis of spectral analysis including high resolution (HR)-EI-MS, 1D NMR and 2D NMR. Three diterpenoid compounds, 5(10)-halimen-15-oic acid (1), 3-cleroden-15-oic acid (2) and 8-labden-15-oic acid (3), which are different from the bioactive compounds in Kuji and Baltic ambers, were isolated from Dominican amber. They inhibited both calcineurin (CN) (IC50=40.0, 21.2 and 34.2μM) and glycogen synthase kinase-3β (GSK-3β) (IC50=48.9, 43.8 and 41.1μM) which are involved in the growth restored activity against the mutant yeast. The most abundant compound 2 showed inhibitory activity against both degranulation and Ca(2+)-influx in RBL-2H3 cells. The compounds having the growth restoring activity against the mutant yeast have potential as anti-allergic compounds.

  1. Yeast Ca(2+)-signal transduction inhibitors isolated from Dominican amber prevent the degranulation of RBL-2H3 cells through the inhibition of Ca(2+)-influx.

    Science.gov (United States)

    Abe, Tomomi; Kobayashi, Miki; Okawa, Yusuke; Inui, Tomoki; Yoshida, Jun; Higashio, Hironori; Shinden, Hisao; Uesugi, Shota; Koshino, Hiroyuki; Kimura, Ken-Ichi

    2016-09-01

    A new norlabdane compound, named kujigamberol has previously been isolated from Kuji amber (but not from Baltic amber) by activity guided fractionation. However, there has been no study of biological compounds in Dominican amber. Biological activities were examined using the hypersensitive mutant yeast (zds1Δ erg3Δ pdr1Δ pdr3Δ) with respect to Ca(2+)-signal transduction, enzymes and rat basophilic leukemia (RBL)-2H3 cells. The structures were elucidated on the basis of spectral analysis including high resolution (HR)-EI-MS, 1D NMR and 2D NMR. Three diterpenoid compounds, 5(10)-halimen-15-oic acid (1), 3-cleroden-15-oic acid (2) and 8-labden-15-oic acid (3), which are different from the bioactive compounds in Kuji and Baltic ambers, were isolated from Dominican amber. They inhibited both calcineurin (CN) (IC50=40.0, 21.2 and 34.2μM) and glycogen synthase kinase-3β (GSK-3β) (IC50=48.9, 43.8 and 41.1μM) which are involved in the growth restored activity against the mutant yeast. The most abundant compound 2 showed inhibitory activity against both degranulation and Ca(2+)-influx in RBL-2H3 cells. The compounds having the growth restoring activity against the mutant yeast have potential as anti-allergic compounds. PMID:27491756

  2. Quantitative analysis of signal transduction in motile and phototactic cells by computerized light stimulation and model based tracking

    Science.gov (United States)

    Streif, Stefan; Staudinger, Wilfried Franz; Oesterhelt, Dieter; Marwan, Wolfgang

    2009-02-01

    To investigate the responses of Halobacterium salinarum to stimulation with light (phototaxis and photokinesis), we designed an experimental setup consisting of optical devices for automatic video image acquisition and computer-controlled light stimulation, and developed algorithms to analyze physiological responses of the cells. Cells are categorized as motile and nonmotile by a classification scheme based on the square displacement of cell positions. Computerized tracking based on a dynamic model of the stochastic cell movement and a Kalman filter-based algorithm allows smoothed estimates of the cell tracks and the detection of physiological responses to complex stimulus patterns. The setup and algorithms were calibrated which allows quantitative measurements and systematic analysis of cellular sensing and response. Overall, the setup is flexible, extensible, and consists mainly of commercially available products. This facilitates modifications of the setup and algorithms for physiological studies of the motility of cells or microorganisms.

  3. Arginine, leucine, and glutamine stimulate proliferation of porcine trophectoderm cells through the MTOR-RPS6K-RPS6-EIF4EBP1 signal transduction pathway.

    Science.gov (United States)

    Kim, Jinyoung; Song, Gwonhwa; Wu, Guoyao; Gao, Haijun; Johnson, Gregory A; Bazer, Fuller W

    2013-05-01

    During the peri-implantation and early placentation periods in pigs, conceptuses (embryo and its extra-embryonic membranes) undergo dramatic morphological changes and differentiation that require the exchange of nutrients (histotroph) and gasses across the trophectoderm and a true epitheliochorial placenta. Of these nutrients, arginine (Arg), leucine (Leu), and glutamine (Gln) are essential components of histotroph; however, little is known about changes in their total amounts in the uterine lumen of cyclic and pregnant gilts and their effects on cell signaling cascades. Therefore, we determined quantities of Arg, Leu, and Gln in uterine luminal fluids and found that total recoverable amounts of these amino acids increased in pregnant but not cyclic gilts between Days 12 and 15 after onset of estrus. We hypothesized that Arg, Leu, and Gln have differential effects on hypertrophy, hyperplasia, and differentiated functions of trophectoderm cells that are critical to conceptus development. Primary porcine trophectoderm (pTr) cells treated with either Arg, Leu, or Gln had increased abundance of phosphorylated RPS6K, RPS6, and EIF4EBP1 compared to basal levels, and this effect was maintained for up to 120 min. When pTr cells were treated with Arg, Leu, and Gln, low levels of pRPS6K and pEIF4EBP1 were detected in the cytosol, but the abundance of nuclear pRPS6K increased. Immunofluorescence analyses revealed abundant amounts of pRPS6 protein in the cytoplasm of pTr cells treated with Arg, Leu, and Gln. These amino acids also increased proliferation of pTr cells. Furthermore, when Arg, Leu, and Gln were combined with siRNAs for either MTOR, RPTOR, or RICTOR, effects of those amino acids on proliferation of pTr cells were significantly inhibited. Collectively, these results indicate that Arg, Leu, and Gln act coordinately to stimulate proliferation of pTr cells through activation of the MTOR-RPS6K-RPS6-EIF4EBP1 signal transduction pathway.

  4. FIST: a sensory domain for diverse signal transduction pathways in prokaryotes and ubiquitin signaling in eukaryotes

    Energy Technology Data Exchange (ETDEWEB)

    Borziak, Kirill [ORNL; Jouline, Igor B [ORNL

    2007-01-01

    Motivation: Sensory domains that are conserved among Bacteria, Archaea and Eucarya are important detectors of common signals detected by living cells. Due to their high sequence divergence, sensory domains are difficult to identify. We systematically look for novel sensory domains using sensitive profile-based searches initi-ated with regions of signal transduction proteins where no known domains can be identified by current domain models. Results: Using profile searches followed by multiple sequence alignment, structure prediction, and domain architecture analysis, we have identified a novel sensory domain termed FIST, which is present in signal transduction proteins from Bacteria, Archaea and Eucarya. Remote similarity to a known ligand-binding fold and chromosomal proximity of FIST-encoding genes to those coding for proteins involved in amino acid metabolism and transport suggest that FIST domains bind small ligands, such as amino acids.

  5. Signal transduction by HLA class II molecules in human T cells: induction of LFA-1-dependent and independent adhesion

    DEFF Research Database (Denmark)

    Odum, Niels; Yoshizumi, H; Okamoto, Y;

    1992-01-01

    Crosslinking HLA-DR molecules by monoclonal antibodies (moAbs) induces protein tyrosine phosphorylation and results in a secondary elevation of free cytoplasmic calcium concentrations in activated human T cells. Binding of bacterial superantigens or moAbs to DR molecules on activated T cells was ...

  6. Gene Expression Pattern of Signal Transduction in Chronic Myeloid Leukemia

    Institute of Scientific and Technical Information of China (English)

    LI Huiyu; JIE Shenghua; GUO Tiannan; HUANG Shi'ang

    2006-01-01

    To explore the transcriptional gene expression profiles of signaling pathway in Chronic myeloid leukemia (CML), a series of cDNA microarray chips were tested. The results showed that differentially expressed genes related to singal transduction in CML were screened out and the genes involved in Phosphoinositide 3-kinases (PI3K), Ras-MAPK (mitogen-activated protein kinase) and other signaling pathway genes simultaneously. The results also showed that most of these genes were up-expression genes , which suggested that signal transduction be overactivated in CML. Further analysis of these differentially expressed signal transduction genes will be helpful to understand the molecular mechanism of CML and find new targets of treatment.

  7. Phosphoproteomics-based systems analysis of signal transduction networks

    Directory of Open Access Journals (Sweden)

    Hiroko eKozuka-Hata

    2012-01-01

    Full Text Available Signal transduction systems coordinate complex cellular information to regulate biological events such as cell proliferation and differentiation. Although the accumulating evidence on widespread association of signaling molecules has revealed essential contribution of phosphorylation-dependent interaction networks to cellular regulation, their dynamic behavior is mostly yet to be analyzed. Recent technological advances regarding mass spectrometry-based quantitative proteomics have enabled us to describe the comprehensive status of phosphorylated molecules in a time-resolved manner. Computational analyses based on the phosphoproteome dynamics accelerate generation of novel methodologies for mathematical analysis of cellular signaling. Phosphoproteomics-based numerical modeling can be used to evaluate regulatory network elements from a statistical point of view. Integration with transcriptome dynamics also uncovers regulatory hubs at the transcriptional level. These omics-based computational methodologies, which have firstly been applied to representative signaling systems such as the epidermal growth factor receptor pathway, have now opened up a gate for systems analysis of signaling networks involved in immune response and cancer.

  8. Staphylococcal enterotoxin-A directly stimulates signal transduction and interferon-gamma production in psoriatic T-cell lines

    DEFF Research Database (Denmark)

    Nielsen, M B; Odum, N; Gerwien, J;

    1998-01-01

    Bacterial superantigens such as staphylococcal enterotoxin-A (SEA) have been implicated in the pathogenesis of psoriasis vulgaris. Major histocompatibility complex (MHC) class II molecules are high affinity receptors for SEA, and T cells found in psoriatic skin lesions express high levels of MHC...... are involved in the autopresentation of SEA by psoriatic T cells. In conclusion, we provide evidence that SEA directly activates MVHC class H-positive psoriatic T-cell lines to produce IFN-gamma, a key cytokine in the pathogenesis of psoriasis vulgaris....... of interferon-gamma (IFN-gamma), but not autocrine mitogenesis in CD8-positive T clones obtained from skin lesions of a patient with psoriasis vulgaris. Psoriatic T cells do not respond to SEA molecules if mutations are introduced in the TCRbeta- or in both the two MHC class II alpha- and beta-binding sites...

  9. A respiratory chain controlled signal transduction cascade in the mitochondrial intermembrane space mediates hydrogen peroxide signaling.

    Science.gov (United States)

    Patterson, Heide Christine; Gerbeth, Carolin; Thiru, Prathapan; Vögtle, Nora F; Knoll, Marko; Shahsafaei, Aliakbar; Samocha, Kaitlin E; Huang, Cher X; Harden, Mark Michael; Song, Rui; Chen, Cynthia; Kao, Jennifer; Shi, Jiahai; Salmon, Wendy; Shaul, Yoav D; Stokes, Matthew P; Silva, Jeffrey C; Bell, George W; MacArthur, Daniel G; Ruland, Jürgen; Meisinger, Chris; Lodish, Harvey F

    2015-10-20

    Reactive oxygen species (ROS) such as hydrogen peroxide (H2O2) govern cellular homeostasis by inducing signaling. H2O2 modulates the activity of phosphatases and many other signaling molecules through oxidation of critical cysteine residues, which led to the notion that initiation of ROS signaling is broad and nonspecific, and thus fundamentally distinct from other signaling pathways. Here, we report that H2O2 signaling bears hallmarks of a regular signal transduction cascade. It is controlled by hierarchical signaling events resulting in a focused response as the results place the mitochondrial respiratory chain upstream of tyrosine-protein kinase Lyn, Lyn upstream of tyrosine-protein kinase SYK (Syk), and Syk upstream of numerous targets involved in signaling, transcription, translation, metabolism, and cell cycle regulation. The active mediators of H2O2 signaling colocalize as H2O2 induces mitochondria-associated Lyn and Syk phosphorylation, and a pool of Lyn and Syk reside in the mitochondrial intermembrane space. Finally, the same intermediaries control the signaling response in tissues and species responsive to H2O2 as the respiratory chain, Lyn, and Syk were similarly required for H2O2 signaling in mouse B cells, fibroblasts, and chicken DT40 B cells. Consistent with a broad role, the Syk pathway is coexpressed across tissues, is of early metazoan origin, and displays evidence of evolutionary constraint in the human. These results suggest that H2O2 signaling is under control of a signal transduction pathway that links the respiratory chain to the mitochondrial intermembrane space-localized, ubiquitous, and ancient Syk pathway in hematopoietic and nonhematopoietic cells.

  10. Evaluating the Role of Wnt Signal Transduction in Promoting the Development of the Heart

    Directory of Open Access Journals (Sweden)

    Leonard M. Eisenberg

    2007-01-01

    Full Text Available Wnts are a family of secreted signaling proteins that are encoded by 19 distinct genes in the vertebrate genome. These molecules initiate several signal transduction pathways: the canonical Wnt, Wnt/Ca2+, and Wnt/planar cell polarity pathways. Wnt proteins have major impact on embryonic development, tumor progression, and stem cell differentiation. Wnt signal transduction also influences the formation of the heart, yet many issues concerning the involvement of Wnt regulation in initiating cardiac development remain unresolved. In this review, we will examine the published record to discern (a what has been shown by experimental studies on the participation of Wnt signaling in cardiogenesis, and (b what are the important questions that need to be addressed to understand the importance and function of Wnt signal transduction in facilitating the development of the heart.

  11. Epidermal growth factor and ras regulate gene expression in GH4 pituitary cells by separate, antagonistic signal transduction pathways

    Energy Technology Data Exchange (ETDEWEB)

    Pickett, C.A.; Gutierrez-Hartmann, A. [Univ. of Colorado Health Sciences Center, Denver, CO (United States)

    1995-12-01

    This report discusses the role of the epidermal growth factor (EGF) in promoting activation of the rat prolactin promoter in neuroendocrine cells via a Ras-independent mechanism. It also discusses the role of phosphotransferases in mediating EGF response. 32 refs., 8 figs., 1 tab.

  12. Monocyte Signal Transduction Receptors in Active and Latent Tuberculosis

    Directory of Open Access Journals (Sweden)

    Magdalena Druszczynska

    2013-01-01

    Full Text Available The mechanisms that promote either resistance or susceptibility to TB disease remain insufficiently understood. Our aim was to compare the expression of cell signaling transduction receptors, CD14, TLR2, CD206, and β2 integrin LFA-1 on monocytes from patients with active TB or nonmycobacterial lung disease and healthy individuals with M.tb latency and uninfected controls to explain the background of the differences between clinical and subclinical forms of M.tb infection. A simultaneous increase in the expression of the membrane bound mCD14 receptor and LFA-1 integrin in patients with active TB may be considered a prodrome of breaking immune control by M.tb bacilli in subjects with the latent TB and absence of clinical symptoms.

  13. Signal transduction around thymic stromal lymphopoietin (TSLP in atopic asthma

    Directory of Open Access Journals (Sweden)

    Kuepper Michael

    2008-08-01

    Full Text Available Abstract Thymic stromal lymphopoietin (TSLP, a novel interleukin-7-like cytokine, triggers dendritic cell-mediated inflammatory responses ultimately executed by T helper cells of the Th2 subtype. TSLP emerged as a central player in the development of allergic symptoms, especially in the airways, and is a prime regulatory cytokine at the interface of virus- or antigen-exposed epithelial cells and dendritic cells (DCs. DCs activated by epithelium-derived TSLP can promote naïve CD4+ T cells to adopt a Th2 phenotype, which in turn recruite eosinophilic and basophilic granulocytes as well as mast cells into the airway mucosa. These different cells secrete inflammatory cytokines and chemokines operative in inducing an allergic inflammation and atopic asthma. TSLP is, thus, involved in the control of both an innate and an adaptive immune response. Since TSLP links contact of allergen with the airway epithelium to the onset and maintainance of the asthmatic syndrome, defining the signal transduction underlying TSLP expression and function is of profound interest for a better understandimg of the disease and for the development of new therapeutics.

  14. Kv7 potassium channels in airway smooth muscle cells: signal transduction intermediates and pharmacological targets for bronchodilator therapy

    OpenAIRE

    Brueggemann, Lioubov I.; Kakad, Priyanka P.; Robert B Love; Solway, Julian; Dowell, Maria L.; Cribbs, Leanne L.; Byron, Kenneth L.

    2011-01-01

    Expression and function of Kv7 (KCNQ) voltage-activated potassium channels in guinea pig and human airway smooth muscle cells (ASMCs) were investigated by quantitative reverse transcriptase polymerase chain reaction (qRT-PCR), patch-clamp electrophysiology, and precision-cut lung slices. qRT-PCR revealed expression of multiple KCNQ genes in both guinea pig and human ASMCs. Currents with electrophysiological and pharmacological characteristics of Kv7 currents were measured in freshly isolated ...

  15. 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.

  16. Phosphoinositide pathway and the signal transduction network in neural development

    Institute of Scientific and Technical Information of China (English)

    Vincenza Rita Lo Vasco

    2012-01-01

    The development of the nervous system is under the strict control of a number of signal transduction pathways,often interconnected.Among them,the phosphoinositide (PI) pathway and the related phospholipase C (PI-PLC) family of enzymes have been attracting much attention.Besides their well-known role in the regulation of intracellular calcium levels,PI-PLC enzymes interact with a number of molecules belonging to further signal transduction pathways,contributing to a specific and complex network in the developing nervous system.In this review,the connections of PI signalling with further transduction pathways acting during neural development are discussed,with special regard to the role of the PI-PLC family of enzymes.

  17. Developing a synthetic signal transduction system in plants.

    Science.gov (United States)

    Morey, Kevin J; Antunes, Mauricio S; Albrecht, Kirk D; Bowen, Tessa A; Troupe, Jared F; Havens, Keira L; Medford, June I

    2011-01-01

    One area of focus in the emerging field of plant synthetic biology is the manipulation of systems involved in sensing and response to environmental signals. Sensing and responding to signals, including ligands, typically involves biological signal transduction. Plants use a wide variety of signaling systems to sense and respond to their environment. One of these systems, a histidine kinase (HK) based signaling system, lends itself to manipulation using the tools of synthetic biology. Both plants and bacteria use HKs to relay signals, which in bacteria can involve as few as two proteins (two-component systems or TCS). HK proteins are evolutionarily conserved between plants and bacteria and plant HK components have been shown to be functional in bacteria. We found that this conservation also applies to bacterial HK components which can function in plants. This conservation of function led us to hypothesize that synthetic HK signaling components can be designed and rapidly tested in bacteria. These novel HK signaling components form the foundation for a synthetic signaling system in plants, but typically require modifications such as codon optimization and proper targeting to allow optimal function. We describe the process and methodology of producing a synthetic signal transduction system in plants. We discovered that the bacterial response regulator (RR) PhoB shows HK-dependent nuclear translocation in planta. Using this discovery, we engineered a partial synthetic pathway in which a synthetic promoter (PlantPho) is activated using a plant-adapted PhoB (PhoB-VP64) and the endogenous HK-based cytokinin signaling pathway. Building on this work, we adapted an input or sensing system based on bacterial chemotactic binding proteins and HKs, resulting in a complete eukaryotic signal transduction system. Input to our eukaryotic signal transduction system is provided by a periplasmic binding protein (PBP), ribose-binding protein (RBP). RBP interacts with the membrane

  18. Signal transduction molecule patterns indicating potential glioblastoma therapy approaches

    Directory of Open Access Journals (Sweden)

    Cruceru ML

    2013-11-01

    Full Text Available Maria Linda Cruceru,1 Ana-Maria Enciu,1,2,7 Adrian Claudiu Popa,1,3 Radu Albulescu,2,4,7 Monica Neagu,2,7 Cristiana Pistol Tanase,2,7 Stefan N Constantinescu5–7 1Carol Davila University of Medicine and Pharmacy, Department of Cellular and Molecular Medicine, Bucharest, Romania; 2Victor Babes National Institute of Pathology, Bucharest, Romania; 3Army Centre for Medical Research, Bucharest, Romania; 4National Institute for Chemical Pharmaceutical R&D, Bucharest, Romania; 5de Duve Institute, Université Catholique de Louvain, Brussels, Belgium; 6Ludwig Institute for Cancer Research, Brussels, Belgium; 7Operational Sectorial Programme for Competitive Economic Growth Canbioprot at Victor Babes National Institute of Pathology, Bucharest, Romania Purpose: The expression of an array of signaling molecules, along with the assessment of real-time cell proliferation, has been performed in U87 glioma cell line and in patients’ glioblastoma established cell cultures in order to provide a better understanding of cellular and molecular events involved in glioblastoma pathogenesis. Experimental therapy was performed using a phosphatydylinositol-3´-kinase (PI3K inhibitor. Patients and methods: xMAP technology was employed to assess expression levels of several signal transduction molecules and real-time xCELLigence platform for cell behavior. Results: PI3K inhibition induced the most significant effects on global signaling pathways in patient-derived cell cultures, especially on members of the mitogen-activated protein-kinase family, P70S6 serine-threonine kinase, and cAMP response element-binding protein expression and further prevented tumor cell proliferation. Conclusion: The PI3K pathway might be a prime target for glioblastoma treatment. Keywords: personalized medicine, PI3K inhibitor, targeted therapy, xCELLigence, xMAP analysis

  19. Kv7 potassium channels in airway smooth muscle cells: signal transduction intermediates and pharmacological targets for bronchodilator therapy.

    Science.gov (United States)

    Brueggemann, Lioubov I; Kakad, Priyanka P; Love, Robert B; Solway, Julian; Dowell, Maria L; Cribbs, Leanne L; Byron, Kenneth L

    2012-01-01

    Expression and function of Kv7 (KCNQ) voltage-activated potassium channels in guinea pig and human airway smooth muscle cells (ASMCs) were investigated by quantitative reverse transcriptase polymerase chain reaction (qRT-PCR), patch-clamp electrophysiology, and precision-cut lung slices. qRT-PCR revealed expression of multiple KCNQ genes in both guinea pig and human ASMCs. Currents with electrophysiological and pharmacological characteristics of Kv7 currents were measured in freshly isolated guinea pig and human ASMCs. In guinea pig ASMCs, Kv7 currents were significantly suppressed by application of the bronchoconstrictor agonists methacholine (100 nM) or histamine (30 μM), but current amplitudes were restored by addition of a Kv7 channel activator, flupirtine (10 μM). Kv7 currents in guinea pig ASMCs were also significantly enhanced by another Kv7.2-7.5 channel activator, retigabine, and by celecoxib and 2,5-dimethyl celecoxib. In precision-cut human lung slices, constriction of airways by histamine was significantly reduced in the presence of flupirtine. Kv7 currents in both guinea pig and human ASMCs were inhibited by the Kv7 channel blocker XE991. In human lung slices, XE991 induced robust airway constriction, which was completely reversed by addition of the calcium channel blocker verapamil. These findings suggest that Kv7 channels in ASMCs play an essential role in the regulation of airway diameter and may be targeted pharmacologically to relieve airway hyperconstriction induced by elevated concentrations of bronchoconstrictor agonists. PMID:21964407

  20. The sugarcane signal transduction (SUCAST catalogue: prospecting signal transduction in sugarcane

    Directory of Open Access Journals (Sweden)

    Glaucia Mendes Souza

    2001-12-01

    Full Text Available EST sequencing has enabled the discovery of many new genes in a vast array of organisms, and the utility of this approach to the scientific community is greatly increased by the establishment of fully annotated databases. The present study aimed to identify sugarcane ESTs sequenced in the sugarcane expressed sequence tag (SUCEST project (http://sucest.lad.ic.unicamp.br that corresponded to signal transduction components. We also produced a sugarcane signal transduction (SUCAST catalogue (http://sucest.lad.ic.unicamp.br/private/mining-reports/QG/QG-mining.htm that covered the main categories and pathways. Expressed sequence tags (ESTs encoding enzymes for hormone (gibberellins, ethylene, auxins, abscisic acid and jasmonic acid biosynthetic pathways were found and tissue specificity was inferred from their relative frequency of occurrence in the different libraries. Whenever possible, transducers of hormones and plant peptide signaling were catalogued to the respective pathway. Over 100 receptors were found in sugarcane, which contains a large family of Ser/Thr kinase receptors and also photoreceptors, histidine kinase receptors and their response regulators. G-protein and small GTPases were analyzed and compared to known members of these families found in mammalian and plant systems. Major kinase and phosphatase pathways were mapped, with special attention being given to the MAP kinase and the inositol pathway, both of which are well known in plants.O sequenciamento de ESTs (etiquetas de sequencias transcritas tem possibilitado a descoberta de muitos novos genes em uma ampla variedade de organismos. Um aumento do aproveitamento desta informação pela comunidade científica tem sido possível graças ao desenvolvimento de base de dados contendo seqüências completamente anotadas. O trabalho aqui relatado teve como objetivo a identificação de ESTs de cana de açúcar seqüenciadas através do projeto SUCEST (http://sucest.lad.ic. unicamp.br que

  1. Signal transduction pathway profiling of individual tumor samples

    Directory of Open Access Journals (Sweden)

    Peterson Carsten

    2005-06-01

    Full Text Available Abstract Background Signal transduction pathways convey information from the outside of the cell to transcription factors, which in turn regulate gene expression. Our objective is to analyze tumor gene expression data from microarrays in the context of such pathways. Results We use pathways compiled from the TRANSPATH/TRANSFAC databases and the literature, and three publicly available cancer microarray data sets. Variation in pathway activity, across the samples, is gauged by the degree of correlation between downstream targets of a pathway. Two correlation scores are applied; one considers all pairs of downstream targets, and the other considers only pairs without common transcription factors. Several pathways are found to be differentially active in the data sets using these scores. Moreover, we devise a score for pathway activity in individual samples, based on the average expression value of the downstream targets. Statistical significance is assigned to the scores using permutation of genes as null model. Hence, for individual samples, the status of a pathway is given as a sign, + or -, and a p-value. This approach defines a projection of high-dimensional gene expression data onto low-dimensional pathway activity scores. For each dataset and many pathways we find a much larger number of significant samples than expected by chance. Finally, we find that several sample-wise pathway activities are significantly associated with clinical classifications of the samples. Conclusion This study shows that it is feasible to infer signal transduction pathway activity, in individual samples, from gene expression data. Furthermore, these pathway activities are biologically relevant in the three cancer data sets.

  2. Signal transduction, receptors, mediators and genes: younger than ever - the 13th meeting of the Signal Transduction Society focused on aging and immunology

    Directory of Open Access Journals (Sweden)

    Klotz Lars-Oliver

    2010-02-01

    Full Text Available Abstract The 13th meeting of the Signal Transduction Society was held in Weimar, from October 28 to 30, 2009. Special focus of the 2009 conference was "Aging and Senescence", which was co-organized by the SFB 728 "Environmentally-Induced Aging Processes" of the University of Düsseldorf and the study group 'Signal Transduction' of the German Society for Cell Biology (DGZ. In addition, several other areas of signal transduction research were covered and supported by different consortia associated with the Signal Transduction Society including the long-term associated study groups of the German Society for Immunology and the Society for Biochemistry and Molecular Biology, and for instance the SFB/Transregio 52 "Transcriptional Programming of Individual T Cell Subsets" located in Würzburg, Mainz and Berlin. The different research areas that were introduced by outstanding keynote speakers attracted more than 250 scientists, showing the timeliness and relevance of the interdisciplinary concept and exchange of knowledge during the three days of the scientific program. This report gives an overview of the presentations of the conference.

  3. Coordinate gene regulation by fimbriae-induced signal transduction

    DEFF Research Database (Denmark)

    Schembri, Mark; Klemm, Per

    2001-01-01

    of Ag43 production. No effect was observed in an oxyR mutant. We conclude that fimbriae expression per se constitutes a signal transduction mechanism that affects a number of unrelated genes via the thiol-disulfide status of OxyR. Thus, phase variation in fimbrial expression is coordinated...

  4. Synthetic modular systems--reverse engineering of signal transduction

    DEFF Research Database (Denmark)

    Pawson, Tony; Linding, Rune

    2005-01-01

    to a deeper and more abstract understanding of signal transduction systems. Designing and successfully introducing synthetic proteins into cellular pathways would provide us with a powerful research tool with many applications, such as development of biosensors, protein drugs and rewiring of biological...

  5. Mitogen-activated protein kinase and abscisic acid signal transduction

    NARCIS (Netherlands)

    Heimovaara-Dijkstra, S.; Testerink, C.; Wang, M.

    1998-01-01

    The phytohormone abscisic acid (ABA) is a classical plant hormone, responsible for regulation of abscission, diverse aspects of plant and seed development, stress responses and germination. It was found that ABA signal transduction in plants can involve the activity of type 2C-phosphatases (PP2C), c

  6. Exploring signal transduction networks using mass spectrometry-based proteomics

    NARCIS (Netherlands)

    Meijer, L.A.T.

    2012-01-01

    Mass spectrometry (MS)-based proteomics can be used to answer a diversity of biological questions. In this thesis, we describe the application of several MS-based proteomics approaches to get insight into several aspects of signal transduction. In Chapter 2, quantitative global phosphoproteomics are

  7. Regulation of apoptotic signal transduction pathways by the heat shock proteins

    Institute of Scientific and Technical Information of China (English)

    LI; Zhengyu; ZHAO; Xia; WEI; Yuquan

    2004-01-01

    The study about apoptotic signal transductions has become a project to reveal the molecular mechanisms of apoptosis. Heat shock proteins (hsps), which play an important role in cell growth and apoptosis, have attracted great attentions. A lot of researches have showed there is a hsps superfamily including hsp90, hsp70, hsp60 and hsp27, etc., which regulates the biological behaviors of cells, particularly apoptotic signal transduction in Fas pathway, JNK/SAPK pathway and caspases pathway at different levels, partly by the function of molecular chaperone.

  8. Modulation of signal transduction by tea catechins and related phytochemicals

    Energy Technology Data Exchange (ETDEWEB)

    Shimizu, Masahito [Herbert Irving Comprehensive Cancer Center and Department of Medicine, Columbia University Medical Center, HHSC-1509, 701 West 168 Street, NY 10032-2704 (United States); Weinstein, I. Bernard [Herbert Irving Comprehensive Cancer Center and Department of Medicine, Columbia University Medical Center, HHSC-1509, 701 West 168 Street, NY 10032-2704 (United States)]. E-mail: ibw1@columbia.edu

    2005-12-11

    Epidemiologic studies in human populations and experimental studies in rodents provide evidence that green tea and its constituents can inhibit both the development and growth of tumors at a variety of tissue sites. In addition, EGCG, a major biologically active component of green tea, inhibits growth and induces apoptosis in a variety of cancer cell lines. The purpose of this paper is to review evidence that these effects are mediated, at least in part, through inhibition of the activity of specific receptor tyrosine kinases (RTKs) and related downstream pathways of signal transduction. We also review evidence indicating that the antitumor effects of the related polyphenolic phytochemicals resveratrol, genistein, curcumin, and capsaicin are exerted via similar mechanisms. Some of these agents (EGCG, genistein, and curcumin) appear to directly target specific RTKs, and all of these compounds cause inhibition of the activity of the transcription factors AP-1 and NF-{kappa}B, thus inhibiting cell proliferation and enhancing apoptosis. Critical areas of future investigation include: (1) identification of the direct molecular target(s) of EGCG and related polyphenolic compounds in cells; (2) the in vivo metabolism and bioavailability of these compounds; (3) the ancillary effects of these compounds on tumor-stromal interactions; (4) the development of synergistic combinations with other antitumor agents to enhance efficacy in cancer prevention and therapy, and also minimize potential toxicities.

  9. Modulation of signal transduction by tea catechins and related phytochemicals

    International Nuclear Information System (INIS)

    Epidemiologic studies in human populations and experimental studies in rodents provide evidence that green tea and its constituents can inhibit both the development and growth of tumors at a variety of tissue sites. In addition, EGCG, a major biologically active component of green tea, inhibits growth and induces apoptosis in a variety of cancer cell lines. The purpose of this paper is to review evidence that these effects are mediated, at least in part, through inhibition of the activity of specific receptor tyrosine kinases (RTKs) and related downstream pathways of signal transduction. We also review evidence indicating that the antitumor effects of the related polyphenolic phytochemicals resveratrol, genistein, curcumin, and capsaicin are exerted via similar mechanisms. Some of these agents (EGCG, genistein, and curcumin) appear to directly target specific RTKs, and all of these compounds cause inhibition of the activity of the transcription factors AP-1 and NF-κB, thus inhibiting cell proliferation and enhancing apoptosis. Critical areas of future investigation include: (1) identification of the direct molecular target(s) of EGCG and related polyphenolic compounds in cells; (2) the in vivo metabolism and bioavailability of these compounds; (3) the ancillary effects of these compounds on tumor-stromal interactions; (4) the development of synergistic combinations with other antitumor agents to enhance efficacy in cancer prevention and therapy, and also minimize potential toxicities

  10. NO, nitrotyrosine, and cyclic GMP in signal transduction

    Science.gov (United States)

    Hanafy, K. A.; Krumenacker, J. S.; Murad, F.

    2001-01-01

    Over the past 25 years, the role of nitric oxide (NO) in biology has evolved from being recognized as an environmental pollutant to an endogenously produced substance involved in cell communication and signal transduction. NO is produced by a family of enzymes called nitric oxide synthases (NOSs), which can be stimulated by a variety of factors that mediate responses to various stimuli. NO can initiate its biological effects through activation of the heterodimeric enzyme, soluble guanylyl cyclase (sGC), or through several other chemical reactions. Activation of sGC results in the production of 3',5'-cyclic guanosine monophosphate (cGMP), an intracellular second messenger signaling molecule, which can subsequently mediate such diverse physiological events such as vasodilatation and immunomodulation. Chemically reactive NO can affect physiological changes through modifications to cellular proteins, one of which is tyrosine nitration. The demonstration that NO is involved in so many biological pathways indicates the importance of this endogenously produced substance, and suggests that there is much more to be discovered about its role in biology in years to come.

  11. One-way calcium spill-over during signal transduction in Paramecium cells: from the cell cortex into cilia, but not in the reverse direction.

    Science.gov (United States)

    Husser, Marc R; Hardt, Martin; Blanchard, Marie-Pierre; Hentschel, Joachim; Klauke, Norbert; Plattner, Helmut

    2004-11-01

    We asked to what extent Ca(2+) signals in two different domains of Paramecium cells remain separated during different stimulations. Wild-type (7S) and pawn cells (strain d4-500r, without ciliary voltage-dependent Ca(2+)-channels) were stimulated for trichocyst exocytosis within 80 ms by quenched-flow preparation and analysed by energy-dispersive X-ray microanalysis (EDX), paralleled by fast confocal fluorochrome analysis. We also analysed depolarisation-dependent calcium signalling during ciliary beat rerversal, also by EDX, after 80-ms stimulation in the quenched-flow mode. EDX and fluorochrome analysis enable to register total and free intracellular calcium concentrations, [Ca] and [Ca(2+)], respectively. After exocytosis stimulation we find by both methods that the calcium signal sweeps into the basis of cilia, not only in 7S but also in pawn cells which then also perform ciliary reversal. After depolarisation we see an increase of [Ca] along cilia selectively in 7S, but not in pawn cells. Opposite to exocytosis stimulation, during depolarisation no calcium spill-over into the nearby cytosol and no exocytosis occurs. In sum, we conclude that cilia must contain a very potent Ca(2+) buffering system and that ciliary reversal induction, much more than exocytosis stimulation, involves strict microdomain regulation of Ca(2+) signals.

  12. Signal transduction through the IL-4 and insulin receptor families.

    Science.gov (United States)

    Wang, L M; Keegan, A; Frankel, M; Paul, W E; Pierce, J H

    1995-07-01

    Activation of tyrosine kinase-containing receptors and intracellular tyrosine kinases by ligand stimulation is known to be crucial for mediating initial and subsequent events involved in mitogenic signal transduction. Receptors for insulin and insulin-like growth factor 1 (IGF-1) contain cytoplasmic tyrosine kinase domains that undergo autophosphorylation upon ligand stimulation. Activation of these receptors also leads to pronounced and rapid tyrosine phosphorylation of insulin receptor substrate 1 (IRS-1) in cells of connective tissue origin. A related substrate, designated 4PS, is similarly phosphorylated by insulin and IGF-1 stimulation in many hematopoietic cell types. IRS-1 and 4PS possess a number of tyrosine phosphorylation sites that are within motifs that bind specific SH2-containing molecules known to be involved in mitogenic signaling such as PI-3 kinase, SHPTP-2 (Syp) and Grb-2. Thus, they appear to act as docking substrates for a variety of signaling molecules. The majority of hematopoietic cytokines bind to receptors that do not possess intrinsic kinase activity, and these receptors have been collectively termed as members of the hematopoietin receptor superfamily. Despite their lack of tyrosine kinase domains, stimulation of these receptors has been demonstrated to activate intracellular kinases leading to tyrosine phosphorylation of multiple substrates. Recent evidence has demonstrated that activation of different members of the Janus family of tyrosine kinases is involved in mediating tyrosine phosphorylation events by specific cytokines. Stimulation of the interleukin 4 (IL-4) receptor, a member of the hematopoietin receptor superfamily, is thought to result in activation of Jak1, Jak3, and/or Fes tyrosine kinases.(ABSTRACT TRUNCATED AT 250 WORDS)

  13. VEGF-A isoforms program differential VEGFR2 signal transduction, trafficking and proteolysis

    Science.gov (United States)

    Fearnley, Gareth W.; Smith, Gina A.; Abdul-Zani, Izma; Yuldasheva, Nadira; Mughal, Nadeem A.; Homer-Vanniasinkam, Shervanthi; Kearney, Mark T.; Zachary, Ian C.; Tomlinson, Darren C.; Harrison, Michael A.; Wheatcroft, Stephen B.; Ponnambalam, Sreenivasan

    2016-01-01

    ABSTRACT Vascular endothelial growth factor A (VEGF-A) binding to the receptor tyrosine kinase VEGFR2 triggers multiple signal transduction pathways, which regulate endothelial cell responses that control vascular development. Multiple isoforms of VEGF-A can elicit differential signal transduction and endothelial responses. However, it is unclear how such cellular responses are controlled by isoform-specific VEGF-A–VEGFR2 complexes. Increasingly, there is the realization that the membrane trafficking of receptor–ligand complexes influences signal transduction and protein turnover. By building on these concepts, our study shows for the first time that three different VEGF-A isoforms (VEGF-A165, VEGF-A121 and VEGF-A145) promote distinct patterns of VEGFR2 endocytosis for delivery into early endosomes. This differential VEGFR2 endocytosis and trafficking is linked to VEGF-A isoform-specific signal transduction events. Disruption of clathrin-dependent endocytosis blocked VEGF-A isoform-specific VEGFR2 activation, signal transduction and caused substantial depletion in membrane-bound VEGFR1 and VEGFR2 levels. Furthermore, such VEGF-A isoforms promoted differential patterns of VEGFR2 ubiquitylation, proteolysis and terminal degradation. Our study now provides novel insights into how different VEGF-A isoforms can bind the same receptor tyrosine kinase and elicit diverse cellular outcomes. PMID:27044325

  14. VEGF-A isoforms program differential VEGFR2 signal transduction, trafficking and proteolysis

    Directory of Open Access Journals (Sweden)

    Gareth W. Fearnley

    2016-05-01

    Full Text Available Vascular endothelial growth factor A (VEGF-A binding to the receptor tyrosine kinase VEGFR2 triggers multiple signal transduction pathways, which regulate endothelial cell responses that control vascular development. Multiple isoforms of VEGF-A can elicit differential signal transduction and endothelial responses. However, it is unclear how such cellular responses are controlled by isoform-specific VEGF-A–VEGFR2 complexes. Increasingly, there is the realization that the membrane trafficking of receptor–ligand complexes influences signal transduction and protein turnover. By building on these concepts, our study shows for the first time that three different VEGF-A isoforms (VEGF-A165, VEGF-A121 and VEGF-A145 promote distinct patterns of VEGFR2 endocytosis for delivery into early endosomes. This differential VEGFR2 endocytosis and trafficking is linked to VEGF-A isoform-specific signal transduction events. Disruption of clathrin-dependent endocytosis blocked VEGF-A isoform-specific VEGFR2 activation, signal transduction and caused substantial depletion in membrane-bound VEGFR1 and VEGFR2 levels. Furthermore, such VEGF-A isoforms promoted differential patterns of VEGFR2 ubiquitylation, proteolysis and terminal degradation. Our study now provides novel insights into how different VEGF-A isoforms can bind the same receptor tyrosine kinase and elicit diverse cellular outcomes.

  15. Matricellular signal transduction involving calmodulin in the social amoebozoan dictyostelium.

    Science.gov (United States)

    O'Day, Danton H; Huber, Robert J

    2013-01-01

    The social amoebozoan Dictyostelium discoideum undergoes a developmental sequence wherein an extracellular matrix (ECM) sheath surrounds a group of differentiating cells. This sheath is comprised of proteins and carbohydrates, like the ECM of mammalian tissues. One of the characterized ECM proteins is the cysteine-rich, EGF-like (EGFL) repeat-containing, calmodulin (CaM)-binding protein (CaMBP) CyrA. The first EGFL repeat of CyrA increases the rate of random cell motility and cyclic AMP-mediated chemotaxis. Processing of full-length CyrA (~63 kDa) releases two major EGFL repeat-containing fragments (~45 kDa and ~40 kDa) in an event that is developmentally regulated. Evidence for an EGFL repeat receptor also exists and downstream intracellular signaling pathways involving CaM, Ras, protein kinase A and vinculin B phosphorylation have been characterized. In total, these results identify CyrA as a true matricellular protein comparable in function to tenascin C and other matricellular proteins from mammalian cells. Insight into the regulation and processing of CyrA has also been revealed. CyrA is the first identified extracellular CaMBP in this eukaryotic microbe. In keeping with this, extracellular CaM (extCaM) has been shown to be present in the ECM sheath where it binds to CyrA and inhibits its cleavage to release the 45 kDa and 40 kDa EGFL repeat-containing fragments. The presence of extCaM and its role in regulating a matricellular protein during morphogenesis extends our understanding of CaM-mediated signal transduction in eukaryotes. PMID:24705101

  16. Matricellular Signal Transduction Involving Calmodulin in the Social Amoebozoan Dictyostelium

    Directory of Open Access Journals (Sweden)

    Danton H. O'Day

    2013-02-01

    Full Text Available The social amoebozoan Dictyostelium discoideum undergoes a developmental sequence wherein an extracellular matrix (ECM sheath surrounds a group of differentiating cells. This sheath is comprised of proteins and carbohydrates, like the ECM of mammalian tissues. One of the characterized ECM proteins is the cysteine-rich, EGF-like (EGFL repeat-containing, calmodulin (CaM-binding protein (CaMBP CyrA. The first EGFL repeat of CyrA increases the rate of random cell motility and cyclic AMP-mediated chemotaxis. Processing of full-length CyrA (~63 kDa releases two major EGFL repeat-containing fragments (~45 kDa and ~40 kDa in an event that is developmentally regulated. Evidence for an EGFL repeat receptor also exists and downstream intracellular signaling pathways involving CaM, Ras, protein kinase A and vinculin B phosphorylation have been characterized. In total, these results identify CyrA as a true matricellular protein comparable in function to tenascin C and other matricellular proteins from mammalian cells. Insight into the regulation and processing of CyrA has also been revealed. CyrA is the first identified extracellular CaMBP in this eukaryotic microbe. In keeping with this, extracellular CaM (extCaM has been shown to be present in the ECM sheath where it binds to CyrA and inhibits its cleavage to release the 45 kDa and 40 kDa EGFL repeat-containing fragments. The presence of extCaM and its role in regulating a matricellular protein during morphogenesis extends our understanding of CaM-mediated signal transduction in eukaryotes.

  17. 中药对肝癌细胞信号转导通路影响的研究进展%Advances in research on Chinese medicines that can induce apoptosis of hepatocellular carcinoma cells by the signal transduction pathway

    Institute of Scientific and Technical Information of China (English)

    濮忠建; 华海清

    2011-01-01

    As the research on the signal transduction pathway of tumor is developing, people has become more aware of the confusion of the signal transduction mechanisms on the tumor cells and their effects on tumor growth, apoptosis, and metastasis. Currently, the research that Chinese medicine and its extract inducing apoptosis and angiogenesis of hepatocellular carcinoma by acting on the signal transduction pathway has made gratifying progress. In this article, we will provide an overview of recent literature about this.%随着对肿瘤信号转导通路研究的不断深入,人们对肿瘤细胞内部复杂的信号转导机制以及它们对肿瘤生长、凋亡和转移等的影响越来越了解.目前,中药及其提取物通过作用于信号转导通路诱导肝癌细胞凋亡、影响肝癌血管生成的研究已取得可喜进步.现对近年来有关文献进行回顾,就此进展作一综述.

  18. Heme oxygenase-1 in cholecystokinin-octapeptipe attenuated injury of pulmonary artery smooth muscle cells induced by lipopolysaccharide and its signal transduction mechanism

    Institute of Scientific and Technical Information of China (English)

    Xin-Li Huang; Yi-Ling Ling; Yi-Qun Ling; Jun-Lin Zhou; Yah Liu; Qiu-Hong Wang

    2004-01-01

    AIM: To study the effect of cholecystokinin-octapeptide (CCK-8) on lipopolysaccharide (LPS) -induced pulmonary artery smooth muscle cell (PASMCs) injury and the role of heme oxygenase-1 (HO-1), and to explore the regulation mechanism of c-Jun N-terminal kinase (JNK) and activator protein-L (AP-1) signal transduction pathway in inducing HO-1 expression further.METHODS: Cultured PASMCs were randomly divided into 4 or 6 groups: normal culture group, LPS (10 mg/L), CCK-8(10-6 mol/L) plus LPS (10 mg/L) group, CCK-8 (10-6 mol/L)group, zinc protoporphyrin 9 (ZnPPIX) (10-6 mol/L) plus LPS (10 mg/L) group, CCK-8 (10-6 mol/L) plus ZnPPIX and LPS (10 mg/L) group. Seven hours after LPS administration,ulterstructrual changes and content of malondialdehyde (MDA) of PASMCs in each group were investigated by electron microscopy and biochemical assay respectively.HO-1 mRNA and protein of PASMCs in the former4 groups were examined by reverse transcriptase polymerase chain reaction (RT-PCR) and immunocytochemistry staining.Changes of c-fos expression and activation of JNK of PASMCs in the former 4 groups were detected with immunocytochemistry staining and Western blot 30 min after LPS administration.RESULTS: The injuries of PASMCs and the increases of MDA content induced by LPS were alleviated and significantly reduced by CCK-8 (P<0.05). The specific HO-1 inhibitorZnPPIX could worsen LPS-induced injuries and weaken the protective effect of CCK-8. The expressions of c-fos,p-JNK protein and HO-1 mRNA and protein were all slightly increased in LPS group, and significantly enhanced by CCK-8 further (P<0.05).CONCLUSION: HO-1 may be a key factor in CCK-8attenuated injuries of PASMCs induced by LPS, and HO-1expression may be related to the activation of JNK and activator protein (AP-1).

  19. Identification of photoperception and light signal transduction pathways in citrus

    Directory of Open Access Journals (Sweden)

    Vera Quecini

    2007-01-01

    Full Text Available Studies employing model species have elucidated several aspects of photoperception and light signal transduction that control plant development. However, the information available for economically important crops is scarce. Citrus genome databases of expressed sequence tags (EST were investigated in order to identify genes coding for functionally characterized proteins responsible for light-regulated developmental control in model plants. Approximately 176,200 EST sequences from 53 libraries were queried and all bona fide and putative photoreceptor gene families were found in citrus species. We have identified 53 orthologs for several families of transcriptional regulators and cytoplasmic proteins mediating photoreceptor-induced responses although some important Arabidopsis phytochrome- and cryptochrome-signaling components are absent from citrus sequence databases. The main gene families responsible for phototropin-mediated signal transduction were present in citrus transcriptome, including general regulatory factors (14-3-3 proteins, scaffolding elements and auxin-responsive transcription factors and transporters. A working model of light perception, signal transduction and response-eliciting in citrus is proposed based on the identified key components. These results demonstrate the power of comparative genomics between model systems and economically important crop species to elucidate several aspects of plant physiology and metabolism.

  20. Resveratrol inhibits phosphorylation within the signal transduction and activator of transcription 3 signaling pathway by activating sirtuin 1 in SW1353 chondrosarcoma cells.

    Science.gov (United States)

    Jin, Haidong; Chen, Hui; Yu, Kehe; Zhang, Jingdong; Li, Bin; Cai, Ningyu; Pan, Jun

    2016-09-01

    The present study assessed the mechanism by which resveratrol (Res) inhibits the growth of SW1353 chondrosarcoma cells and examined whether sirtuin 1 (Sirt1) activation affects phosphorylation within the signal transduction and activator of transcription 3 (STAT3) signaling pathway. The present study used SW1353 chondrosarcoma cells in the logarithmic phase of growth (control and treatment groups). The latter group was treated with Res at 25 and 50 µmol/l for 24 h, and cell viability, proliferation and apoptosis were analyzed using the cell counting kit‑8 assay, colony counting and Hoechst staining, respectively. The expression levels of caspase‑3, cleaved caspase‑3, B‑cell lymphoma‑2 (BCL‑2), BCL-2 associated X protein (Bax), STAT3 and phosphorylated (p‑)STAT3) were measured by Western blotting. SW1353 cells were transfected with small interfering (si)RNA targeting Sirt1 and the expression levels of Sirt1, STAT3 and p-STAT3 were assessed. Exposure of SW1353 cells to Res reduced cell viability in a dose‑dependent manner (P<0.01). Additionally, cell proliferation was significantly inhibited and the cell nuclei exhibited apoptotic characteristics. Cleaved caspase‑3, Sirt1 and Bax levels were upregulated. The expression levels of BCL‑2 and p‑STAT3 were downregulated. Additionally, the BCL‑2/Bax ratio was reduced compared with the control group. The total STAT3 level was unaffected. Res treatment activated Sirt1, however, in cells transfected with Sirt1‑siRNA, the ability of resveratrol to suppress p‑STAT3 expression was compromised. Overall, it was revealed that Res treatment induced apoptosis, inhibited proliferation and affected phosphorylation within the STAT3 signaling pathway by activating Sirt1 in SW1353 chondrosarcoma cells.

  1. Bio-inspired signal transduction with heterogeneous networks of nanoscillators

    Science.gov (United States)

    Cervera, Javier; Manzanares, José A.; Mafé, Salvador

    2012-02-01

    Networks of single-electron transistors mimic some of the essential properties of neuron populations, because weak electrical signals trigger network oscillations with a frequency proportional to the input signal. Input potentials representing the pixel gray level of a grayscale image can then be converted into rhythms and the image can be recovered from these rhythms. Networks of non-identical nanoscillators complete the noisy transduction more reliably than identical ones. These results are important for signal processing schemes and could support recent studies suggesting that neuronal variability enhances the processing of biological information.

  2. Towards the systematic discovery of signal transduction networks using phosphorylation dynamics data

    Directory of Open Access Journals (Sweden)

    Yachie Nozomu

    2010-05-01

    Full Text Available Abstract Background Phosphorylation is a ubiquitous and fundamental regulatory mechanism that controls signal transduction in living cells. The number of identified phosphoproteins and their phosphosites is rapidly increasing as a result of recent mass spectrometry-based approaches. Results We analyzed time-course phosphoproteome data obtained previously by liquid chromatography mass spectrometry with the stable isotope labeling using amino acids in cell culture (SILAC method. This provides the relative phosphorylation activities of digested peptides at each of five time points after stimulating HeLa cells with epidermal growth factor (EGF. We initially calculated the correlations between the phosphorylation dynamics patterns of every pair of peptides and connected the strongly correlated pairs to construct a network. We found that peptides extracted from the same intracellular fraction (nucleus vs. cytoplasm tended to be close together within this phosphorylation dynamics-based network. The network was then analyzed using graph theory and compared with five known signal-transduction pathways. The dynamics-based network was correlated with known signaling pathways in the NetPath and Phospho.ELM databases, and especially with the EGF receptor (EGFR signaling pathway. Although the phosphorylation patterns of many proteins were drastically changed by the EGF stimulation, our results suggest that only EGFR signaling transduction was both strongly activated and precisely controlled. Conclusions The construction of a phosphorylation dynamics-based network provides a useful overview of condition-specific intracellular signal transduction using quantitative time-course phosphoproteome data under specific experimental conditions. Detailed prediction of signal transduction based on phosphoproteome dynamics remains challenging. However, since the phosphorylation profiles of kinase-substrate pairs on the specific pathway were localized in the dynamics

  3. The new sideway of CNTF signal transduction pathway

    Institute of Scientific and Technical Information of China (English)

    2001-01-01

    The action of ciliary neurotrophic factor (CNTF) on intercellular free Ca2+ concentrations [Ca2+]I induced by glutamate (Glu) in primary cultured hippocampal neurons were detected with Fura2/AM,a Ca2+-sensitive fluorophore,and the morphological influence of G-protein on it was ob- jected. Glu could induce rapid increase of [Ca2+]I in hippo- campal neurons. CNTF had no significant action on [Ca2+]I in resting hippocampal neurons. However,after incubation of CNTF for 5 min,the increase of [Ca2+]I in hippocampal neurons rapidly induced by Glu was inhibited. Pretussis toxin (PTX)-sensitive G protein could block the action. These results indicate that a new non-genomic rapid sideway might exist in the upper stream of CNTF signal transduction pathway,which was related to Ca2+ signal transduction.

  4. Study of spatial signal transduction in bistable switches

    Science.gov (United States)

    Zhao, Qi; Yao, Cheng-Gui; Tang, Jun; Liu, Li-Wei

    2016-10-01

    Bistable switch modules are among the most important fundamental motifs in signal-transduction pathways. To better understand their spatial signal transduction, we model the diffusion process in the one-dimensional (1-D) domain. We find that when none of the elements diffuse, the response of the system exhibits a spatial switch-like property. However, when one of the elements is highly diffusible, the response of the system does not show any spatial switching behavior. Furthermore, we observe that the spatial responses of the system are more sensitive to the time constant of the switch when none of the elements are diffusible. Further, a slow loop keeps the system in the high steady state more positions than that in the fast loop. Finally, we consolidate our numerical results analytically by performing a mathematical method.

  5. Molecular methods for the study of signal transduction in plants

    KAUST Repository

    Irving, Helen R.

    2013-09-03

    Novel and improved analytical methods have led to a rapid increase in our understanding of the molecular mechanism underlying plant signal transduction. Progress has been made both at the level of single-component analysis and in vivo imaging as well as at the systems level where transcriptomics and particularly phosphoproteomics afford a window into complex biological responses. Here we review the role of the cyclic nucleotides cAMP and cGMP in plant signal transduction as well as the discovery and biochemical and biological characterization of an increasing number of complex multi-domain nucleotide cyclases that catalyze the synthesis of cAMP and cGMP from ATP and GTP, respectively. © Springer Science+Business Media New York 2013.

  6. Sensory cilia and integration of signal transduction in human health and disease

    DEFF Research Database (Denmark)

    Christensen, Søren T; Pedersen, Lotte B; Schneider, Linda;

    2007-01-01

    The primary cilium is a hallmark of mammalian tissue cells. Recent research has shown that these organelles display unique sets of selected signal transduction modules including receptors, ion channels, effector proteins and transcription factors that relay chemical and physical stimuli from the ...

  7. Knowledge representation model for systems-level analysis of signal transduction networks.

    Science.gov (United States)

    Lee, Dong-Yup; Zimmer, Ralf; Lee, Sang-Yup; Hanisch, Daniel; Park, Sunwon

    2004-01-01

    A Petri-net based model for knowledge representation has been developed to describe as explicitly and formally as possible the molecular mechanisms of cell signaling and their pathological implications. A conceptual framework has been established for reconstructing and analyzing signal transduction networks on the basis of the formal representation. Such a conceptual framework renders it possible to qualitatively understand the cell signaling behavior at systems-level. The mechanisms of the complex signaling network are explored by applying the established framework to the signal transduction induced by potent proinflammatory cytokines, IL-1beta and TNF-alpha The corresponding expert-knowledge network is constructed to evaluate its mechanisms in detail. This strategy should be useful in drug target discovery and its validation.

  8. Identification of photoperception and light signal transduction pathways in citrus

    OpenAIRE

    Vera Quecini

    2007-01-01

    Studies employing model species have elucidated several aspects of photoperception and light signal transduction that control plant development. However, the information available for economically important crops is scarce. Citrus genome databases of expressed sequence tags (EST) were investigated in order to identify genes coding for functionally characterized proteins responsible for light-regulated developmental control in model plants. Approximately 176,200 EST sequences from 53 libraries...

  9. 结肠癌干细胞表面标志的研究和信号传导%Colon cancer stem cell surface markers and signal transduction research

    Institute of Scientific and Technical Information of China (English)

    陈远崇

    2011-01-01

    背景:近年来研究表明,结肠癌干细胞参与肿瘤的复发和转移,为恶性肿瘤靶向治疗带来新的希望.目的:探讨结肠癌干细胞特异表面标志的分离和鉴定方法,以及与结肠癌干细胞研究紧密相关的信号通路.方法:以"结肠癌干细胞,肿瘤干细胞,细胞表面标志,信号传导"为中文关键词,以"colon cancer stem cell,cancer stem cell,cell surface sign,signal transduction"为英文关键词,采用计算机检索Medline和CNKI数据库2000-01/2011-06有关结肠癌干细胞表面标志和信号传导的相关文章,排除重复研究或Meta分析类文章,筛选纳入40篇文献进行评价.结果与结论:CD133+与CD44+可作结肠癌干细胞的表面标志.与结肠癌干细胞紧密相关的信号通路有Wnt和Notch等,Wnt信号通路在干细胞内环境稳定中起重要作用,Notch信号通路是干细胞信号网络的重要通路.通过研究结肠癌干细胞的表面标志,可以及早地检测出肿瘤的存在;掌握结肠癌干细胞的生物学特性和信号转导路径,可减少肿瘤的复发,为结肠癌的诊断和治疗降低难度.%BACKGROUND: In recent years, studies have shown that colon cancer stem cells are involved in tumor recurrence andmetastasis, which have brought a new hope for cancer targeted therapy.OBJECTIVE: To investigate the isolation and identification method of colon cancer stem cell surface markers as well as relevantsignal transduction pathways.METHODS: A computer-based search of Medline and CNKI databases (2000-01/2011-06) was performed to retrieve coloncancer stem cell surface markers and signal transduction using the keywords of "colon cancer stem cell, cancer stem cell, cellsurface sign, signal transduction" in English and Chinese, respectively. Repetitive articles or Meta analyses were excluded, andfinally 40 articles were included in result analysis.RESULTS AND CONCLUSION: CD133+ and CD44+ are used as colon cancer stem cell surface markers. Closely related

  10. Molecular mechanism of cellular reception of ionizing radiation and of activation of signal transduction pathway

    Energy Technology Data Exchange (ETDEWEB)

    Suzuki, Keiji [Nagasaki Univ. (Japan). Faculty of Pharmaceutical Sciences

    1997-03-01

    The author reviewed what in cells receives ionizing radiation as a stress and which signal transduction pathway is activated to induce the stress reaction in the following order: Activation of protein kinase C (PKC) pathway by radiation, activation of MAP kinase superfamily by radiation, induction of p53 function by radiation, and radiation exposure and stress reaction pathway. Conclusion was as follows: Cellular receptors to radiation can be cell membrane and DNA. Membrane reception of radiation induces activation of tyrosine kinase and sphingomyelinase, which resulting in activation of PKC- and MAP kinase-mediated signal transduction. The signal generated in the nucleus participates in regulation of cell cycle and in DNA repair. Therefore, it seems that irradiation of ionizing radiation gives energy to various cellular receptor sites as well as DNA, which generate various independent signals to be transduced and accumulated in the nucleus, and leading to cellular response. (K.H.). 63 refs.

  11. State-time spectrum of signal transduction logic models

    Science.gov (United States)

    MacNamara, Aidan; Terfve, Camille; Henriques, David; Peñalver Bernabé, Beatriz; Saez-Rodriguez, Julio

    2012-08-01

    Despite the current wealth of high-throughput data, our understanding of signal transduction is still incomplete. Mathematical modeling can be a tool to gain an insight into such processes. Detailed biochemical modeling provides deep understanding, but does not scale well above relatively a few proteins. In contrast, logic modeling can be used where the biochemical knowledge of the system is sparse and, because it is parameter free (or, at most, uses relatively a few parameters), it scales well to large networks that can be derived by manual curation or retrieved from public databases. Here, we present an overview of logic modeling formalisms in the context of training logic models to data, and specifically the different approaches to modeling qualitative to quantitative data (state) and dynamics (time) of signal transduction. We use a toy model of signal transduction to illustrate how different logic formalisms (Boolean, fuzzy logic and differential equations) treat state and time. Different formalisms allow for different features of the data to be captured, at the cost of extra requirements in terms of computational power and data quality and quantity. Through this demonstration, the assumptions behind each formalism are discussed, as well as their advantages and disadvantages and possible future developments.

  12. DMPD: LPS/TLR4 signal transduction pathway. [Dynamic Macrophage Pathway CSML Database

    Lifescience Database Archive (English)

    Full Text Available 18304834 LPS/TLR4 signal transduction pathway. Lu YC, Yeh WC, Ohashi PS. Cytokine. ...2008 May;42(2):145-51. Epub 2008 Mar 4. (.png) (.svg) (.html) (.csml) Show LPS/TLR4 signal transduction path...way. PubmedID 18304834 Title LPS/TLR4 signal transduction pathway. Authors Lu YC, Yeh WC, Ohashi PS. Publica

  13. Changes in gene expression and signal transduction in microgravity

    Science.gov (United States)

    Hughes-Fulford, M.

    2001-01-01

    Studies from space flights over the past three decades have demonstrated that basic physiological changes occur in humans during space flight. These changes include cephalic fluid shifts, loss of fluid and electrolytes, loss of muscle mass, space motion sickness, anemia, reduced immune response, and loss of calcium and mineralized bone. The cause of most of these manifestations is not known and until recently, the general approach was to investigate general systemic changes, not basic cellular responses to microgravity. This laboratory has recently studied gene growth and activation of normal osteoblasts (MC3T3-El) during spaceflight. Osteoblast cells were grown on glass coverslips and loaded in the Biorack plunger boxes. The osteoblasts were launched in a serum deprived state, activated in microgravity and collected in microgravity. The osteoblasts were examined for changes in gene expression and signal transduction. Approximately one day after growth activation significant changes were observed in gene expression in 0-G flight samples. Immediate early growth genes/growth factors cox-2, c-myc, bcl2, TGF beta1, bFGF and PCNA showed a significant diminished mRNA induction in microgravity FCS activated cells when compared to ground and 1-G flight controls. Cox-1 was not detected in any of the samples. There were no significant differences in the expression of reference gene mRNA between the ground, 0-G and 1-G samples. The data suggest that quiescent osteoblasts are slower to enter the cell cycle in microgravity and that the lack of gravity itself may be a significant factor in bone loss in spaceflight. Preliminary data from our STS 76 flight experiment support our hypothesis that a basic biological response occurs at the tissue, cellular, and molecular level in 0-G. Here we examine ground-based and space flown data to help us understand the mechanism of bone loss in microgravity.

  14. Deciphering Parameter Sensitivity in the BvgAS Signal Transduction.

    Directory of Open Access Journals (Sweden)

    Tarunendu Mapder

    Full Text Available To understand the switching of different phenotypic phases of Bordetella pertussis, we propose an optimized mathematical framework for signal transduction through BvgAS two-component system. The response of the network output to the sensory input has been demonstrated in steady state. An analysis in terms of local sensitivity amplification characterizes the nature of the molecular switch. The sensitivity analysis of the model parameters within the framework of various correlation coefficients helps to decipher the contribution of the modular structure in signal propagation. Once classified, the model parameters are tuned to generate the behavior of some novel strains using simulated annealing, a stochastic optimization technique.

  15. Deciphering Parameter Sensitivity in the BvgAS Signal Transduction.

    Science.gov (United States)

    Mapder, Tarunendu; Talukder, Srijeeta; Chattopadhyay, Sudip; Banik, Suman K

    2016-01-01

    To understand the switching of different phenotypic phases of Bordetella pertussis, we propose an optimized mathematical framework for signal transduction through BvgAS two-component system. The response of the network output to the sensory input has been demonstrated in steady state. An analysis in terms of local sensitivity amplification characterizes the nature of the molecular switch. The sensitivity analysis of the model parameters within the framework of various correlation coefficients helps to decipher the contribution of the modular structure in signal propagation. Once classified, the model parameters are tuned to generate the behavior of some novel strains using simulated annealing, a stochastic optimization technique.

  16. Deciphering Parameter Sensitivity in the BvgAS Signal Transduction.

    Science.gov (United States)

    Mapder, Tarunendu; Talukder, Srijeeta; Chattopadhyay, Sudip; Banik, Suman K

    2016-01-01

    To understand the switching of different phenotypic phases of Bordetella pertussis, we propose an optimized mathematical framework for signal transduction through BvgAS two-component system. The response of the network output to the sensory input has been demonstrated in steady state. An analysis in terms of local sensitivity amplification characterizes the nature of the molecular switch. The sensitivity analysis of the model parameters within the framework of various correlation coefficients helps to decipher the contribution of the modular structure in signal propagation. Once classified, the model parameters are tuned to generate the behavior of some novel strains using simulated annealing, a stochastic optimization technique. PMID:26812153

  17. Deciphering Parameter Sensitivity in the BvgAS Signal Transduction

    Science.gov (United States)

    Mapder, Tarunendu; Talukder, Srijeeta; Chattopadhyay, Sudip; Banik, Suman K.

    2016-01-01

    To understand the switching of different phenotypic phases of Bordetella pertussis, we propose an optimized mathematical framework for signal transduction through BvgAS two-component system. The response of the network output to the sensory input has been demonstrated in steady state. An analysis in terms of local sensitivity amplification characterizes the nature of the molecular switch. The sensitivity analysis of the model parameters within the framework of various correlation coefficients helps to decipher the contribution of the modular structure in signal propagation. Once classified, the model parameters are tuned to generate the behavior of some novel strains using simulated annealing, a stochastic optimization technique. PMID:26812153

  18. 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)....

  19. Determinants of specificity in two-component signal transduction.

    Science.gov (United States)

    Podgornaia, Anna I; Laub, Michael T

    2013-04-01

    Maintaining the faithful flow of information through signal transduction pathways is critical to the survival and proliferation of organisms. This problem is particularly challenging as many signaling proteins are part of large, paralogous families that are highly similar at the sequence and structural levels, increasing the risk of unwanted cross-talk. To detect environmental signals and process information, bacteria rely heavily on two-component signaling systems comprised of sensor histidine kinases and their cognate response regulators. Although most species encode dozens of these signaling pathways, there is relatively little cross-talk, indicating that individual pathways are well insulated and highly specific. Here, we review the molecular mechanisms that enforce this specificity. Further, we highlight recent studies that have revealed how these mechanisms evolve to accommodate the introduction of new pathways by gene duplication. PMID:23352354

  20. Regulation of drug-induced liver injury by signal transduction pathways: critical role of mitochondria

    OpenAIRE

    Han, Derick; Dara, Lily; Win, Sanda; Than, Tin Aung; Yuan, Liyun; Abbasi, Sadeea Q; Liu, Zhang-Xu; Kaplowitz, Neil

    2013-01-01

    Drugs that cause liver injury often “stress” mitochondria and activate signal transduction pathways important in determining cell survival or death. In most cases, hepatocytes adapt to the drug-induced stress by activating adaptive signaling pathways, such as mitochondrial adaptive responses and erythroid 2-related factor 2 (Nrf-2), a transcription factor that upregulates antioxidant defenses. Due to adaptation, drugs alone rarely cause liver injury, with acetaminophen being the notable excep...

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

    Institute of Scientific and Technical Information of China (English)

    2006-01-01

    Background 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 β1 andβ2 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). Methods Basophils (purity of 10%-50%) were preincubated with anti-CD29 or anti-CD18 blocking antibodies before used for adhesion study. Basophils were preincubated with the pharmacological inhibitors wortmannin, PP1, PD98059 before used for adhesion and HR study. Cell adherence to bovine serum albumin (BSA) or fibronectin (Fn) was monitored using cell associated histamine as a basophil marker and the histamine was measured by the glass fiber assay.Results Basophil spontaneous adhesion to Fn was inhibited by anti-CD29. Interleukin (IL)-3, granulocyte/macrophage colony stimulating factor (GM-CSF) induced adhesion to BSA was inhibited by anti-CD18. Wortmannin at 1 μmol/L and PP1 at 20 μmol/L strongly interfered with, whereas PD98059 at 50 μmol/L weakly inhibited basophil spontaneous adhesion to Fn. One μmol/L wortmannin strongly inhibited IL-3, IL-5, GM-CSF and anti-IgE induced adhesion to BSA. PP1 at 20 μmol/L partly inhibited anti-IgE induced adhesion. Fifty μmol/L PD98059 marginally inhibited IL-5, weakly inhibited anti-IgE, partly inhibited GM-CSF induced adhesion. Wortmannin, PP1 and PD98059 inhibited anti-IgE (1:100 or 1:1000) induced basophil HR in a dose dependent manner. They inhibited calcium ionophore A23187 (10 μmol/L, 5 μmol/L) induced basophil HR in a dose dependent manner, but to different extend with PP1 being the most efficient.Conclusions Basophil spontaneous adhesion to Fn is mediated by β1-integrins whereas cytokine induced adhesion

  2. Model for external influences on cellular signal transduction pathways including cytosolic calcium oscillations

    Energy Technology Data Exchange (ETDEWEB)

    Eichwald, C.; Kaiser, F. [Technical Univ. of Darmstadt (Germany)

    1995-06-01

    Experiments on the effects of extremely-low-frequency (ELF) electric and magnetic fields on cells of the immune system, T-lymphocytes in particular, suggest that the external field interacts with the cell at the level of intracellular signal transduction pathways. These are directly connected with changes in the calcium-signaling processes of the cell. Based on these findings, a theoretical model for receptor-controlled cytosolic calcium oscillations and for external influences on the signal transduction pathway is presented. The authors discuss the possibility that the external field acts on the kinetics of the signal transduction between the activated receptors at the cell membrane and the G-proteins. It is shown that, depending on the specific combination of cell internal biochemical and external physical parameters, entirely different responses of the cell can occur. The authors compare the effects of a coherent (periodic) modulation and of incoherent perturbations (noise). The model and the calculations are based on the theory of self-sustained, nonlinear oscillators. It is argued that these systems form an ideal basis for information-encoding processes in biological systems.

  3. Signal Transduction and Intracellular Trafficking by the Interleukin 36 Receptor*

    Science.gov (United States)

    Saha, Siddhartha S.; Singh, Divyendu; Raymond, Ernest L.; Ganesan, Rajkumar; Caviness, Gary; Grimaldi, Christine; Woska, Joseph R.; Mennerich, Detlev; Brown, Su-Ellen; Mbow, M. Lamine; Kao, C. Cheng

    2015-01-01

    Improper signaling of the IL-36 receptor (IL-36R), a member of the IL-1 receptor family, has been associated with various inflammation-associated diseases. However, the requirements for IL-36R signal transduction remain poorly characterized. This work seeks to define the requirements for IL-36R signaling and intracellular trafficking. In the absence of cognate agonists, IL-36R was endocytosed and recycled to the plasma membrane. In the presence of IL-36, IL-36R increased accumulation in LAMP1+ lysosomes. Endocytosis predominantly used a clathrin-mediated pathway, and the accumulation of the IL-36R in lysosomes did not result in increased receptor turnover. The ubiquitin-binding Tollip protein contributed to IL-36R signaling and increased the accumulation of both subunits of the IL-36R. PMID:26269592

  4. Sensory Transduction of the CO2 Response of Guard Cells

    Energy Technology Data Exchange (ETDEWEB)

    Dr. Eduardo Zeiger

    2003-06-30

    Stomata have a key role in the regulation of gas exchange and intercellular CO2 concentrations of leaves. Guard cells sense internal and external signals in the leaf environment and transduce these signals into osmoregulatory processes that control stomatal apertures. This research proposal addresses the characterization of the sensory transduction of the CO2 signal in guard cells. Recent studies have shown that in Vicia leaves kept at constant light and temperature in a growth chamber, changes in ambient CO2 concentrations cause large changes in guard cell zeaxanthin that are linear with CO2-dependent changes in stomatal apertures. Research proposed here will test the hypothesis that zeaxanthin function as a transducer of CO2 signals in guard cells. Three central aspects of this hypothesis will be investigated: CO2 sensing by the carboxylation reaction of Rubisco in the guard cell chloroplast, which would modulate zeaxanthin concentrations via changes in lumen pH; transduction of the CO2 signal by zeaxanthin via a transducing cascade that controls guard cell osmoregulation; and blue light dependence of the CO2 signal transduction by zeaxanthin, required for the formation of an isomeric form of zeaxanthin that is physiologically active as a transducer. The role of Rubisco in CO2 sensing will be investigated in experiments characterizing the stomatal response to CO2 in the Arabidopsis mutants R100 and rca-, which have reduced rates of Rubisco-dependent carboxylation. The role of zeaxanthin as a CO2 transducer will be studied in npq1, a zeaxanthin-less mutant. The blue light-dependence of CO2 sensing will be studied in experiments characterizing the stomatal response to CO2 under red light. Arabidopsis mutants will also be used in further studies of an acclimation of the stomatal response to CO2, and a possible role of the xanthophyll cycle of the guard cell chloroplast in acclimations of the stomatal response to CO2. Studies on the osmoregulatory role of sucrose in

  5. On the nanotoxicity of PAMAM dendrimers: Superfect® stimulates the EGFR-ERK1/2 signal transduction pathway via an oxidative stress-dependent mechanism in HEK 293 cells.

    Science.gov (United States)

    Akhtar, Saghir; Chandrasekhar, Bindu; Attur, Sreeja; Yousif, Mariam H M; Benter, Ibrahim F

    2013-05-01

    Polyamidoamine (PAMAM) dendrimers are cationic branch-like macromolecules that may serve as drug delivery systems for gene-based therapies such as RNA interference. For their safe use in the clinic, they should ideally only enhance drug delivery to target tissues and exhibit no adverse effects. However, little is known about their toxicological profiles in terms of their interactions with cellular signal transduction pathways such as the epidermal growth factor receptor (EGFR). The EGFR is an important signaling cascade that regulates cell growth, differentiation, migration, survival and apoptosis. Here, we investigated the impact of naked, unmodified Superfect (SF), a commercially available generation 6 PAMAM dendrimer, on the epidermal growth factor receptor (EGFR) tyrosine kinase-extracellular-regulated kinase 1/2 (ERK1/2) signaling pathway in human embryonic kidney (HEK 293) cells. At concentrations routinely used for transfection, SF exhibited time and dose-dependent stimulation of EGFR and ERK1/2 phosphorylation whereas AG1478, a selective EGFR tyrosine kinase antagonist, inhibited EGFR-ERK1/2 signaling. SF-induced phosphorylation of EGFR for 1h was partly reversible upon removal of the dendrimer and examination of cells 24 later. Co-treatment of SF with epidermal growth factor (EGF) ligand resulted in greater EGFR stimulation than either agent alone implying that the stimulatory effects of SF and the ligand are synergistic. Dendrimer-induced stimulation of EGFR-ERK1/2 signaling could be attenuated by the antioxidants apocynin, catalase and tempol implying that an oxidative stress dependent mechanism was involved. These results show for the first time that PAMAM dendrimers, aside from their ability to improve drug delivery, can modulate the important EGFR-ERK1/2 cellular signal transduction pathway - a novel finding that may have a bearing on their safe application as drug delivery systems.

  6. Ion channels and the transduction of light signals

    Science.gov (United States)

    Spalding, E. P.; Evans, M. L. (Principal Investigator)

    2000-01-01

    Studies of biological light-sensing mechanisms are revealing important roles for ion channels. Photosensory transduction in plants is no exception. In this article, the evidence that ion channels perform such signal-transducing functions in the complex array of mechanisms that bring about plant photomorphogenesis will be reviewed and discussed. The examples selected for discussion range from light-gradient detection in unicellular algae to the photocontrol of stem growth in Arabidopsis. Also included is some discussion of the technical aspects of studies that combine electrophysiology and photobiology.

  7. Signal perception, transduction, and gene expression involved in anthocyanin biosynthesis

    International Nuclear Information System (INIS)

    Anthocyanin pigments provide fruits and flowers with their bright red and blue colors and are induced in vegetative tissues by various signals. The biosynthetic pathway probably represents one of the best‐studied examples of higher plant secondary metabolism. It has attracted much attention of plant geneticists because of the dispensable nature of the compounds it produces. Not unexpectedly, several excellent reviews on anthocyanin biosynthesis have been published over the last 5 years (Dooner et al., 1991; Martin and Gerats, 1993a, 1993b; Koes et al., 1994; Holton and Cornish, 1995). These reviews emphasize the late steps of pigment biosynthesis rather than the early and intermediate events of signal perception and transduction. This review is broader and not only covers the identification of components of the anthocyanin signal perception/transduction networks but also provides a description of our current understanding of how they evoke the responses that they do. Progress has derived from a combination of biochemical, molecular and genetic studies. We discuss a range of relevant research to highlight the different experimental approaches being used and the diverse biological systems under investigation. (author)

  8. Advances in NF-κB Signaling Transduction and Transcription

    Institute of Scientific and Technical Information of China (English)

    Weihua Xiao

    2004-01-01

    The molecular mechanisms for NF-κB signaling transduction and transcription have been the most attractive subjects for both basic research and pharmaceutical industries due to its important roles in both physiological and pathogenesis, particularly the close association of dysregulated NF-κB with tumorgenesis and inflammation. Several novel intracellular molecular events that regulate NF-κB activity have been described recently, including the discovery of an alternative signaling pathway that appears inducing a specific subset genes involved in adoptive immune response. Multi-level and multi-dimensional regulation of NF-κB activity by phosphorylation and acetylation modifications have unveiled and became the hottest targets for potentially tissue specific molecular interventions. Another emerging mechanism for NF-κB-responsive gene's regulation where NF-κB participates the transcriptional regulation independent of its cognate regulatory binding site within the target gene's promoter but facilitating the transaction activity of other involved transcription factors,that implicated an novel transcriptional activities for NF-κB. Thus, the current review will focus on these recent progresses that have been made on NF-κB signaling transduction and transcription. Cellular & Molecular Immunology. 2004;1(6):425-435.

  9. Advances in NF-κB Signaling Transduction and Transcription

    Institute of Scientific and Technical Information of China (English)

    2004-01-01

    The molecular mechanisms for NF-κB signaling transduction and transcription have been the most attractive subjects for both basic research and pharmaceutical industries due to its important roles in both physiological and pathogenesis, particularly the close association of dysregulated NF-κB with tumorgenesis and inflammation. Several novel intracellular molecular events that regulate NF-κB activity have been described recently, including the discovery of an alternative signaling pathway that appears inducing a specific subset genes involved in adoptive immune response. Multi-level and multi-dimensional regulation of NF-κB activity by phosphorylation and acetylation modifications have unveiled and became the hottest targets for potentially tissue specific molecular interventions. Another emerging mechanism for NF-κB-responsive gene's regulation where NF-κB participates the transcriptional regulation independent of its cognate regulatory binding site within the target gene's promoter but facilitating the transaction activity of other involved transcription factors,that implicated an novel transcriptional activities for NF-κB. Thus, the current review will focus on these recent progresses that have been made on NF-κB signaling transduction and transcription. Cellular & Molecular Immunology. 2004; 1(6):425-435.

  10. Perspective: Adhesion Mediated Signal Transduction in Bacterial Pathogens

    Science.gov (United States)

    Moorthy, Sudha; Keklak, Julia; Klein, Eric A.

    2016-01-01

    During the infection process, pathogenic bacteria undergo large-scale transcriptional changes to promote virulence and increase intrahost survival. While much of this reprogramming occurs in response to changes in chemical environment, such as nutrient availability and pH, there is increasing evidence that adhesion to host-tissue can also trigger signal transduction pathways resulting in differential gene expression. Determining the molecular mechanisms of adhesion-mediated signaling requires disentangling the contributions of chemical and mechanical stimuli. Here we highlight recent work demonstrating that surface attachment drives a transcriptional response in bacterial pathogens, including uropathogenic Escherichia coli (E. coli), and discuss the complexity of experimental design when dissecting the specific role of adhesion-mediated signaling during infection. PMID:26901228

  11. Melusin Promotes a Protective Signal Transduction Cascade in Stressed Hearts

    Science.gov (United States)

    Sorge, Matteo; Brancaccio, Mara

    2016-01-01

    Melusin is a chaperone protein selectively expressed in heart and skeletal muscles. Melusin expression levels correlate with cardiac function in pre-clinical models and in human patients with aortic stenosis. Indeed, previous studies in several animal models indicated that Melusin plays a broad cardioprotective role in different pathological conditions. Chaperone proteins, besides playing a role in protein folding, are also able to facilitate supramolecular complex formation and conformational changes due to activation/deactivation of signaling molecules. This role sets chaperone proteins as crucial regulators of intracellular signal transduction pathways. In particular Melusin activates AKT and ERK1/2 signaling, protects cardiomyocytes from apoptosis and induces a compensatory hypertrophic response in several pathological conditions. Therefore, selective delivery of the Melusin gene in heart via cardiotropic adenoviral associated virus serotype 9 (AAV9), may represent a new promising gene-therapy approach for different cardiac pathologies. PMID:27672636

  12. Molecular Mechanisms of Two-Component Signal Transduction.

    Science.gov (United States)

    Zschiedrich, Christopher P; Keidel, Victoria; Szurmant, Hendrik

    2016-09-25

    Two-component systems (TCS) comprising sensor histidine kinases and response regulator proteins are among the most important players in bacterial and archaeal signal transduction and also occur in reduced numbers in some eukaryotic organisms. Given their importance to cellular survival, virulence, and cellular development, these systems are among the most scrutinized bacterial proteins. In the recent years, a flurry of bioinformatics, genetic, biochemical, and structural studies have provided detailed insights into many molecular mechanisms that underlie the detection of signals and the generation of the appropriate response by TCS. Importantly, it has become clear that there is significant diversity in the mechanisms employed by individual systems. This review discusses the current knowledge on common themes and divergences from the paradigm of TCS signaling. An emphasis is on the information gained by a flurry of recent structural and bioinformatics studies.

  13. Physician Education: The Erythropoietin Receptor and Signal Transduction.

    Science.gov (United States)

    Yoshimura; Arai

    1996-01-01

    binds to the tyrosine phosphorylation site of the receptor and a second messenger is born. It is known that this pathway is a requirement for DNA synthesis in certain types of fibroblasts. However, these signal transduction pathways are not unique to the EPO receptor, and they are also activated by most growth factor receptors, so they are not necessarily required for EPO-induced proliferation. Conversely, the tyrosine phosphatase SH-PTP1 (also called HCP) that has an SH2 domain and is specific to blood cells associates with the tyrosine phosphorylation site of the receptor and promotes the dephosphorylation of JAK2. In other words, the role of SH-PTP1 is to stop generation of the signal [8]. Therefore, in mutations lacking this cytoplasmic tail region of the receptor far from the plasma membrane, the receptors do not undergo tyrosine phosphorylation, JAK2 activation continues for a longer period of time, and thus the signal is generated more efficiently. In fact, in one patient with a mild case of familial erythrocytosis a mutation was discovered in which the C-terminus of the EPO receptor was missing 70 amino acids [9]. This was a dominant genetic trait, and the patient's erythroblasts showed an increased sensitivity to EPO. In this family the impairment was not severe enough to be called an illness, and in fact it is said that this patient was proficient enough athletically to compete for a gold medal at the Olympics. More specifically, the reason that athletes undergo training at high altitudes is to boost EPO production because of the lower oxygen partial pressure, and this brings about the desired effect of sustained athletic capability due to a resultant increase in red blood cells. However, the same effect has occurred naturally in this athlete thanks to accelerated receptor capability. PMID:10388012

  14. Hypergravity modifies the signal transduction of ionizing radiation through p53

    Energy Technology Data Exchange (ETDEWEB)

    Okaichi, Kumio; Usui, Aya; Okumura, Yutaka [Nagasaki Univ. (Japan). Atomic Disease Inst.; Ohnishi, Takeo [Nara Medical Univ., Kashihara (Japan)

    2002-12-01

    To determine the possible effect of hypergravity to modify the signal transduction of ionizing radiation, we analyzed the accumulation of p53 and the expression of p53-dependent genes, Waf-1 and Bax, using the western blot analysis. Hypergravity (20 x g) induced the accumulation of p53 in the human glioblastoma cell line A172 after 3 h of incubation. Low-dose (0.5 Gy) irradiation to the cells accumulated p53 1.5 h after irradiation, and induced Waf-1 and Bax. Under the condition of hypergravity (20 x g), the peak of p53 accumulation was shifted from 1.5 h to 3 h after irradiation, and the inductions of Waf-1 and Bax were suppressed entirely. These results indicate that hypergravity modifies the signal transduction of ionizing radiation through p53 in the cells. (author)

  15. Excitation and Adaptation in Bacteria–a Model Signal Transduction System that Controls Taxis and Spatial Pattern Formation

    Directory of Open Access Journals (Sweden)

    Chuan Xue

    2013-04-01

    Full Text Available The machinery for transduction of chemotactic stimuli in the bacterium E. coli is one of the most completely characterized signal transduction systems, and because of its relative simplicity, quantitative analysis of this system is possible. Here we discuss models which reproduce many of the important behaviors of the system. The important characteristics of the signal transduction system are excitation and adaptation, and the latter implies that the transduction system can function as a “derivative sensor” with respect to the ligand concentration in that the DC component of a signal is ultimately ignored if it is not too large. This temporal sensing mechanism provides the bacterium with a memory of its passage through spatially- or temporally-varying signal fields, and adaptation is essential for successful chemotaxis. We also discuss some of the spatial patterns observed in populations and indicate how cell-level behavior can be embedded in population-level descriptions.

  16. Central functions of bicarbonate in S-type anion channel activation and OST1 protein kinase in CO 2 signal transduction in guard cell

    KAUST Repository

    Xue, Shaowu

    2011-03-18

    Plants respond to elevated CO(2) via carbonic anhydrases that mediate stomatal closing, but little is known about the early signalling mechanisms following the initial CO(2) response. It remains unclear whether CO(2), HCO(3)(-) or a combination activates downstream signalling. Here, we demonstrate that bicarbonate functions as a small-molecule activator of SLAC1 anion channels in guard cells. Elevated intracellular [HCO(3)(-)](i) with low [CO(2)] and [H(+)] activated S-type anion currents, whereas low [HCO(3)(-)](i) at high [CO(2)] and [H(+)] did not. Bicarbonate enhanced the intracellular Ca(2+) sensitivity of S-type anion channel activation in wild-type and ht1-2 kinase mutant guard cells. ht1-2 mutant guard cells exhibited enhanced bicarbonate sensitivity of S-type anion channel activation. The OST1 protein kinase has been reported not to affect CO(2) signalling. Unexpectedly, OST1 loss-of-function alleles showed strongly impaired CO(2)-induced stomatal closing and HCO(3)(-) activation of anion channels. Moreover, PYR/RCAR abscisic acid (ABA) receptor mutants slowed but did not abolish CO(2)/HCO(3)(-) signalling, redefining the convergence point of CO(2) and ABA signalling. A new working model of the sequence of CO(2) signalling events in gas exchange regulation is presented.

  17. Influence of Unweighting on Insulin Signal Transduction in Muscle

    Science.gov (United States)

    Tischler, Marc E.

    2002-01-01

    Unweighting of the juvenile soleus muscle is characterized by an increased binding capacity for insulin relative to muscle mass due to sparing of the receptors during atrophy. Although carbohydrate metabolism and protein degradation in the unweighted muscle develop increased sensitivity to insulin in vivo, protein synthesis in vivo and system A amino acid transport in vitro do not appear to develop such an enhanced response. The long-term goal is to identify the precise nature of this apparent resistance in the insulin signal transduction pathway and to consider how reduced weight-bearing may elicit this effect, by evaluating specific components of the insulin signalling pathway. Because the insulin-signalling pathway has components in common with the signal transduction pathway for insulin-like growth factor (IGF-1) and potentially other growth factors, the study could have important implications in the role of weight-bearing function on muscle growth and development. Since the insulin signalling pathway diverges following activation of insulin receptor tyrosine kinase, the immediate specific aims will be to study the receptor tyrosine kinase (IRTK) and those branches, which lead to phosphorylation of insulin receptor substrate-1 (IRS-1) and of Shc protein. To achieve these broader objectives, we will test in situ, by intramuscular injection, the responses of glucose transport, system A amino acid transport and protein synthesis to insulin analogues for which the receptor has either a weaker or much stronger binding affinity compared to insulin. Studies will include: (1) estimation of the ED(sub 50) for each analogue for these three processes; (2) the effect of duration (one to four days) of unweighting on the response of each process to all analogues tested; (3) the effect of unweighting and the analogues on IRTK activity; and (4) the comparative effects of unweighting and analogue binding on the tyrosine phosphorylation of IRTK, IRS-1, and Shc protein.

  18. Expansion of Signal Transduction Pathways in Fungi by Extensive Genome Duplication.

    Science.gov (United States)

    Corrochano, Luis M; Kuo, Alan; Marcet-Houben, Marina; Polaino, Silvia; Salamov, Asaf; Villalobos-Escobedo, José M; Grimwood, Jane; Álvarez, M Isabel; Avalos, Javier; Bauer, Diane; Benito, Ernesto P; Benoit, Isabelle; Burger, Gertraud; Camino, Lola P; Cánovas, David; Cerdá-Olmedo, Enrique; Cheng, Jan-Fang; Domínguez, Angel; Eliáš, Marek; Eslava, Arturo P; Glaser, Fabian; Gutiérrez, Gabriel; Heitman, Joseph; Henrissat, Bernard; Iturriaga, Enrique A; Lang, B Franz; Lavín, José L; Lee, Soo Chan; Li, Wenjun; Lindquist, Erika; López-García, Sergio; Luque, Eva M; Marcos, Ana T; Martin, Joel; McCluskey, Kevin; Medina, Humberto R; Miralles-Durán, Alejandro; Miyazaki, Atsushi; Muñoz-Torres, Elisa; Oguiza, José A; Ohm, Robin A; Olmedo, María; Orejas, Margarita; Ortiz-Castellanos, Lucila; Pisabarro, Antonio G; Rodríguez-Romero, Julio; Ruiz-Herrera, José; Ruiz-Vázquez, Rosa; Sanz, Catalina; Schackwitz, Wendy; Shahriari, Mahdi; Shelest, Ekaterina; Silva-Franco, Fátima; Soanes, Darren; Syed, Khajamohiddin; Tagua, Víctor G; Talbot, Nicholas J; Thon, Michael R; Tice, Hope; de Vries, Ronald P; Wiebenga, Ad; Yadav, Jagjit S; Braun, Edward L; Baker, Scott E; Garre, Victoriano; Schmutz, Jeremy; Horwitz, Benjamin A; Torres-Martínez, Santiago; Idnurm, Alexander; Herrera-Estrella, Alfredo; Gabaldón, Toni; Grigoriev, Igor V

    2016-06-20

    Plants and fungi use light and other signals to regulate development, growth, and metabolism. The fruiting bodies of the fungus Phycomyces blakesleeanus are single cells that react to environmental cues, including light, but the mechanisms are largely unknown [1]. The related fungus Mucor circinelloides is an opportunistic human pathogen that changes its mode of growth upon receipt of signals from the environment to facilitate pathogenesis [2]. Understanding how these organisms respond to environmental cues should provide insights into the mechanisms of sensory perception and signal transduction by a single eukaryotic cell, and their role in pathogenesis. We sequenced the genomes of P. blakesleeanus and M. circinelloides and show that they have been shaped by an extensive genome duplication or, most likely, a whole-genome duplication (WGD), which is rarely observed in fungi [3-6]. We show that the genome duplication has expanded gene families, including those involved in signal transduction, and that duplicated genes have specialized, as evidenced by differences in their regulation by light. The transcriptional response to light varies with the developmental stage and is still observed in a photoreceptor mutant of P. blakesleeanus. A phototropic mutant of P. blakesleeanus with a heterozygous mutation in the photoreceptor gene madA demonstrates that photosensor dosage is important for the magnitude of signal transduction. We conclude that the genome duplication provided the means to improve signal transduction for enhanced perception of environmental signals. Our results will help to understand the role of genome dynamics in the evolution of sensory perception in eukaryotes. PMID:27238284

  19. Fetus Sound Stimulation: Cilia Memristor Effect of Signal Transduction

    Directory of Open Access Journals (Sweden)

    Svetlana Jankovic-Raznatovic

    2014-01-01

    Full Text Available Background. This experimental study evaluates fetal middle cerebral artery (MCA circulation after the defined prenatal acoustical stimulation (PAS and the role of cilia in hearing and memory and could explain signal transduction and memory according to cilia optical-acoustical properties. Methods. PAS was performed twice on 119 no-risk term pregnancies. We analyzed fetal MCA circulation before, after first and second PAS. Results. Analysis of the Pulsatility index basic (PIB and before PAS and Pulsatility index reactive after the first PAS (PIR 1 shows high statistical difference, representing high influence on the brain circulation. Analysis of PIB and Pulsatility index reactive after the second PAS (PIR 2 shows no statistical difference. Cilia as nanoscale structure possess magnetic flux linkage that depends on the amount of charge that has passed between two-terminal variable resistors of cilia. Microtubule resistance, as a function of the current through and voltage across the structure, leads to appearance of cilia memory with the “memristor” property. Conclusion. Acoustical and optical cilia properties play crucial role in hearing and memory processes. We suggest that fetuses are getting used to sound, developing a kind of memory patterns, considering acoustical and electromagnetically waves and involving cilia and microtubules and try to explain signal transduction.

  20. Signal Transduction Model of Magnetic Sensing in Cryptochrome Mediated Photoreception

    Science.gov (United States)

    Todd, Phillise Tiffeny

    While migratory birds have long been known to use the Earth's magnetic field for navigation, the precise biophysical mechanism behind this magnetic sense remains unconfirmed. A leading theory of magnetoreception suggests a chemical compass model with a yet undetermined molecular reaction site and unknown magnetically sensitive reactants. The cryptochrome photoreceptor has emerged as a promising candidate site. This investigation numerically models the first order kinetics of cryptochrome mediated photoreception, in order to evaluate its ability to function as a magnetic sensor and transduce orientation information along a neural pathway. A signal-to-noise ratio is defined to quantify the threshold for the functioning of a cryptochrome-based chemical compass. The model suggests that a flavin-superoxide radical pair in cryptochrome functions as the chemical reactants for magnetoreception. Such a cryptochrome-based signal transduction model reasonably predicts the general light intensity and wavelength effects that have been experimentally observed in migratory birds.

  1. Information content and cross-talk in biological signal transduction: An information theory study

    Science.gov (United States)

    Prasad, Ashok; Lyons, Samanthe

    2014-03-01

    Biological cells respond to chemical cues provided by extra-cellular chemical signals, but many of these chemical signals and the pathways they activate interfere and overlap with one another. How well cells can distinguish between interfering extra-cellular signals is thus an important question in cellular signal transduction. Here we use information theory with stochastic simulations of networks to address the question of what happens to total information content when signals interfere. We find that both total information transmitted by the biological pathway, as well as its theoretical capacity to discriminate between overlapping signals, are relatively insensitive to cross-talk between the extracellular signals, until significantly high levels of cross-talk have been reached. This robustness of information content against cross-talk requires that the average amplitude of the signals are large. We predict that smaller systems, as exemplified by simple phosphorylation relays (two-component systems) in bacteria, should be significantly much less robust against cross-talk. Our results suggest that mammalian signal transduction can tolerate a high amount of cross-talk without degrading information content, while smaller bacterial systems cannot.

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

    Energy Technology Data Exchange (ETDEWEB)

    Le, Uyenchi N.; Min, Jung Joon; Moon, Sung Min; Bom, Hee Seung [School of Midicine, Chonnam National University, Gwangju (Korea, Republic of)

    2004-07-01

    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{sup 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.

  3. Role of Glycolytic Intermediates in Global Regulation and Signal Transduction. Final Report

    Energy Technology Data Exchange (ETDEWEB)

    Liao, J.C.

    2000-05-08

    The goal of this project is to determine the role of glycolytic intermediates in regulation of cell physiology. It is known that many glycolytic intermediates are involved in regulation of enzyme activities at the kinetic level. However, little is known regarding the role of these metabolites in global regulation and signal transduction. This project aims to investigate the role of glycolytic intermediates in the regulation of gene expression.

  4. Pheromone-induced signal transduction in Saccharomyces cerevisiae requires the sequential function of three protein kinases.

    OpenAIRE

    Z.Zhou; Gartner, A...; Cade, R.; Ammerer, G; Errede, B

    1993-01-01

    Protein phosphorylation plays an important role in pheromone-induced differentiation processes of haploid yeast cells. Among the components necessary for signal transduction are the STE7 and STE11 kinases and either one of the redundant FUS3 and KSS1 kinases. FUS3 and presumably KSS1 are phosphorylated and activated during pheromone induction by a STE7-dependent mechanism. Pheromone also induces the accumulation of STE7 in a hyperphosphorylated form. This modification of STE7 requires the STE...

  5. An increase in galectin-3 causes cellular unresponsiveness to IFN-γ-induced signal transduction and growth inhibition in gastric cancer cells

    Science.gov (United States)

    Tseng, Po-Chun; Chen, Chia-Ling; Shan, Yan-Shen; Lin, Chiou-Feng

    2016-01-01

    Glycogen synthase kinase (GSK)-3β facilitates interferon (IFN)-γ signaling by inhibiting Src homology-2 domain-containing phosphatase (SHP) 2. Mutated phosphoinositide 3-kinase (PI3K) and phosphatase and tensin homolog (PTEN) cause AKT activation and GSK-3β inactivation to induce SHP2-activated cellular unresponsiveness to IFN-γ in human gastric cancer AGS cells. This study investigated the potential role of galectin-3, which acts upstream of AKT/GSK-3β/SHP2, in gastric cancer cells. Increasing or decreasing galectin-3 altered IFN-γ signaling. Following cisplatin-induced galectin-3 upregulation, surviving cells showed cellular unresponsiveness to IFN-γ. Galectin-3 induced IFN-γ resistance independent of its extracellular β-galactoside-binding activity. Galectin-3 expression was not regulated by PI3K activation or by a decrease in PTEN. Increased galectin-3 may cause GSK-3β inactivation and SHP2 activation by promoting PDK1-induced AKT phosphorylation at a threonine residue. Overexpression of AKT, inactive GSK-3βR96A, SHP2, or active SHP2D61A caused cellular unresponsiveness to IFN-γ in IFN-γ-sensitive MKN45 cells. IFN-γ-induced growth inhibition and apoptosis in AGS cells were observed until galectin-3 expression was downregulated. These results demonstrate that an increase in galectin-3 facilitates AKT/GSK-3β/SHP2 signaling, causing cellular unresponsiveness to IFN-γ. PMID:26934444

  6. Genetic Basis of Ethylene Perception and Signal Transduction in Arabidopsis

    Institute of Scientific and Technical Information of China (English)

    Ziqiang Zhu; Hongwei Guo

    2008-01-01

    Ethylene is a simple gaseous hormone in plants. It plays important roles in plant development and stress tolerance. In the presence of ethylene treatment, all ethylene receptors are in an activated form, which can physically interact with CTR1 and consequently recruit CTR1 protein to endoplasmic reticulum membrane to activate it. Activated CTR1 suppresses the downstream signal transduction by an unknown mechanism. Upon binding to its receptors, ethylene will inactivate the receptor/CTR1 module and in turn alleviate their inhibitory effect on two positive regulators acting downstream of CTRI: EIN2 and EIN3. Genetic study reveals that EIN2 is an essential component in the ethylene signaling pathway but its biochemical function remains a mystery. EIN3 is a plant-specific transcription factor and its protein abundance in the nucleus is rapidly induced upon ethylene treatment. In the absence of ethylene signal, EIN3 protein is degraded by an SCF complex containing one of the two F-box proteins EBF1/EBF2 in a 26S proteasome-dependent manner. EIN3 can bind to the promoter sequences of a number of downstream components, such as ERFs, which in turn bind to a GCC box,a cis-element found in many ethylene-regulated defense genes. Ethylene has been shown to also regulate many other hormones' signaling pathways including auxin, abscisic acid and jasmonic acid, implying the existence of complicated signaling networks in the growth, development and defense responses of various plants.

  7. Decoding the phosphorylation code in Hedgehog signal transduction

    Institute of Scientific and Technical Information of China (English)

    Yongbin Chen; Jin Jiang

    2013-01-01

    Hedgehog (Hh) signaling plays pivotal roles in embryonic development and adult tissue homeostasis,and its deregulation leads to numerous human disorders including cancer.Binding of Hh to Patched (Ptc),a twelve-transmembrane protein,alleviates its inhibition of Smoothened (Smo),a seven-transmembrane protein related to G-proteincoupled receptors (GPCRs),leading to Smo phosphorylation and activation.Smo acts through intracellular signaling complexes to convert the latent transcription factor Cubitus interruptus (Ci)/Gli from a truncated repressor to a fulllength activator,leading to derepression/activation of Hh target genes.Increasing evidence suggests that phosphorylation participates in almost every step in the signal relay from Smo to Ci/Gli,and that differential phosphorylation of several key pathway components may be crucial for translating the Hh morphogen gradient into graded pathway activities.In this review,we focus on the multifaceted roles that phosphorylation plays in Hh signal transduction,and discuss the conservation and difference between Drosophila and mammalian Hh signaling mechanisms.

  8. The interleukin-4 receptor: signal transduction by a hematopoietin receptor.

    Science.gov (United States)

    Keegan, A D; Pierce, J H

    1994-02-01

    Over the last several years, the receptors for numerous cytokines have been molecularly characterized. Analysis of their amino acid sequences shows that some of these receptors bear certain motifs in their extracellular domains that define a family of receptors called the Hematopoietin receptor superfamily. Significant advances in characterizing the structure, function, and mechanisms of signal transduction have been made for several members of this family. The purpose of this review is to discuss the recent advances made for one of the family members, the interleukin (IL) 4 receptor. Other receptor systems have recently been reviewed elsewhere. The IL-4 receptor consists of, at the minimum, the cloned 140 kDa IL-4-binding chain with the potential for associating with other chains. The IL-4 receptor transduces its signal by activating a tyrosine kinase that phosphorylates cellular substrates, including the receptor itself, and the 170 kDa substrate called 4PS. Phosphorylated 4PS interacts with the SH2 domain of the enzyme PI-3'-kinase and increases its enzymatic activity. These early events in the IL-4 receptor initiated signaling pathway may trigger a series of signals that will ultimately lead to an IL-4 specific biologic outcome.

  9. Simulation of signal transduction in model multiprotein systems

    Science.gov (United States)

    Su, Julius

    2009-03-01

    To simulate the dynamics of multiprotein machines, I have developed a method called multiconformer Brownian dynamics (mcBD). In this method, proteins rotate and translate via Brownian motion while their conformations are varied among a prestored set of structures on a simplified energy landscape, taking into account inter-protein interactions. As an example, I build a simple model of a G-protein coupled receptor/G-protein complex, and show that ligand binding causes conformational shifts, which induce GDP to leave, GTP to bind, and the complex to dissociate. The two proteins couple their fast fluctuations together into large-scale coordinated functional motions, resulting in signal transduction. I vary the shapes, electrostatics, and energy landscapes of the proteins independently and examine the impact this has on the system's function. In one result, increasing the binding between proteins improves the fidelity of communication, but at the expense of overall switching frequency.

  10. Reactive oxygen species mediate insulin signal transduction in mouse hypothalamus.

    Science.gov (United States)

    Onoue, Takeshi; Goto, Motomitsu; Tominaga, Takashi; Sugiyama, Mariko; Tsunekawa, Taku; Hagiwara, Daisuke; Banno, Ryoichi; Suga, Hidetaka; Sugimura, Yoshihisa; Arima, Hiroshi

    2016-04-21

    In the hypothalamus, several reports have implied that ROS mediate physiological effects of insulin. In this study, we investigated the mechanisms of insulin-induced ROS production and the effect of ROS on insulin signal transduction in mouse hypothalamic organotypic cultures. Insulin increased intracellular ROS, which were suppressed by NADPH oxidase inhibitor. H2O2 increased phospho-insulin receptor β (p-IRβ) and phospho-Akt (p-Akt) levels. Insulin-induced increases in p-IRβ and p-Akt levels were attenuated by ROS scavenger or NADPH oxidase inhibitor. Our data suggest that insulin-induced phosphorylation of IRβ and Akt is mediated via ROS which are predominantly produced by NADPH oxidase in mouse hypothalamus.

  11. Involvement of Ca2+/CaM in the signal transduction of acetylcholine regulating stomatal movement

    Institute of Scientific and Technical Information of China (English)

    2003-01-01

    It has been known that the neurotransmitter acetylcholine (ACh) also exists in plants and is able to regulate the movement of stomata. In another aspect, Ca2+/CaM as the second messengers have a critical role of signal transduction in stomatal guard-cell. Here we showed that Ca2+/CaM were also involved in theACh regulated stomatal movement. In the medium containing Ca2+, the Ca2+ channel blockers (NIF and Ver) and CaM inhibitors (TFP and W7) could neutralize the ACh induced stomatal opening, however, they are ineffective in the medium containing K+. Those results indicated that Ca2+/CaM were involved in the signal transduction pathway of ACh regulating stomatal movement.

  12. Regulation of drug-induced liver injury by signal transduction pathways: critical role of mitochondria.

    Science.gov (United States)

    Han, Derick; Dara, Lily; Win, Sanda; Than, Tin Aung; Yuan, Liyun; Abbasi, Sadeea Q; Liu, Zhang-Xu; Kaplowitz, Neil

    2013-04-01

    Drugs that cause liver injury often 'stress' mitochondria and activate signal transduction pathways important in determining cell survival or death. In most cases, hepatocytes adapt to the drug-induced stress by activating adaptive signaling pathways, such as mitochondrial adaptive responses and nuclear factor erythroid 2-related factor 2 (Nrf-2), a transcription factor that upregulates antioxidant defenses. Owing to adaptation, drugs alone rarely cause liver injury, with acetaminophen (APAP) being the notable exception. Drug-induced liver injury (DILI) usually involves other extrinsic factors, such as the adaptive immune system, that cause 'stressed' hepatocytes to become injured, leading to idiosyncratic DILI, the rare and unpredictable adverse drug reaction in the liver. Hepatocyte injury, due to drug and extrinsic insult, causes a second wave of signaling changes associated with adaptation, cell death, and repair. If the stress and injury reach a critical threshold, then death signaling pathways such as c-Jun N-terminal kinase (JNK) become dominant and hepatocytes enter a failsafe mode to undergo self-destruction. DILI can be seen as an active process involving recruitment of death signaling pathways that mediate cell death rather than a passive process due to overwhelming biochemical injury. In this review, we highlight the role of signal transduction pathways, which frequently involve mitochondria, in the development of DILI. PMID:23453390

  13. Signal transduction in human pancreatic cancer: roles of transforming growth factor beta, somatostatin receptors, and other signal intermediates.

    Science.gov (United States)

    Li, Min; Becnel, Lauren S; Li, Wei; Fisher, William E; Chen, Changyi; Yao, Qizhi

    2005-01-01

    Pancreatic cancer is a devastating disease because of the lack of early detection markers and effective treatments. It is the fourth leading cause of cancer-related death in western countries, including the United States. The mechanisms of pancreatic cancer progression remain unknown. Transforming growth factor beta (TGF-beta), a multifunctional cytokine, regulates cell growth and differentiation in healthy tissues, yet fails to do so in pancreatic cancer. Alterations of the TGF-beta and TGF-beta receptor/Smad signal transduction pathway have been implicated in pancreatic cancer. Furthermore, both the TGF-beta receptor and Smad proteins interact with a variety of cellular signal pathways, such as the somatostatin receptors (SSTRs), ERK1/2, and Wnt signal transduction cascades. This suggests that pancreatic cancer is a multi-gene-controlled malignancy and that effective treatments for pancreatic cancer should be aimed at multiple targets. In this review, we summarized the major signal intermediates involved in pancreatic cancer signal transduction pathways and specifically discussed how alterations in the regulatory functions of TGF-beta and Smad proteins allow for pancreatic carcinogenesis. PMID:16314822

  14. Substance P Activates the Wnt Signal Transduction Pathway and Enhances the Differentiation of Mouse Preosteoblastic MC3T3-E1 Cells

    Directory of Open Access Journals (Sweden)

    Gang Mei

    2014-04-01

    Full Text Available Recent experiments have explored the impact of Wnt/β-catenin signaling and Substance P (SP on the regulation of osteogenesis. However, the molecular regulatory mechanisms of SP on the formation of osteoblasts is still unknown. In this study, we investigated the impact of SP on the differentiation of MC3T3-E1 cells. The osteogenic effect of SP was observed at different SP concentrations (ranging from 10−10 to 10−8 M. To unravel the underlying mechanism, the MC3T3-E1 cells were treated with SP after the pretreatment by neurokinin-1 (NK1 antagonists and Dickkopf-1 (DKK1 and gene expression levels of Wnt/β-catenin signaling pathway components, as well as osteoblast differentiation markers (collagen type I, alkaline phosphatase, osteocalcin, and Runx2, were measured using quantitative polymerase chain reaction (PCR. Furthermore, protein levels of Wnt/β-catenin signaling pathway were detected using Western blotting and the effects of SP, NK1 antagonist, and DKK1 on β-catenin activation were investigated by immunofluorescence staining. Our data indicated that SP (10−9 to 10−8 M significantly up-regulated the expressions of osteoblastic genes. SP (10−8 M also elevated the mRNA level of c-myc, cyclin D1, and lymphocyte enhancer factor-1 (Lef1, as well as c-myc and β-catenin protein levels, but decreased the expression of Tcf7 mRNA. Moreover, SP (10−8 M promoted the transfer of β-catenin into nucleus. The effects of SP treatment were inhibited by the NK1 antagonist and DKK1. These findings suggest that SP may enhance differentiation of MC3T3-E1 cells via regulation of the Wnt/β-catenin signaling pathway.

  15. Calcitonin gene-related peptide promotes the expression of osteoblastic genes and activates the WNT signal transduction pathway in bone marrow stromal stem cells

    Science.gov (United States)

    ZHOU, RI; YUAN, ZHI; LIU, JIERONG; LIU, JIAN

    2016-01-01

    Calcitonin gene-related peptide (CGRP) is known to induce osteoblastic differentiation and alkaline phosphatase activity in bone marrow stromal stem cells (BMSCs). However, it has remained elusive whether this effect is mediated by CGRP receptors directly or whether other signaling pathways are involved. The present study assessed the possible involvement of the Wnt/β-catenin signaling pathway in the activation of CGRP signaling during the differentiation of BMSCs. First, the differentiation of BMSCs was induced in vitro and the expression of CGRP receptors was examined by western blot analysis. The effects of exogenous CGRP and LiCl, a stimulator of the Wnt/β-catenin signaling pathway, on the osteoblastic differentiation of BMSCs were assessed; furthermore, the expression of mRNA and proteins involved in the Wnt/β-catenin signaling pathway was assessed using quantitative PCR and western blot analyses. The results revealed that CGRP receptors were expressed throughout the differentiation of BMSCs, at days 7 and 14. Incubation with CGRP and LiCl led to the upregulation of the expression of osteoblastic genes associated with the Wnt/β-catenin pathway, including the mRNA of c-myc, cyclin D1, Lef1, Tcf7 and β-catenin as well as β-catenin protein. However, the upregulation of these genes and β-catenin protein was inhibited by CGRP receptor antagonist or secreted frizzled-related protein, an antagonist of the Wnt/β-catenin pathway. The results of the present study therefore suggested that the Wnt/β-catenin signaling pathway may be involved in CGRP- and LiCl-promoted osteoblastic differentiation of BMSCs. PMID:27082317

  16. Signal transduction of gap junctional genes, connexin32,connexin43 in human hepatocarcinogenesis

    Institute of Scientific and Technical Information of China (English)

    Xiang-Dong Ma; Xing Ma; Yan-Fang Sui; Weng-Liang Wang; Chun-Mei Wang

    2003-01-01

    AIM: To investigate gap junctional intercellular communication (GJIC) in hepatocellular carcinoma cell lines, and signal transduction mechanism of gap junction genes connexin32(cx32),connexin43(cx43) in human hepatocarcinogenesis.METHODS: Scarped loading and dye transfer (SLDT) was employed with Lucifer Yellow (LY) to detect GJIC function in hepatocellular carcinoma cell lines HHCC, SMMC-7721and normal control liver cell line QZG. After Fluo-3AM loading, laser scanning confocal microscope (LSCM) was used to measure concentrations of intracellular calcium [Ca2+]i in the cells. The phosphorylation on tyrosine of connexin proteins was examined by immunoblot.RESULTS: SLDT showed that ability of GJIC function was higher in QZG cell than that in HHCC and SMMC-7721 cell lines. By laser scanning confocal microscopy, concentrations of intracellular free calcium [Ca2+]i was much higher in QZG cell line (108.37 nmol/L) than those in HHCC (35.13nmol/L) and SMMC-7721 (47.08 nmol/L) cells. Western blot suggested that only QZG cells had unphosphorylated tyrosine in Cx32 protein of 32 ku and Cx43 protein of 43ku; SMMC-7721 cells showed phosphorylated tyrosine Cx43 protein.CONCLUSION: The results indicated that carcinogenesis and development of human hepatocellular carcinoma related with the abnormal expression of cx genes and disorder of its signal transduction pathway, such as decrease of [Ca2+]i,post-translation phosphorylation on tyrosine of Cx proteins which led to a dramatic disruption of GJIC.

  17. Oxidative Stress in Fungi: Its Function in Signal Transduction, Interaction with Plant Hosts, and Lignocellulose Degradation

    Directory of Open Access Journals (Sweden)

    Michael Breitenbach

    2015-04-01

    Full Text Available In this review article, we want to present an overview of oxidative stress in fungal cells in relation to signal transduction, interaction of fungi with plant hosts, and lignocellulose degradation. We will discuss external oxidative stress which may occur through the interaction with other microorganisms or plant hosts as well as internally generated oxidative stress, which can for instance originate from NADPH oxidases or “leaky” mitochondria and may be modulated by the peroxiredoxin system or by protein disulfide isomerases thus contributing to redox signaling. Analyzing redox signaling in fungi with the tools of molecular genetics is presently only in its beginning. However, it is already clear that redox signaling in fungal cells often is linked to cell differentiation (like the formation of perithecia, virulence (in plant pathogens, hyphal growth and the successful passage through the stationary phase.

  18. Oxidative stress in fungi: its function in signal transduction, interaction with plant hosts, and lignocellulose degradation.

    Science.gov (United States)

    Breitenbach, Michael; Weber, Manuela; Rinnerthaler, Mark; Karl, Thomas; Breitenbach-Koller, Lore

    2015-01-01

    In this review article, we want to present an overview of oxidative stress in fungal cells in relation to signal transduction, interaction of fungi with plant hosts, and lignocellulose degradation. We will discuss external oxidative stress which may occur through the interaction with other microorganisms or plant hosts as well as internally generated oxidative stress, which can for instance originate from NADPH oxidases or "leaky" mitochondria and may be modulated by the peroxiredoxin system or by protein disulfide isomerases thus contributing to redox signaling. Analyzing redox signaling in fungi with the tools of molecular genetics is presently only in its beginning. However, it is already clear that redox signaling in fungal cells often is linked to cell differentiation (like the formation of perithecia), virulence (in plant pathogens), hyphal growth and the successful passage through the stationary phase. PMID:25854186

  19. BowTieBuilder: modeling signal transduction pathways

    OpenAIRE

    Schröder Adrian; Dräger Andreas; Planatscher Hannes; Spangenberg Lucía; Supper Jochen; Zell Andreas

    2009-01-01

    Abstract Background Sensory proteins react to changing environmental conditions by transducing signals into the cell. These signals are integrated into core proteins that activate downstream target proteins such as transcription factors (TFs). This structure is referred to as a bow tie, and allows cells to respond appropriately to complex environmental conditions. Understanding this cellular processing of information, from sensory proteins (e.g., cell-surface proteins) to target proteins (e.g...

  20. Both membrane-dependent and DNA damage-dependent signal transduction chains are activated following UV irradiation

    Energy Technology Data Exchange (ETDEWEB)

    Blattner, C.; Knebel, A.; Bender, K.; Rahmsdorf, H.J.; Herrlich, P. [Forschungszentrum Karlsruhe (Germany). Inst. fuer Genetik

    1997-03-01

    Irradiation of cultured cells with short wave length ultraviolet light (UVC) activates at least two types of signal transduction chains which ultimately lead to changes in gene expression. One type involves cell surface receptors and is activated with very rapid kinetics. One or several membrane associated protein tyrosine phosphatases are inhibited in less than one minute following UV exposure. Consequently the dephosphorylation of tyrosine-phosphorylated growth factor receptors is impaired. This process is ligand-independent and suggests spontaneous autophosphorylation activity of receptor tyrosine kinases. The UV-induced auto-phosphorylations trigger-signal transduction to the nucleus and activate transcription of immediate early genes such as c-fos. The other type of signal transduction chain has its origin in DNA damage. It occurs with delayed kinetics. We analyzed several human fibroblastic cell lines with distinct deficiencies in nucleotide excision repair mechanisms for the dose dependence of UV-induced late appearing and stable collagenase I mRNA. Several cell lines with deficiencies in the preferential repair of transcribed genes required lower doses of UV than wild type cells or cells solely deficient in the repair of the overall genome. These data suggest the existence of a signal transduction cascade whose stimulation is elicited by lesions in transcribed genes. It appears that similar or identical transcription factors are activated by both types of UV-induced signal transduction. For instance the transcription factor NF{kappa}B is activated by both, a DNA damage independent and a DNA damage dependent signal transduction chain. (authors)

  1. Both membrane-dependent and DNA damage-dependent signal transduction chains are activated following UV irradiation

    International Nuclear Information System (INIS)

    Irradiation of cultured cells with short wave length ultraviolet light (UVC) activates at least two types of signal transduction chains which ultimately lead to changes in gene expression. One type involves cell surface receptors and is activated with very rapid kinetics. One or several membrane associated protein tyrosine phosphatases are inhibited in less than one minute following UV exposure. Consequently the dephosphorylation of tyrosine-phosphorylated growth factor receptors is impaired. This process is ligand-independent and suggests spontaneous autophosphorylation activity of receptor tyrosine kinases. The UV-induced auto-phosphorylations trigger-signal transduction to the nucleus and activate transcription of immediate early genes such as c-fos. The other type of signal transduction chain has its origin in DNA damage. It occurs with delayed kinetics. We analyzed several human fibroblastic cell lines with distinct deficiencies in nucleotide excision repair mechanisms for the dose dependence of UV-induced late appearing and stable collagenase I mRNA. Several cell lines with deficiencies in the preferential repair of transcribed genes required lower doses of UV than wild type cells or cells solely deficient in the repair of the overall genome. These data suggest the existence of a signal transduction cascade whose stimulation is elicited by lesions in transcribed genes. It appears that similar or identical transcription factors are activated by both types of UV-induced signal transduction. For instance the transcription factor NFκB is activated by both, a DNA damage independent and a DNA damage dependent signal transduction chain. (authors)

  2. Girdin/GIV is upregulated by cyclic tension, propagates mechanical signal transduction, and is required for the cellular proliferation and migration of MG-63 cells

    International Nuclear Information System (INIS)

    To explore how Girdin/GIV is regulated by cyclic tension and propagates downstream signals to affect cell proliferation and migration. Human osteoblast-like MG-63 cells were exposed to cyclic tension force at 4000 μstrain and 0.5 Hz for 6 h, produced by a four-point bending system. Cyclic tension force upregulated Girdin and Akt expression and phosphorylation in cultured MG-63 cells. Girdin and Akt each promoted the phosphorylation of the other under stimulated tension. In vitro MTT and transwell assays showed that Girdin and Akt are required for cell proliferation and migration during cellular quiescence. Moreover, STAT3 was determined to be essential for Girdin expression under stimulated tension force in the physiological condition, as well as for osteoblast proliferation and migration during quiescence. These findings suggest that the STAT3/Girdin/Akt pathway activates in osteoblasts in response to mechanical stimulation and may play a significant role in triggering osteoblast proliferation and migration during orthodontic treatment. - Highlights: • Tension force upregulates Girdin and Akt expression and phosphorylation. • Girdin and Akt promotes the phosphorylation of each other under tension stimulation. • Girdin and Akt are required for MG-63 cell proliferation and migration. • STAT3 is essential for Girdin expression after application of the tension forces

  3. Girdin/GIV is upregulated by cyclic tension, propagates mechanical signal transduction, and is required for the cellular proliferation and migration of MG-63 cells

    Energy Technology Data Exchange (ETDEWEB)

    Hu, Jiang-Tian; Li, Yan; Yu, Bing; Gao, Guo-Jie; Zhou, Ting; Li, Song, E-mail: song_li59@126.com

    2015-08-21

    To explore how Girdin/GIV is regulated by cyclic tension and propagates downstream signals to affect cell proliferation and migration. Human osteoblast-like MG-63 cells were exposed to cyclic tension force at 4000 μstrain and 0.5 Hz for 6 h, produced by a four-point bending system. Cyclic tension force upregulated Girdin and Akt expression and phosphorylation in cultured MG-63 cells. Girdin and Akt each promoted the phosphorylation of the other under stimulated tension. In vitro MTT and transwell assays showed that Girdin and Akt are required for cell proliferation and migration during cellular quiescence. Moreover, STAT3 was determined to be essential for Girdin expression under stimulated tension force in the physiological condition, as well as for osteoblast proliferation and migration during quiescence. These findings suggest that the STAT3/Girdin/Akt pathway activates in osteoblasts in response to mechanical stimulation and may play a significant role in triggering osteoblast proliferation and migration during orthodontic treatment. - Highlights: • Tension force upregulates Girdin and Akt expression and phosphorylation. • Girdin and Akt promotes the phosphorylation of each other under tension stimulation. • Girdin and Akt are required for MG-63 cell proliferation and migration. • STAT3 is essential for Girdin expression after application of the tension forces.

  4. The emerging role of phosphoinositide clustering in intracellular trafficking and signal transduction

    Science.gov (United States)

    Picas, Laura; Gaits-Iacovoni, Frederique; Goud, Bruno

    2016-01-01

    Phosphoinositides are master regulators of multiple cellular processes: from vesicular trafficking to signaling, cytoskeleton dynamics, and cell growth. They are synthesized by the spatiotemporal regulated activity of phosphoinositide-metabolizing enzymes. The recent observation that some protein modules are able to cluster phosphoinositides suggests that alternative or complementary mechanisms might operate to stabilize the different phosphoinositide pools within cellular compartments. Herein, we discuss the different known and potential molecular players that are prone to engage phosphoinositide clustering and elaborate on how such a mechanism might take part in the regulation of intracellular trafficking and signal transduction. PMID:27092250

  5. An Integrated Model of Epidermal Growth Factor Receptor Trafficking and Signal Transduction

    Energy Technology Data Exchange (ETDEWEB)

    Resat, Haluk; Ewald, Jonathan A.; Dixon, David A.; Wiley, H. S.

    2003-08-01

    Endocytic trafficking of many types of receptors can have profound effects on subsequent signaling events. Quantitative models of these processes, however, have usually considered trafficking and signaling independently. Here, we present an integrated model of both the trafficking and signaling pathway of the epidermal growth factor receptor (EGFR) using a probability weighted-dynamic Monte Carlo simulation. Our model consists of hundreds of distinct endocytic compartments and about 13,000 reactions/events that occur over a broad spatio-temporal range. By using a realistic multi-compartment model, we can investigate the distribution of the receptors among cellular compartments as well as their potential signal transduction characteristics. Our new model also allows the incorporation of physio-chemical aspects of ligand-receptor interactions, such as pH-dependent binding in different endosomal compartments. To determine the utility of this approach, we simulated the differential activation of the EGFR by two of its ligands, epidermal growth factor (EGF) and transforming growth factor- alpha (TGF-a). Our simulations predict that when EGFR is activated with TGF-a, receptor activation is biased toward the cell surface whereas EGF produces a signaling bias towards the endosomal compartment. Experiments confirm these predictions from our model and simulations. Our model accurately predicts the kinetics and extent of receptor down-regulation induced by either EGF or TGF-a. Our results suggest that receptor trafficking controls the compartmental bias of signal transduction, rather than simply modulating signal magnitude. Our model provides a new approach to evaluating the complex effect of receptor trafficking on signal transduction. Importantly, the stochastic and compartmental nature of the simulation allows these models to be directly tested by high-throughput approaches, such as quantitative image analysis.

  6. An integrated model of epidermal growth factor receptor trafficking and signal transduction.

    Science.gov (United States)

    Resat, Haluk; Ewald, Jonathan A; Dixon, David A; Wiley, H Steven

    2003-08-01

    Endocytic trafficking of many types of receptors can have profound effects on subsequent signaling events. Quantitative models of these processes, however, have usually considered trafficking and signaling independently. Here, we present an integrated model of both the trafficking and signaling pathway of the epidermal growth factor receptor (EGFR) using a probability weighted-dynamic Monte Carlo simulation. Our model consists of hundreds of distinct endocytic compartments and approximately 13,000 reactions/events that occur over a broad spatio-temporal range. By using a realistic multicompartment model, we can investigate the distribution of the receptors among cellular compartments as well as their potential signal transduction characteristics. Our new model also allows the incorporation of physiochemical aspects of ligand-receptor interactions, such as pH-dependent binding in different endosomal compartments. To determine the utility of this approach, we simulated the differential activation of the EGFR by two of its ligands, epidermal growth factor (EGF) and transforming growth factor-alpha (TGF-alpha). Our simulations predict that when EGFR is activated with TGF-alpha, receptor activation is biased toward the cell surface whereas EGF produces a signaling bias toward the endosomal compartment. Experiments confirm these predictions from our model and simulations. Our model accurately predicts the kinetics and extent of receptor downregulation induced by either EGF or TGF-alpha. Our results suggest that receptor trafficking controls the compartmental bias of signal transduction, rather than simply modulating signal magnitude. Our model provides a new approach to evaluating the complex effect of receptor trafficking on signal transduction. Importantly, the stochastic and compartmental nature of the simulation allows these models to be directly tested by high-throughput approaches, such as quantitative image analysis. PMID:12885624

  7. Signal transduction and information processing in mammalian taste buds

    OpenAIRE

    Roper, Stephen D.

    2007-01-01

    The molecular machinery for chemosensory transduction in taste buds has received considerable attention within the last decade. Consequently, we now know a great deal about sweet, bitter, and umami taste mechanisms and are gaining ground rapidly on salty and sour transduction. Sweet, bitter, and umami tastes are transduced by G-protein-coupled receptors. Salty taste may be transduced by epithelial Na channels similar to those found in renal tissues. Sour transduction appears to be initiated b...

  8. Receptor clustering affects signal transduction at the membrane level in the reaction-limited regime

    Science.gov (United States)

    Caré, Bertrand R.; Soula, Hédi A.

    2013-01-01

    Many types of membrane receptors are found to be organized as clusters on the cell surface. We investigate the potential effect of such receptor clustering on the intracellular signal transduction stage. We consider a canonical pathway with a membrane receptor (R) activating a membrane-bound intracellular relay protein (G). We use Monte Carlo simulations to recreate biochemical reactions using different receptor spatial distributions and explore the dynamics of the signal transduction. Results show that activation of G by R is severely impaired by R clustering, leading to an apparent blunted biological effect compared to control. Paradoxically, this clustering decreases the half maximal effective dose (ED50) of the transduction stage, increasing the apparent affinity. We study an example of inter-receptor interaction in order to account for possible compensatory effects of clustering and observe the parameter range in which such interactions slightly counterbalance the loss of activation of G. The membrane receptors’ spatial distribution affects the internal stages of signal amplification, suggesting a functional role for membrane domains and receptor clustering independently of proximity-induced receptor-receptor interactions.

  9. p53 amplifies Toll-like receptor 5 response in human primary and cancer cells through interaction with multiple signal transduction pathways

    Science.gov (United States)

    Shatz, Maria; Shats, Igor; Menendez, Daniel; Resnick, Michael A.

    2015-01-01

    The p53 tumor suppressor regulates transcription of genes associated with diverse cellular functions including apoptosis, growth arrest, DNA repair and differentiation. Recently, we established that p53 can modulate expression of Toll-like receptor (TLR) innate immunity genes but the degree of cross-talk between p53 and TLR pathways remained unclear. Here, using gene expression profiling we characterize the global effect of p53 on the TLR5-mediated transcription in MCF7 cells. We found that combined activation of p53 and TLR5 pathways synergistically increases expression of over 200 genes, mostly associated with immunity and inflammation. The synergy was observed in several human cancer cells and primary lymphocytes. The p53-dependent amplification of transcriptional response to TLR5 activation required expression of NFκB subunit p65 and was mediated by several molecular mechanisms including increased phosphorylation of p38 MAP kinase, PI3K and STAT3 signaling. Additionally, p53 induction increased cytokine expression in response to TNFα, another activator of NFκB and MAP kinase pathways, suggesting a broad interaction between p53 and these signaling pathways. The expression of many synergistically induced genes is elevated in breast cancer patients responsive to chemotherapy. We suggest that p53's capacity to enhance immune response could be exploited to increase antitumor immunity and to improve cancer treatment. PMID:26220208

  10. The ubiquitin–proteasome system and signal transduction pathways regulating Epithelial Mesenchymal transition of cancer

    Directory of Open Access Journals (Sweden)

    Voutsadakis Ioannis A

    2012-07-01

    Full Text Available Abstract Epithelial to Mesenchymal transition (EMT in cancer, a process permitting cancer cells to become mobile and metastatic, has a signaling hardwire forged from development. Multiple signaling pathways that regulate carcinogenesis enabling characteristics in neoplastic cells such as proliferation, resistance to apoptosis and angiogenesis are also the main players in EMT. These pathways, as almost all cellular processes, are in their turn regulated by ubiquitination and the Ubiquitin-Proteasome System (UPS. Ubiquitination is the covalent link of target proteins with the small protein ubiquitin and serves as a signal to target protein degradation by the proteasome or to other outcomes such as endocytosis, degradation by the lysosome or specification of cellular localization. This paper reviews signal transduction pathways regulating EMT and being regulated by ubiquitination.

  11. Signal transduction meets vesicle traffic: the software and hardware of GLUT4 translocation.

    Science.gov (United States)

    Klip, Amira; Sun, Yi; Chiu, Tim Ting; Foley, Kevin P

    2014-05-15

    Skeletal muscle is the major tissue disposing of dietary glucose, a function regulated by insulin-elicited signals that impart mobilization of GLUT4 glucose transporters to the plasma membrane. This phenomenon, also central to adipocyte biology, has been the subject of intense and productive research for decades. We focus on muscle cell studies scrutinizing insulin signals and vesicle traffic in a spatiotemporal manner. Using the analogy of an integrated circuit to approach the intersection between signal transduction and vesicle mobilization, we identify signaling relays ("software") that engage structural/mechanical elements ("hardware") to enact the rapid mobilization and incorporation of GLUT4 into the cell surface. We emphasize how insulin signal transduction switches from tyrosine through lipid and serine phosphorylation down to activation of small G proteins of the Rab and Rho families, describe key negative regulation step of Rab GTPases through the GTPase-activating protein activity of the Akt substrate of 160 kDa (AS160), and focus on the mechanical effectors engaged by Rabs 8A and 10 (the molecular motor myosin Va), and the Rho GTPase Rac1 (actin filament branching and severing through Arp2/3 and cofilin). Finally, we illustrate how actin filaments interact with myosin 1c and α-Actinin4 to promote vesicle tethering as preamble to fusion with the membrane.

  12. Studies on the mitogenic effect of transferrin by membrane signal transduction

    Institute of Scientific and Technical Information of China (English)

    LEUNGTM; PLLIM; 等

    1990-01-01

    One of the earliest events leading to cell activation and growth is the hydrolysis of inositol phospholipids producing various membrane signals induced by an interaction between growth factors or hormones with their respective receptors on the cell membrane [1].To demonstrate the mitogenic action of transferrin,our results show that an addition of transferrin to “serum-deprived” rat hepatoma cells produced a rapid but transient rise in inositol 1,4,5-trisphosphate(IP3) level,and at the same time,an increased intracellular Ca2+ activity and a cytoplasmic alkalinization were observed.These signal transductions further lend support to the mitogenic nature of transferrin.In addition,a possible link between the receptor-mediated endocytosis of transferrin with the generation of intracellular signals is discussed herewith.

  13. Cytokinin signal transduction: Known simplicity and unknown complexity

    Institute of Scientific and Technical Information of China (English)

    ZHENG Binglian; SUN Jiaqiang; ZHANG Suzhi; DENG Yan; ZUO Jianru

    2003-01-01

    Cytokinin plays a critical role in plant growth and development by regulating cell divisions and cell differentiation. Recent studies suggest that cytokinin signaling is presumably mediated by a two-component system analogous to those found in bacteria and fungi, which transduces an external signal via a phosphorelay from the plasma membrane-anchored receptors to downstream effectors andregulators. Moreover, cytokinin signaling is highly interactive with other pathways, and many components of the pathway appear to be functionally redundant. Proper address of these questions will be crucial for our further understanding onthis important network.

  14. Roles of ABA Signal Transduction during Higher Plant Seed Development and Germination

    Institute of Scientific and Technical Information of China (English)

    Shao Hongbo; Liang Zongsuo; Shao Mingan

    2003-01-01

    ABA is one of the 5 phytohormones in higher plants, which is also the most important hormone that regulates higher plants in response to environmental stress, by ABA signal transduction. Understanding ABA signal transduction at the molecular level is crucial to biology and ecology, and rational breeding complied with corresponding eco-environmental changes.Great advancements have taken place over the past 10 years by application of the 4rabidopsis experimental system. Many components involved in ABA signal transduction have been isolated and identified and a clear overall picture of gene expression and control for this transduction has become an Accepted fact. On the basis of the work in our laboratory, in conjunction with the data available at the moment, the authors have attempted to integrate ABA signal transduction pathways into a common one and give some insights into the relationship between ABA signal transduction and other hormone signal transduction pathways, with an emphasis upon the ABA signal transduction during higher plant seed development. A future challenge in this field is that different experimental systems are applied and various receptors and genes need to be characterized through the utilization of microarray chips.

  15. Molecular mechanisms of gravity perception and signal transduction in plants.

    Science.gov (United States)

    Kolesnikov, Yaroslav S; Kretynin, Serhiy V; Volotovsky, Igor D; Kordyum, Elizabeth L; Ruelland, Eric; Kravets, Volodymyr S

    2016-07-01

    Gravity is one of the environmental cues that direct plant growth and development. Recent investigations of different gravity signalling pathways have added complexity to how we think gravity is perceived. Particular cells within specific organs or tissues perceive gravity stimulus. Many downstream signalling events transmit the perceived information into subcellular, biochemical, and genomic responses. They are rapid, non-genomic, regulatory, and cell-specific. The chain of events may pass by signalling lipids, the cytoskeleton, intracellular calcium levels, protein phosphorylation-dependent pathways, proteome changes, membrane transport, vacuolar biogenesis mechanisms, or nuclear events. These events culminate in changes in gene expression and auxin lateral redistribution in gravity response sites. The possible integration of these signalling events with amyloplast movements or with other perception mechanisms is discussed. Further investigation is needed to understand how plants coordinate mechanisms and signals to sense this important physical factor. PMID:26215561

  16. Characterization of the pharmacology, signal transduction and internalization of the fluorescent PACAP ligand, fluor-PACAP, on NIH/3T3 cells expressing PAC1.

    Science.gov (United States)

    Germano, P M; Stalter, J; Le, S V; Wu, M; Yamaguchi, D J; Scott, D; Pisegna, J R

    2001-06-01

    Fluor-PACAP, a fluorescent derivative of PACAP-27, has been confirmed to share a high affinity for PAC1 receptors transfected into NIH/3T3 cells and to have comparable pharmacological characteristics to the unconjugated, native form. Through competitive binding with 125I-PACAP-27, the two ligands exhibited similar dose- dependent inhibition. Additional examination of the efficacy of activating adenylyl cyclase revealed that both ligands analogously stimulated the production of cyclic AMP. Furthermore, PAC1 internalization visualized by our Fluor-PACAP, is compareable to that performed with the radioligand, 125I-PACAP-27, with maximal internalization achieved within thirty minutes. Thus, Fluor-PACAP exhibits intracellular signaling abilities homologous to the native ligand.

  17. Effect of calcitonin gene related peptide regulated nuclear factor kappa B signal transduction on c-kit+ cardiac stem cells in hypoxia state

    Directory of Open Access Journals (Sweden)

    Xian-ping LONG

    2015-11-01

    Full Text Available Objective To investigate the effects of calcitonin gene-related peptide (CGRP on the apoptosis of c-kit+ cardiac stem cells in hypoxia. Methods Ischemia and hypoxia models of c-kit+ cardiac stem cells were reproduced in vitro. The models were divided into hypoxia+CGRP group, hypoxia+CGRP8-37 (antagonist of CGRP group, hypoxia control group, normal oxygen group, and hypoxia+BAY11-7082 [antagonist of nuclear factor kappa B (NF-κB] group. NF-κB translocation after hypoxia was detected by immunofluorescence, and NF-κB channel proteins were determined with Western blotting. The NF-κB translocation and the expression of NF-κB channel proteins after CGRP intervention were detected, and the cell apoptosis rate after intervention was determined with flow cytometry in each group. Results Under hypoxia the NF-κB signal pathway was activated, and nuclear translocation occurred in NF-κBP65 (red fluorescence. Compared with hypoxia control group, the expressions of NF-κB related proteins such as P-I-κB, NF-κBP65 and NF-κBP50 decreased obviously (P<0.05. Compared with the hypoxia+CGRP group, the expressions of NF-κB related proteins increased significantly (P<0.05 as mentioned above in hypoxia+CGRP8-37 group. Both the early and late apoptotic rates declined in hypoxia+CGRP group compared with that of hypoxia control group (P<0.05, however, the early apoptotic rate increased markedly in hypoxia+CGRP8-37 group as compared with that of hypoxia+CGRP group (P<0.05. Conclusion Under hypoxia, CGRP may regulate the NF-κB signal pathway, and at the same time suppress the apoptosis of c-kit+ cardiac stem cells. DOI: 10.11855/j.issn.0577-7402.2015.10.03

  18. Signal transduction during mating and meiosis in S. pombe

    DEFF Research Database (Denmark)

    Nielsen, O; Nielsen, Olaf

    1993-01-01

    When starved, the fission yeast Schizosaccharomyces pombe responds by producing mating factors or pheromones that signal to cells of the opposite sex to initiate mating. Like its distant relative Saccharomyces cerevisiae, cells of the two mating types of S. pombe each produce a distinct pheromone...

  19. Post-translational modification of PII signal transduction proteins

    Directory of Open Access Journals (Sweden)

    Mike eMerrick

    2015-01-01

    Full Text Available The PII proteins constitute one of the most widely distributed families of signal transduction proteins in nature. They are pivotal players in the control of nitrogen metabolism in bacteria and archaea, and are also found in the plastids of plants. Quite remarkably PII proteins control the activities of a diverse range of enzymes, transcription factors and membrane transport proteins, and in all known cases they achieve their regulatory effect by direct interaction with their target. PII proteins in the Proteobacteria and the Actinobacteria are subject to post-translational modification by uridylylation or adenylylation respectively, whilst in some Cyanobacteria they can be modified by phosphorylation. In all these cases the protein’s modification state is influenced by the cellular nitrogen status and is thought to regulate its activity. However in many organisms there is no evidence for modification of PII proteins and indeed the ability of these proteins to respond to the cellular nitrogen status is fundamentally independent of post-translational modification. In this review we explore the role of post-translational modification in PII proteins in the light of recent studies.

  20. Mannotriose regulates learning and memory signal transduction in the hippocampus

    Institute of Scientific and Technical Information of China (English)

    Lina Zhang; Weiwei Dai; Xueli Zhang; Zhangbin Gong; Guoqin Jin

    2013-01-01

    Rehmannia is a commonly used Chinese herb, which improves learning and memory. However, the crucial components of the signal transduction pathway associated with this effect remain elusive. Pri-mary hippocampal neurons were cultured in vitro, insulted with high-concentration (1 × 10-4 mol/L) cor-ticosterone, and treated with 1 × 10-4 mol/L mannotriose. Thiazolyl blue tetrazolium bromide assay and western blot analysis showed that hippocampal neuron survival rates and protein levels of glucocorti-coid receptor, serum and glucocorticoid-regulated protein kinase, and brain-derived neurotrophic factor were al dramatical y decreased after high-concentration corticosterone-induced injury. This effect was reversed by mannotriose, to a similar level as RU38486 and donepezil. Our findings indicate that mannotriose could protect hippocampal neurons from high-concentration corticosterone-induced injury. The mechanism by which this occurred was associated with levels of glucocorticoid receptor protein, serum and glucocorticoid-regulated protein kinase, and brain-derived neurotrophic factor.

  1. Development in research on triggering receptor expressed on myeloid cells-1 signal transduction%髓样细胞表达的触发受体-1与炎症信号转导的研究进展

    Institute of Scientific and Technical Information of China (English)

    苏龙翔; 解立新

    2012-01-01

    The triggering receptor expressed on myeloid cells-1 (TREM-1) is a recently identified molecule involved in the cascade amplification of inflammatory response.Several microbial components can up-regulate the surface expression of TREM-1 and synergizes with the ligand of TREM-1 in activating this receptor.Activation via TREM-1 induces production of pro-inflammatory cytokices and related inflammatory responses because TREM-1 can noticeably amplify the inflammatory response in endotoxemia arisen from lipopolysaccharide (LPS).There are lots of investigations about the TREM-1 activation signal pathway that have been done and have shown some progress.Otherwise,TREM-1 synergizes with the Toll-like receptors signaling pathway in amplifying the inflammatory response mediated by LPS,but the specific mechanism is not clear enough.In this review,we will focus on the mechanism of TREM-1 signal transduction,clarifying the function of some relative signal moleculars such as TLR,DAP-12,MAPKs,NTAL,CARD9,NLRs.TREM-1 signal transduction mechanism in-depth study will further clarify the pathogenesis of sepsis and to find new therapeutic targets.%研究表明髓样细胞表达的触发受体-1(TREM-1)参与了炎性反应的级联放大过程.细菌的某些成分可以上调细胞表面TREM-1的表达,并且能和TREM-1配体协同激活TREM-1受体向下游传递信号.TREM-1被激活后会诱导前炎性因子的产生并引起相关的炎症反应.由于TREM-1是明显放大内毒素脂多糖(LPS)所引起的炎性反应的关键介质,因此对于TREM-1激活炎症信号通路的研究取得了一定的进展.然而,TREM-1在协同Toll样受体激活炎性反应的信号通路的具体机制尚未完全明晰.专注于TREM-1的信号转导,阐明与此通路相关的信号分子,如TLR、DAP-12、MAPKs、NTAL、CARD9、NLRs的作用,为进一步揭示脓毒症的发病机制并寻找新的治疗靶点.

  2. l-glutamine Improves Skeletal Muscle Cell Differentiation and Prevents Myotube Atrophy After Cytokine (TNF-α) Stress Via Reduced p38 MAPK Signal Transduction.

    Science.gov (United States)

    Girven, Matthew; Dugdale, Hannah F; Owens, Daniel J; Hughes, David C; Stewart, Claire E; Sharples, Adam P

    2016-12-01

    Tumour Necrosis Factor-Alpha (TNF-α) is chronically elevated in conditions where skeletal muscle loss occurs. As l-glutamine can dampen the effects of inflamed environments, we investigated the role of l-glutamine in both differentiating C2C12 myoblasts and existing myotubes in the absence/presence of TNF-α (20 ng · ml(-1) ) ± l-glutamine (20 mM). TNF-α reduced the proportion of cells in G1 phase, as well as biochemical (CK activity) and morphological differentiation (myotube number), with corresponding reductions in transcript expression of: Myogenin, Igf-I, and Igfbp5. Furthermore, when administered to mature myotubes, TNF-α induced myotube loss and atrophy underpinned by reductions in Myogenin, Igf-I, Igfbp2, and glutamine synthetase and parallel increases in Fox03, Cfos, p53, and Bid gene expression. Investigation of signaling activity suggested that Akt and ERK1/2 were unchanged, JNK increased (non-significantly) whereas P38 MAPK substantially and significantly increased in both myoblasts and myotubes in the presence of TNF-α. Importantly, 20 mM l-glutamine reduced p38 MAPK activity in TNF-α conditions back to control levels, with a corresponding rescue of myoblast differentiation and a reversal of atrophy in myotubes. l-glutamine resulted in upregulation of genes associated with growth and survival including; Myogenin, Igf-Ir, Myhc2 & 7, Tnfsfr1b, Adra1d, and restored atrophic gene expression of Fox03 back to baseline in TNF-α conditions. In conclusion, l-glutamine supplementation rescued suppressed muscle cell differentiation and prevented myotube atrophy in an inflamed environment via regulation of p38 MAPK. l-glutamine administration could represent an important therapeutic strategy for reducing muscle loss in catabolic diseases and inflamed ageing. J. Cell. Physiol. 9999: 231: 2720-2732, 2016. © 2016 Wiley Periodicals, Inc.

  3. l-glutamine Improves Skeletal Muscle Cell Differentiation and Prevents Myotube Atrophy After Cytokine (TNF-α) Stress Via Reduced p38 MAPK Signal Transduction.

    Science.gov (United States)

    Girven, Matthew; Dugdale, Hannah F; Owens, Daniel J; Hughes, David C; Stewart, Claire E; Sharples, Adam P

    2016-12-01

    Tumour Necrosis Factor-Alpha (TNF-α) is chronically elevated in conditions where skeletal muscle loss occurs. As l-glutamine can dampen the effects of inflamed environments, we investigated the role of l-glutamine in both differentiating C2C12 myoblasts and existing myotubes in the absence/presence of TNF-α (20 ng · ml(-1) ) ± l-glutamine (20 mM). TNF-α reduced the proportion of cells in G1 phase, as well as biochemical (CK activity) and morphological differentiation (myotube number), with corresponding reductions in transcript expression of: Myogenin, Igf-I, and Igfbp5. Furthermore, when administered to mature myotubes, TNF-α induced myotube loss and atrophy underpinned by reductions in Myogenin, Igf-I, Igfbp2, and glutamine synthetase and parallel increases in Fox03, Cfos, p53, and Bid gene expression. Investigation of signaling activity suggested that Akt and ERK1/2 were unchanged, JNK increased (non-significantly) whereas P38 MAPK substantially and significantly increased in both myoblasts and myotubes in the presence of TNF-α. Importantly, 20 mM l-glutamine reduced p38 MAPK activity in TNF-α conditions back to control levels, with a corresponding rescue of myoblast differentiation and a reversal of atrophy in myotubes. l-glutamine resulted in upregulation of genes associated with growth and survival including; Myogenin, Igf-Ir, Myhc2 & 7, Tnfsfr1b, Adra1d, and restored atrophic gene expression of Fox03 back to baseline in TNF-α conditions. In conclusion, l-glutamine supplementation rescued suppressed muscle cell differentiation and prevented myotube atrophy in an inflamed environment via regulation of p38 MAPK. l-glutamine administration could represent an important therapeutic strategy for reducing muscle loss in catabolic diseases and inflamed ageing. J. Cell. Physiol. 9999: 231: 2720-2732, 2016. © 2016 Wiley Periodicals, Inc. PMID:26991744

  4. Elucidating the Functional Roles of Spatial Organization in Cross-Membrane Signal Transduction by a Hybrid Simulation Method.

    Science.gov (United States)

    Chen, Jiawen; Xie, Zhong-Ru; Wu, Yinghao

    2016-07-01

    The ligand-binding of membrane receptors on cell surfaces initiates the dynamic process of cross-membrane signal transduction. It is an indispensable part of the signaling network for cells to communicate with external environments. Recent experiments revealed that molecular components in signal transduction are not randomly mixed, but spatially organized into distinctive patterns. These patterns, such as receptor clustering and ligand oligomerization, lead to very different gene expression profiles. However, little is understood about the molecular mechanisms and functional impacts of this spatial-temporal regulation in cross-membrane signal transduction. In order to tackle this problem, we developed a hybrid computational method that decomposes a model of signaling network into two simulation modules. The physical process of binding between receptors and ligands on cell surfaces are simulated by a diffusion-reaction algorithm, while the downstream biochemical reactions are modeled by stochastic simulation of Gillespie algorithm. These two processes are coupled together by a synchronization framework. Using this method, we tested the dynamics of a simple signaling network in which the ligand binding of cell surface receptors triggers the phosphorylation of protein kinases, and in turn regulates the expression of target genes. We found that spatial aggregation of membrane receptors at cellular interfaces is able to either amplify or inhibit downstream signaling outputs, depending on the details of clustering mechanism. Moreover, by providing higher binding avidity, the co-localization of ligands into multi-valence complex modulates signaling in very different ways that are closely related to the binding affinity between ligand and receptor. We also found that the temporal oscillation of the signaling pathway that is derived from genetic feedback loops can be modified by the spatial clustering of membrane receptors. In summary, our method demonstrates the functional

  5. New insights into the organization of plasma membrane and its role in signal transduction.

    Science.gov (United States)

    Suzuki, Kenichi G N

    2015-01-01

    Plasma membranes have heterogeneous structures for efficient signal transduction, required to perform cell functions. Recent evidence indicates that the heterogeneous structures are produced by (1) compartmentalization by actin-based membrane skeleton, (2) raft domains, (3) receptor-receptor interactions, and (4) the binding of receptors to cytoskeletal proteins. This chapter provides an overview of recent studies on diffusion, clustering, raft association, actin binding, and signal transduction of membrane receptors, especially glycosylphosphatidylinositol (GPI)-anchored receptors. Studies on diffusion of GPI-anchored receptors suggest that rafts may be small and/or short-lived in plasma membranes. In steady state conditions, GPI-anchored receptors form transient homodimers, which may represent the "standby state" for the stable homodimers and oligomers upon ligation. Furthermore, It is proposed that upon ligation, the binding of GPI-anchored receptor clusters to cytoskeletal actin filaments produces a platform for downstream signaling, and that the pulse-like signaling easily maintains the stability of the overall signaling activity.

  6. 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.

  7. 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.

  8. Highly active microbial phosphoantigen induces rapid yet sustained MEK/Erk- and PI-3K/Akt-mediated signal transduction in anti-tumor human gammadelta T-cells.

    Directory of Open Access Journals (Sweden)

    Daniel V Correia

    Full Text Available BACKGROUND: The unique responsiveness of Vgamma9Vdelta2 T-cells, the major gammadelta subset of human peripheral blood, to non-peptidic prenyl pyrophosphate antigens constitutes the basis of current gammadelta T-cell-based cancer immunotherapy strategies. However, the molecular mechanisms responsible for phosphoantigen-mediated activation of human gammadelta T-cells remain unclear. In particular, previous reports have described a very slow kinetics of activation of T-cell receptor (TCR-associated signal transduction pathways by isopentenyl pyrophosphate and bromohydrin pyrophosphate, seemingly incompatible with direct binding of these antigens to the Vgamma9Vdelta2 TCR. Here we have studied the most potent natural phosphoantigen yet identified, (E-4-hydroxy-3-methyl-but-2-enyl pyrophosphate (HMB-PP, produced by Eubacteria and Protozoa, and examined its gammadelta T-cell activation and anti-tumor properties. METHODOLOGY/PRINCIPAL FINDINGS: We have performed a comparative study between HMB-PP and the anti-CD3epsilon monoclonal antibody OKT3, used as a reference inducer of bona fide TCR signaling, and followed multiple cellular and molecular gammadelta T-cell activation events. We show that HMB-PP activates MEK/Erk and PI-3K/Akt pathways as rapidly as OKT3, and induces an almost identical transcriptional profile in Vgamma9(+ T-cells. Moreover, MEK/Erk and PI-3K/Akt activities are indispensable for the cellular effects of HMB-PP, including gammadelta T-cell activation, proliferation and anti-tumor cytotoxicity, which are also abolished upon antibody blockade of the Vgamma9(+ TCR Surprisingly, HMB-PP treatment does not induce down-modulation of surface TCR levels, and thereby sustains gammadelta T-cell activation upon re-stimulation. This ultimately translates in potent human gammadelta T-cell anti-tumor function both in vitro and in vivo upon transplantation of human leukemia cells into lymphopenic mice, CONCLUSIONS/SIGNIFICANCE: The development of

  9. Computational study of noise in a large signal transduction network

    Directory of Open Access Journals (Sweden)

    Ruohonen Keijo

    2011-06-01

    Full Text Available Abstract Background Biochemical systems are inherently noisy due to the discrete reaction events that occur in a random manner. Although noise is often perceived as a disturbing factor, the system might actually benefit from it. In order to understand the role of noise better, its quality must be studied in a quantitative manner. Computational analysis and modeling play an essential role in this demanding endeavor. Results We implemented a large nonlinear signal transduction network combining protein kinase C, mitogen-activated protein kinase, phospholipase A2, and β isoform of phospholipase C networks. We simulated the network in 300 different cellular volumes using the exact Gillespie stochastic simulation algorithm and analyzed the results in both the time and frequency domain. In order to perform simulations in a reasonable time, we used modern parallel computing techniques. The analysis revealed that time and frequency domain characteristics depend on the system volume. The simulation results also indicated that there are several kinds of noise processes in the network, all of them representing different kinds of low-frequency fluctuations. In the simulations, the power of noise decreased on all frequencies when the system volume was increased. Conclusions We concluded that basic frequency domain techniques can be applied to the analysis of simulation results produced by the Gillespie stochastic simulation algorithm. This approach is suited not only to the study of fluctuations but also to the study of pure noise processes. Noise seems to have an important role in biochemical systems and its properties can be numerically studied by simulating the reacting system in different cellular volumes. Parallel computing techniques make it possible to run massive simulations in hundreds of volumes and, as a result, accurate statistics can be obtained from computational studies.

  10. Second-chance signal transduction explains cooperative flagellar switching.

    Directory of Open Access Journals (Sweden)

    Henry G Zot

    Full Text Available The reversal of flagellar motion (switching results from the interaction between a switch complex of the flagellar rotor and a torque-generating stationary unit, or stator (motor unit. To explain the steeply cooperative ligand-induced switching, present models propose allosteric interactions between subunits of the rotor, but do not address the possibility of a reaction that stimulates a bidirectional motor unit to reverse direction of torque. During flagellar motion, the binding of a ligand-bound switch complex at the dwell site could excite a motor unit. The probability that another switch complex of the rotor, moving according to steady-state rotation, will reach the same dwell site before that motor unit returns to ground state will be determined by the independent decay rate of the excited-state motor unit. Here, we derive an analytical expression for the energy coupling between a switch complex and a motor unit of the stator complex of a flagellum, and demonstrate that this model accounts for the cooperative switching response without the need for allosteric interactions. The analytical result can be reproduced by simulation when (1 the motion of the rotor delivers a subsequent ligand-bound switch to the excited motor unit, thereby providing the excited motor unit with a second chance to remain excited, and (2 the outputs from multiple independent motor units are constrained to a single all-or-none event. In this proposed model, a motor unit and switch complex represent the components of a mathematically defined signal transduction mechanism in which energy coupling is driven by steady-state and is regulated by stochastic ligand binding. Mathematical derivation of the model shows the analytical function to be a general form of the Hill equation (Hill AV (1910 The possible effects of the aggregation of the molecules of haemoglobin on its dissociation curves. J Physiol 40: iv-vii.

  11. Insulin signal transduction in skeletal muscle : special consideration for insulin resistance and diabetes

    OpenAIRE

    Song, Xiao Mei

    2000-01-01

    This dissertation work is focused on the insulin-signal-transduction pathways to glucose transport in skeletal muscle from animal models of NIDDM. The overall objective is to determine the effectiveness of different pharmacological treatments to improve insulin action in skeletal muscle. Muscle-fiber-type-specific differences in insulin signal transduction was first considered. We noted increased insulin action on insulin signaling events including; IR, IRS- 1, IRS-2, PI...

  12. Methionine Regulates mTORC1 via the T1R1/T1R3-PLCβ-Ca2+-ERK1/2 Signal Transduction Process in C2C12 Cells

    Directory of Open Access Journals (Sweden)

    Yuanfei Zhou

    2016-10-01

    Full Text Available The mammalian target of rapamycin complex 1 (mTORC1 integrates amino acid (AA availability to support protein synthesis and cell growth. Taste receptor type 1 member (T1R is a G protein-coupled receptor that functions as a direct sensor of extracellular AA availability to regulate mTORC1 through Ca2+ stimulation and extracellular signal–regulated kinases 1 and 2 (ERK1/2 activation. However, the roles of specific AAs in T1R1/T1R3-regulated mTORC1 are poorly defined. In this study, T1R1 and T1R3 subunits were expressed in C2C12 myotubes, and l-AA sensing was accomplished by T1R1/T1R3 to activate mTORC1. In response to l-AAs, such as serine (Ser, arginine (Arg, threonine (Thr, alanine (Ala, methionine (Met, glutamine (Gln, and glycine (Gly, Met induced mTORC1 activation and promoted protein synthesis. Met also regulated mTORC1 via T1R1/T1R3-PLCβ-Ca2+-ERK1/2 signal transduction. Results revealed a new role for Met-regulated mTORC1 via an AA receptor. Further studies should be performed to determine the role of T1R1/T1R3 in mediating extracellular AA to regulate mTOR signaling and to reveal its mechanism.

  13. Methionine Regulates mTORC1 via the T1R1/T1R3-PLCβ-Ca2+-ERK1/2 Signal Transduction Process in C2C12 Cells

    Science.gov (United States)

    Zhou, Yuanfei; Ren, Jiao; Song, Tongxing; Peng, Jian; Wei, Hongkui

    2016-01-01

    The mammalian target of rapamycin complex 1 (mTORC1) integrates amino acid (AA) availability to support protein synthesis and cell growth. Taste receptor type 1 member (T1R) is a G protein-coupled receptor that functions as a direct sensor of extracellular AA availability to regulate mTORC1 through Ca2+ stimulation and extracellular signal–regulated kinases 1 and 2 (ERK1/2) activation. However, the roles of specific AAs in T1R1/T1R3-regulated mTORC1 are poorly defined. In this study, T1R1 and T1R3 subunits were expressed in C2C12 myotubes, and l-AA sensing was accomplished by T1R1/T1R3 to activate mTORC1. In response to l-AAs, such as serine (Ser), arginine (Arg), threonine (Thr), alanine (Ala), methionine (Met), glutamine (Gln), and glycine (Gly), Met induced mTORC1 activation and promoted protein synthesis. Met also regulated mTORC1 via T1R1/T1R3-PLCβ-Ca2+-ERK1/2 signal transduction. Results revealed a new role for Met-regulated mTORC1 via an AA receptor. Further studies should be performed to determine the role of T1R1/T1R3 in mediating extracellular AA to regulate mTOR signaling and to reveal its mechanism. PMID:27727170

  14. Transmembrane signal transduction by peptide hormones via family B G protein-coupled receptors

    Directory of Open Access Journals (Sweden)

    Kelly J Culhane

    2015-11-01

    Full Text Available Although family B G protein-coupled receptors (GPCRs contain only 15 members, they play key roles in transmembrane signal transduction of hormones. Family B GPCRs are drug targets for developing therapeutics for diseases ranging from metabolic to neurological disorders. Despite their importance, the molecular mechanism of activation of family B GPCRs remains largely unexplored due to the challenges in expression and purification of functional receptors to the quantity for biophysical characterization. Currently, there is no crystal structure available of a full-length family B GPCR. However, structures of key domains, including the extracellular ligand binding regions and seven-helical transmembrane regions, have been solved by X-ray crystallography and NMR, providing insights into the mechanisms of ligand recognition and selectivity, and helical arrangements within the cell membrane. Moreover, biophysical and biochemical methods have been used to explore functions, key residues for signaling, and the kinetics and dynamics of signaling processes. This review summarizes the current knowledge of the signal transduction mechanism of family B GPCRs at the molecular level and comments on the challenges and outlook for mechanistic studies of family B GPCRs.

  15. Modeling Signal Transduction Networks: A comparison of two Stochastic Kinetic Simulation Algorithms

    Energy Technology Data Exchange (ETDEWEB)

    Pettigrew, Michel F.; Resat, Haluk

    2005-09-15

    Simulations of a scalable four compartment reaction model based on the well known epidermal growth factor receptor (EGFR) signal transduction system are used to compare two stochastic algorithms ? StochSim and the Gibson-Gillespie. It is concluded that the Gibson-Gillespie is the algorithm of choice for most realistic cases with the possible exception of signal transduction networks characterized by a moderate number (< 100) of complex types, each with a very small population, but with a high degree of connectivity amongst the complex types. Keywords: Signal transduction networks, Stochastic simulation, StochSim, Gillespie

  16. DMPD: Signal transduction by the lipopolysaccharide receptor, Toll-like receptor-4. [Dynamic Macrophage Pathway CSML Database

    Lifescience Database Archive (English)

    Full Text Available 15379975 Signal transduction by the lipopolysaccharide receptor, Toll-like receptor... Signal transduction by the lipopolysaccharide receptor, Toll-like receptor-4. PubmedID 15379975 Title Signa...l transduction by the lipopolysaccharide receptor, Toll-like receptor-4. Authors

  17. Involvement of the second messenger cAMP in gravity-signal transduction in physarum

    Science.gov (United States)

    Block, I.; Rabien, H.; Ivanova, K.

    The aim of the investigation was to clarify, whether cellular signal processing following graviperception involves second messenger pathways. The test object was a most gravisensitive free-living ameboid cell, the myxomycete (acellular slime mold) Physarum polycephalum. It was demonstrated that the motor response is related to acceleration-dependent changes in the levels of the cellular second messenger cyclic adenosine monophosphate (cAMP). Rotating Physarum plasmodia in the gravity field of the Earth about a horizontal axis increased their cAMP concentration. Depriving the cells for a few days of the acceleration stimulus (near weightlessness in a space experiment on STS-69) slightly lowered plasmodial cAMP levels. Thus, the results provide first indications that the acceleration-stimulus signal transduction chain of Physarum uses an ubiquitous second messenger pathway.

  18. Evaluation of signal transduction pathways after transient cutaneous adenoviral gene delivery

    Directory of Open Access Journals (Sweden)

    Steinau Hans-Ulrich

    2011-01-01

    Full Text Available Abstract Background Adenoviral vectors have provided effective methods for in vivo gene delivery in therapeutic applications. However, these vectors can induce immune responses that may severely affect the ability of vector re-application. There is limited information about the mechanisms and signal transduction pathways involved in adenoviral recognition. For optimization of cutaneous gene therapy it is necessary to investigate molecular mechanisms of virus recognition in epidermal cells. The aim of this study was to investigate the signal transduction of the innate immunity after adenoviral DNA internalization in keratinocytes. Methods In vitro, keratinocytes were transfected with DNA, in the presence and absence of inhibitors for signalling molecules. In vivo, immunocompetent and athymic mice (n = 3 per group were twice transduced with an Ad-vector. Results The results show an acute induction of type-I-interferon after in vitro transfection. Inhibition of PI3K, p38 MAPK, JNK and NFkappaB resulted in a decreased expression of type-I-interferon. In contrast to immunocompetent mice, athymic mice demonstrated a constant transgene expression and reduced inflammatory response in vivo. Conclusion The results suggest an induction of the innate immunity triggered by cytoplasm localised DNA which is mediated by PI3K-, p38 MAPK-, JNK-, NFkappaB-, JAK/STAT- and ERK1/2-dependent pathways. A stable transgene expression and a reduced inflammatory response in immunodeficient mice have been observed. These results provide potential for an effective adenoviral gene delivery into immunosupressed skin.

  19. Sentra : a database of signal transduction proteins for comparative genome analysis.

    Energy Technology Data Exchange (ETDEWEB)

    D' Souza, M.; Glass, E. M.; Syed, M. H.; Zhang, Y.; Rodriguez, A.; Maltsev, N.; Galerpin, M. Y.; Mathematics and Computer Science; Univ. of Chicago; NIH

    2007-01-01

    Sentra (http://compbio.mcs.anl.gov/sentra), a database of signal transduction proteins encoded in completely sequenced prokaryotic genomes, has been updated to reflect recent advances in understanding signal transduction events on a whole-genome scale. Sentra consists of two principal components, a manually curated list of signal transduction proteins in 202 completely sequenced prokaryotic genomes and an automatically generated listing of predicted signaling proteins in 235 sequenced genomes that are awaiting manual curation. In addition to two-component histidine kinases and response regulators, the database now lists manually curated Ser/Thr/Tyr protein kinases and protein phosphatases, as well as adenylate and diguanylate cyclases and c-di-GMP phosphodiesterases, as defined in several recent reviews. All entries in Sentra are extensively annotated with relevant information from public databases (e.g. UniProt, KEGG, PDB and NCBI). Sentra's infrastructure was redesigned to support interactive cross-genome comparisons of signal transduction capabilities of prokaryotic organisms from a taxonomic and phenotypic perspective and in the framework of signal transduction pathways from KEGG. Sentra leverages the PUMA2 system to support interactive analysis and annotation of signal transduction proteins by the users.

  20. Plasma membrane calcium ATPase proteins as novel regulators of signal transduction pathways

    Institute of Scientific and Technical Information of China (English)

    Mary; Louisa; Holton; Michael; Emerson; Ludwig; Neyses; Angel; L; Armesilla

    2010-01-01

    Emerging evidence suggests that plasma membrane calcium ATPases (PMCAs) play a key role as regulators of calcium-triggered signal transduction pathways via interaction with partner proteins. PMCAs regulate these pathways by targeting specific proteins to cellular sub-domains where the levels of intracellular freecalcium are kept low by the calcium ejection properties of PMCAs. According to this model, PMCAs have been shown to interact functionally with the calcium-sensitive proteins neuronal nitric oxide synthase, calmodulindependent serine protein kinase, calcineurin and endothelial nitric oxidase synthase. Transgenic animals with altered expression of PMCAs are being used to evaluate the physiological significance of these interactions. To date, PMCA interactions with calcium-dependent partner proteins have been demonstrated to play a crucial role in the pathophysiology of the cardiovascular system via regulation of the nitric oxide and calcineurin/nuclear factor of activated T cells pathways. This new evidence suggests that PMCAs play a more sophisticated role than the mere ejection of calcium from the cells, by acting as modulators of signaling transduction pathways.

  1. Signal Transduction of Platelet-Induced Liver Regeneration and Decrease of Liver Fibrosis

    Directory of Open Access Journals (Sweden)

    Soichiro Murata

    2014-03-01

    Full Text Available Platelets contain three types of granules: alpha granules, dense granules, and lysosomal granules. Each granule contains various growth factors, cytokines, and other physiological substances. Platelets trigger many kinds of biological responses, such as hemostasis, wound healing, and tissue regeneration. This review presents experimental evidence of platelets in accelerating liver regeneration and improving liver fibrosis. The regenerative effect of liver by platelets consists of three mechanisms; i.e., the direct effect on hepatocytes, the cooperative effect with liver sinusoidal endothelial cells, and the collaborative effect with Kupffer cells. Many signal transduction pathways are involved in hepatocyte proliferation. One is activation of Akt and extracellular signal-regulated kinase (ERK1/2, which are derived from direct stimulation from growth factors in platelets. The other is signal transducer and activator of transcription-3 (STAT3 activation by interleukin (IL-6 derived from liver sinusoidal endothelial cells and Kupffer cells, which are stimulated by contact with platelets during liver regeneration. Platelets also improve liver fibrosis in rodent models by inactivating hepatic stellate cells to decrease collagen production. The level of intracellular cyclic adenosine monophosphate (cyclic AMP is increased by adenosine through its receptors on hepatic stellate cells, resulting in inactivation of these cells. Adenosine is produced by the degradation of adenine nucleotides such as adenosine diphosphate (ADP and adenosine tri-phosphate (ATP, which are stored in abundance within the dense granules of platelets.

  2. Protein tyrosine kinases p53/56lyn and p72syk in MHC class I-mediated signal transduction in B lymphoma cells

    DEFF Research Database (Denmark)

    Pedersen, Anders Elm; Bregenholt, S; Skov, S;

    1998-01-01

    Crosslinking of major histocompatibility complex class I (MHC-I) molecules on the surface of human B lymphoma cells was shown to induce protein tyrosine phosphorylation and mobilization of intracellular free calcium. Immunoprecipitations indicated that the protein tyrosine kinases p53/56lyn and p72......syk are among the tyrosine-phosphorylated proteins. The kinetics of phosphorylation of these kinases after MHC-I crosslinking differ from the kinetics observed after crosslinking of the B cell antigen receptor (BCR). Additional experiments were performed with chicken lyn- and syk-negative DT40 B cells...... and the results indicate that these two kinases have different substrate specificity and regulate intracellular free calcium differently in response to MHC-I crosslinking. In addition MHC-I crosslinking of a sIgM-negative DT40 chicken B cell variant results in less activity of tyrosine kinases and less...

  3. 2R and remodeling of vertebrate signal transduction engine

    Directory of Open Access Journals (Sweden)

    Huminiecki Lukasz

    2010-12-01

    Full Text Available Abstract Background Whole genome duplication (WGD is a special case of gene duplication, observed rarely in animals, whereby all genes duplicate simultaneously through polyploidisation. Two rounds of WGD (2R-WGD occurred at the base of vertebrates, giving rise to an enormous wave of genetic novelty, but a systematic analysis of functional consequences of this event has not yet been performed. Results We show that 2R-WGD affected an overwhelming majority (74% of signalling genes, in particular developmental pathways involving receptor tyrosine kinases, Wnt and transforming growth factor-β ligands, G protein-coupled receptors and the apoptosis pathway. 2R-retained genes, in contrast to tandem duplicates, were enriched in protein interaction domains and multifunctional signalling modules of Ras and mitogen-activated protein kinase cascades. 2R-WGD had a fundamental impact on the cell-cycle machinery, redefined molecular building blocks of the neuronal synapse, and was formative for vertebrate brains. We investigated 2R-associated nodes in the context of the human signalling network, as well as in an inferred ancestral pre-2R (AP2R network, and found that hubs (particularly involving negative regulation were preferentially retained, with high connectivity driving retention. Finally, microarrays and proteomics demonstrated a trend for gradual paralog expression divergence independent of the duplication mechanism, but inferred ancestral expression states suggested preferential subfunctionalisation among 2R-ohnologs (2ROs. Conclusions The 2R event left an indelible imprint on vertebrate signalling and the cell cycle. We show that 2R-WGD preferentially retained genes are associated with higher organismal complexity (for example, locomotion, nervous system, morphogenesis, while genes associated with basic cellular functions (for example, translation, replication, splicing, recombination; with the notable exception of cell cycle tended to be excluded. 2R

  4. Signal transduction regulating meristem development in Arabidopsis. Final report

    Energy Technology Data Exchange (ETDEWEB)

    Cark, Steven E.

    2003-09-10

    Research support by DE-FG02-96ER20227 focused on the CLV loci and their regulation of organ formation at the Arabidopsis shoot meristem. Shoot meristem function is central to plant development as all of the above-ground organs and tissues of the plant are derived post-embryonically from the shoot meristem. At the shoot meristem, stem cells are maintained, and progeny cells undergo a switch toward differentiation and organ formation. The CLV loci, represented by three genes CLV1, CLV2 and CLV3 are key regulators of meristem development. Each of the CLV loci encode a putative receptor-mediated signaling component. When this work began, virtually nothing was known about receptor-mediated signaling in plants. Thus, our goal was to both characterize these genes and the proteins they encode as regulators of meristem development, and to investigate how receptor-mediated signaling might function in plants. Our work lead to several major publications that were significant contributions to understanding this system.

  5. The role of calcium in hypoxia-induced signal transduction and gene expression.

    Science.gov (United States)

    Seta, Karen A; Yuan, Yong; Spicer, Zachary; Lu, Gang; Bedard, James; Ferguson, Tsuneo K; Pathrose, Peterson; Cole-Strauss, Allyson; Kaufhold, Alexa; Millhorn, David E

    2004-01-01

    Mammalian cells require a constant supply of oxygen in order to maintain adequate energy production, which is essential for maintaining normal function and for ensuring cell survival. Sustained hypoxia can result in cell death. Sophisticated mechanisms have therefore evolved which allow cells to respond and adapt to hypoxia. Specialized oxygen-sensing cells have the ability to detect changes in oxygen tension and transduce this signal into organ system functions that enhance the delivery of oxygen to tissue in a wide variety of different organisms. An increase in intracellular calcium levels is a primary response of many cell types to hypoxia/ischemia. The response to hypoxia is complex and involves the regulation of multiple signaling pathways and coordinated expression of perhaps hundreds of genes. This review discusses the role of calcium in hypoxia-induced regulation of signal transduction pathways and gene expression. An understanding of the molecular events initiated by changes in intracellular calcium will lead to the development of therapeutic approaches toward the treatment of hypoxic/ischemic diseases and tumors. PMID:15261489

  6. Granulosa cells from bovine follicles activate different signal transduction pathways dependent on follicle health status and ability to convert androstenedione to estrogen

    Science.gov (United States)

    Since steroidogenesis is a critical component in the development of competent preovulatory follicles we hypothesized that granulosa cells from follicles of cows treated with normal levels of progesterone (CIDR) or with melengestrol acetate (MGA), which results in the development of persistent follic...

  7. THOC5, a member of the mRNA export complex: a novel link between mRNA export machinery and signal transduction pathways in cell proliferation and differentiation.

    Science.gov (United States)

    Tran, Doan D H; Koch, Alexandra; Tamura, Teruko

    2014-01-01

    Cell growth, differentiation, and commitment to a restricted lineage are guided by a timely expressed set of growth factor/cytokine receptors and their down-stream transcription factor genes. Transcriptional control mechanisms of gene expression during differentiation have been mainly studied by focusing on the cis- and trans-elements in promoters however, the role of mRNA export machinery during differentiation has not been adequately examined. THO (Suppressors of the transcriptional defects of hpr1 delta by overexpression) complex 5 (THOC5) is a member of THO complex which is a subcomplex of the transcription/export complex (TREX). THOC5 is evolutionarily conserved in higher eukaryotes, however the exact roles of THOC5 in transcription and mRNA export are still unclear. In this review, we focus on recently uncovered aspects of the role of THOC5 in signal transduction induced by extracellular stimuli. THOC5 is phosphorylated by several protein kinases at multiple residues upon extracellular stimuli. These include stimulation with growth factors/cytokines/chemokines, or DNA damage reagents. Furthermore, THOC5 is a substrate for several oncogenic tyrosine kinases, suggesting that THOC5 may be involved in cancer development. Recent THOC5 knockout mouse data reveal that THOC5 is an essential element in the maintenance of stem cells and growth factor/cytokine-mediated differentiation/proliferation. Furthermore, depletion of THOC5 influences less than 1% of total mRNA export in the steady state, however it influences more than 90% of growth factor/cytokine induced genes. THOC5, thereby contributes to the 3' processing and/or export of immediate-early genes induced by extracellular stimuli. These studies bring new insight into the link between the mRNA export complex and immediate-early gene response. The data from these studies also suggest that THOC5 may be a useful tool for studying stem cell biology, for modifying the differentiation processes and for cancer therapy.

  8. Nonreceptor protein tyrosine kinase involvement in signal transduction and immunodeficiency disease.

    Science.gov (United States)

    Saouaf, S J; Burkhardt, A L; Bolen, J B

    1995-09-01

    The nonreceptor protein tyrosine kinases (PTKs) have been grouped into 10 different enzyme families based on predicted amino acid sequences. As the number of enzymes belonging to the nonreceptor class of PTK is increasing, one challenge is to determine how these various classes of PTKs interact within the cell to promote signal transduction. Herein, the activation of four classes of nonreceptor PTKs is discussed in relation to their interactions with each other as well as with other signaling molecules during the process of lymphocyte surface antigen receptor-mediated activation. Recent findings of nonreceptor PTK loss-of-function mutations in different immunodeficiency diseases has revealed the important contribution of this group of enzymes to lymphocyte development. PMID:7554458

  9. Control of cancer-related signal transduction networks

    Science.gov (United States)

    Albert, Reka

    2013-03-01

    Intra-cellular signaling networks are crucial to the maintenance of cellular homeostasis and for cell behavior (growth, survival, apoptosis, movement). Mutations or alterations in the expression of elements of cellular signaling networks can lead to incorrect behavioral decisions that could result in tumor development and/or the promotion of cell migration and metastasis. Thus, mitigation of the cascading effects of such dysregulations is an important control objective. My group at Penn State is collaborating with wet-bench biologists to develop and validate predictive models of various biological systems. Over the years we found that discrete dynamic modeling is very useful in molding qualitative interaction information into a predictive model. We recently demonstrated the effectiveness of network-based targeted manipulations on mitigating the disease T cell large granular lymphocyte (T-LGL) leukemia. The root of this disease is the abnormal survival of T cells which, after successfully fighting an infection, should undergo programmed cell death. We synthesized the relevant network of within-T-cell interactions from the literature, integrated it with qualitative knowledge of the dysregulated (abnormal) states of several network components, and formulated a Boolean dynamic model. The model indicated that the system possesses a steady state corresponding to the normal cell death state and a T-LGL steady state corresponding to the abnormal survival state. For each node, we evaluated the restorative manipulation consisting of maintaining the node in the state that is the opposite of its T-LGL state, e.g. knocking it out if it is overexpressed in the T-LGL state. We found that such control of any of 15 nodes led to the disappearance of the T-LGL steady state, leaving cell death as the only potential outcome from any initial condition. In four additional cases the probability of reaching the T-LGL state decreased dramatically, thus these nodes are also possible control

  10. Immunocytochemical evidence for co-expression of Type III IP3 receptor with signaling components of bitter taste transduction

    Directory of Open Access Journals (Sweden)

    Kinnamon Sue C

    2001-04-01

    Full Text Available Abstract Background Taste receptor cells are responsible for transducing chemical stimuli into electrical signals that lead to the sense of taste. An important second messenger in taste transduction is IP3, which is involved in both bitter and sweet transduction pathways. Several components of the bitter transduction pathway have been identified, including the T2R/TRB taste receptors, phospholipase C β2, and the G protein subunits α-gustducin, β3, and γ13. However, the identity of the IP3 receptor subtype in this pathway is not known. In the present study we used immunocytochemistry on rodent taste tissue to identify the IP3 receptors expressed in taste cells and to examine taste bud expression patterns for IP3R3. Results Antibodies against Type I, II, and III IP3 receptors were tested on sections of rat and mouse circumvallate papillae. Robust cytoplasmic labeling for the Type III IP3 receptor (IP3R3 was found in a large subset of taste cells in both species. In contrast, little or no immunoreactivity was seen with antibodies against the Type I or Type II IP3 receptors. To investigate the potential role of IP3R3 in bitter taste transduction, we used double-label immunocytochemistry to determine whether IP3R3 is expressed in the same subset of cells expressing other bitter signaling components. IP3R3 immunoreactive taste cells were also immunoreactive for PLCβ2 and γ13. Alpha-gustducin immunoreactivity was present in a subset of IP3R3, PLCβ2, and γ13 positive cells. Conclusions IP3R3 is the dominant form of the IP3 receptor expressed in taste cells and our data suggest it plays an important role in bitter taste transduction.

  11. The Roles of Peroxiredoxin and Thioredoxin in Hydrogen Peroxide Sensing and in Signal Transduction

    Science.gov (United States)

    Netto, Luis E. S.; Antunes, Fernando

    2016-01-01

    A challenge in the redox field is the elucidation of the molecular mechanisms, by which H2O2 mediates signal transduction in cells. This is relevant since redox pathways are disturbed in some pathologies. The transcription factor OxyR is the H2O2 sensor in bacteria, whereas Cys-based peroxidases are involved in the perception of this oxidant in eukaryotic cells. Three possible mechanisms may be involved in H2O2 signaling that are not mutually exclusive. In the simplest pathway, H2O2 signals through direct oxidation of the signaling protein, such as a phosphatase or a transcription factor. Although signaling proteins are frequently observed in the oxidized state in biological systems, in most cases their direct oxidation by H2O2 is too slow (101 M−1s−1 range) to outcompete Cys-based peroxidases and glutathione. In some particular cellular compartments (such as vicinity of NADPH oxidases), it is possible that a signaling protein faces extremely high H2O2 concentrations, making the direct oxidation feasible. Alternatively, high H2O2 levels can hyperoxidize peroxiredoxins leading to local building up of H2O2 that then could oxidize a signaling protein (floodgate hypothesis). In a second model, H2O2 oxidizes Cys-based peroxidases that then through thiol-disulfide reshuffling would transmit the oxidized equivalents to the signaling protein. The third model of signaling is centered on the reducing substrate of Cys-based peroxidases that in most cases is thioredoxin. Is this model, peroxiredoxins would signal by modulating the thioredoxin redox status. More kinetic data is required to allow the identification of the complex network of thiol switches. PMID:26813662

  12. Elucidation of the Signal Transduction Pathways Activated by the Plant Natriuretic Peptide AtPNP-A

    KAUST Repository

    Turek, Ilona

    2014-11-01

    Plant natriuretic peptides (PNPs) comprise a novel class of hormones that share some sequence similarity in the active site with their animal analogues that function as regulators of salt and water balance. A PNP present in Arabidopsis thaliana (AtPNP-A) has been assigned a role in abiotic and biotic stress responses, and the recombinant protein has been demonstrated to elicit cyclic guanosine monophosphate (cGMP)-dependent stomatal guard cell opening, regulate ion movements, and induce osmoticum-dependent water uptake. Although the importance of the hormone in maintaining ion and fluid homeostasis has been established, key components of the AtPNP-A-dependent signal transduction pathway remain unknown. Since identification of the binding partners of AtPNP-A, including its receptor(s), is fundamental to understanding the mode of its action at the molecular level, comprehensive protein-protein interaction studies, involving yeast two-hybrid screening, affinity-based assays, protein cross-linking and co-immunoprecipitation followed by mass spectrometric (MS) analyses have been performed. Several candidate binding partners of AtPNP-A identified with at least two independent methods were subsequently expressed as recombinant proteins, purified, and the specificity of their interactions with the recombinant AtPNP-A was verified using surface plasmon resonance. Several specific binary interactants of AtPNP-A were subjected to functional assays aimed at unraveling the consequences of the interactions in planta. These experiments have revealed that reactive oxygen species (ROS) are novel secondary messengers involved in the transduction of AtPNP-A signal in suspension-cultured cells of A. thaliana (Col-0). Further insight into the AtPNP-A dependent signalling events occurring in suspension-cultured cells in ROS-dependent or ROS-independent manner have been obtained from the large-scale proteomics study employing tandem mass tag (TMT) labelling followed by MS analysis to

  13. Regulation between nitric oxide and MAPK signal transduction in mammals

    Institute of Scientific and Technical Information of China (English)

    TAO Yong; ZHANG Meijia; HONG Haiyan; XIA Guoliang

    2005-01-01

    Nitric oxide (NO) is an important biological messenger in the regulation of tissue homeostasis. It exhibits a wide range of effects during physiological and pathophysiological processes. Typical beneficial properties of NO include the regulation of vascular tone,the protection of cells against apoptosis, the modulation of immune responses, and the killing of microbial pathogens. On the other hand,NO may cause severe vasodilation and myocardial depression during bacterial sepsis or act as a cytotoxic and tissue-damaging molecule in autoimmune diseases. Mitogen-activated protein kinase (MAPK) is a family of serine/threonine protein kinases that are widely distributed in mammalian cells. MAPK cascade plays pivotal roles in gene expression, cell proliferation, differentiation, neuronal survival and programmed cell death under a variety of experimental conditions. MAPKs transduce the signal for the cellular response to extracellular stresses or stimuli. The relation between them, however, has never been reviewed. Based on our researches and other reports in the field, we review their reciprocal regulatory functions.

  14. XB130: A novel adaptor protein in cancer signal transduction

    Science.gov (United States)

    ZHANG, RUIYAO; ZHANG, JINGYAO; WU, QIFEI; MENG, FANDI; LIU, CHANG

    2016-01-01

    Adaptor proteins are functional proteins that contain two or more protein-binding modules to link signaling proteins together, which affect cell growth and shape and have no enzymatic activity. The actin filament-associated protein (AFAP) family is an important member of the adaptor proteins, including AFAP1, AFAP1L1 and AFAP1L2/XB130. AFAP1 and AFAP1L1 share certain common characteristics and function as an actin-binding protein and a cSrc-activating protein. XB130 exhibits certain unique features in structure and function. The mRNA of XB130 is expressed in human spleen, thyroid, kidney, brain, lung, pancreas, liver, colon and stomach, and the most prominent disease associated with XB130 is cancer. XB130 has a controversial effect on cancer. Studies have shown that XB130 can promote cancer progression and downregulation of XB130-reduced growth of tumors derived from certain cell lines. A higher mRNA level of XB130 was shown to be associated with a better survival in non-small cell lung cancer. Previous studies have shown that XB130 can regulate cell growth, migration and invasion and possibly has the effect through the cAMP-cSrc-phosphoinositide 3-kinase/Akt pathway. Except for cancer, XB130 is also associated with other pathological or physiological procedures, such as airway repair and regeneration. PMID:26998266

  15. 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

  16. Discovery of intramolecular signal transduction network based on a new protein dynamics model of energy dissipation.

    Directory of Open Access Journals (Sweden)

    Cheng-Wei Ma

    Full Text Available A novel approach to reveal intramolecular signal transduction network is proposed in this work. To this end, a new algorithm of network construction is developed, which is based on a new protein dynamics model of energy dissipation. A key feature of this approach is that direction information is specified after inferring protein residue-residue interaction network involved in the process of signal transduction. This enables fundamental analysis of the regulation hierarchy and identification of regulation hubs of the signaling network. A well-studied allosteric enzyme, E. coli aspartokinase III, is used as a model system to demonstrate the new method. Comparison with experimental results shows that the new approach is able to predict all the sites that have been experimentally proved to desensitize allosteric regulation of the enzyme. In addition, the signal transduction network shows a clear preference for specific structural regions, secondary structural types and residue conservation. Occurrence of super-hubs in the network indicates that allosteric regulation tends to gather residues with high connection ability to collectively facilitate the signaling process. Furthermore, a new parameter of propagation coefficient is defined to determine the propagation capability of residues within a signal transduction network. In conclusion, the new approach is useful for fundamental understanding of the process of intramolecular signal transduction and thus has significant impact on rational design of novel allosteric proteins.

  17. An adaptive coarse graining method for signal transduction in three dimensions

    Science.gov (United States)

    Archuleta, Michelle N.; McDermott, Jason E.; Edwards, Jeremy S.; Resat, Haluk

    2013-01-01

    The spatio-temporal landscape of the plasma membrane regulates activation and signal transduction of membrane bound receptors by restricting their two-dimensional mobility and by inducing receptor clustering. This regulation also extends to complex formation between receptors and adaptor proteins, which are the intermediate signaling molecules involved in cellular signaling that relay the received cues from cell surface to cytoplasm and eventually to the nucleus. Although their investigation poses challenging technical difficulties, there is a crucial need to understand the impact of the receptor diffusivity, clustering, and spatial heterogeneity, and of receptor-adaptor protein complex formation on the cellular signal transduction patterns. Building upon our earlier studies, we have developed an adaptive coarse-grained Monte Carlo method that can be used to investigate the role of diffusion, clustering and membrane corralling on receptor association and receptor-adaptor protein complex formation dynamics in three dimensions. The new Monte Carlo lattice based approach allowed us to introduce spatial resolution on the 2-D plasma membrane and to model the cytoplasm in three-dimensions. Being a multi-resolution approach, our new method makes it possible to represent various parts of the cellular system at different levels of detail and enabled us to utilize the locally homogeneous assumption when justified (e.g., cytoplasmic region away from the cell membrane) and avoid its use when high spatial resolution is needed (e.g., cell membrane and cytoplasmic region near the membrane) while keeping the required computational complexity manageable. Our results have shown that diffusion has a significant impact on receptor-receptor dimerization and receptor-adaptor protein complex formation kinetics. We have observed an “adaptor protein hopping” mechanism where the receptor binding proteins may hop between receptors to form short-lived transient complexes. This increased

  18. Cell signalling and phospholipid metabolism

    Energy Technology Data Exchange (ETDEWEB)

    Boss, W.F.

    1990-01-01

    These studies explored whether phosphoinositide (PI) has a role in plants analogous to its role in animal cells. Although no parallel activity of PI in signal transduction was found in plant cells, activity of inositol phospholipid kinase was found to be modulated by light and by cell wall degrading enzymes. These studies indicate a major role for inositol phospholipids in plant growth and development as membrane effectors but not as a source of second messengers.

  19. A computational approach for ordering signal transduction pathway components from genomics and proteomics Data

    Directory of Open Access Journals (Sweden)

    Zhao Hongyu

    2004-10-01

    Full Text Available Abstract Background Signal transduction is one of the most important biological processes by which cells convert an external signal into a response. Novel computational approaches to mapping proteins onto signaling pathways are needed to fully take advantage of the rapid accumulation of genomic and proteomics information. However, despite their importance, research on signaling pathways reconstruction utilizing large-scale genomics and proteomics information has been limited. Results We have developed an approach for predicting the order of signaling pathway components, assuming all the components on the pathways are known. Our method is built on a score function that integrates protein-protein interaction data and microarray gene expression data. Compared to the individual datasets, either protein interactions or gene transcript abundance measurements, the integrated approach leads to better identification of the order of the pathway components. Conclusions As demonstrated in our study on the yeast MAPK signaling pathways, the integration analysis of high-throughput genomics and proteomics data can be a powerful means to infer the order of pathway components, enabling the transformation from molecular data into knowledge of cellular mechanisms.

  20. Epidermal growth factor stimulates proliferation and migration of porcine trophectoderm cells through protooncogenic protein kinase 1 and extracellular-signal-regulated kinases 1/2 mitogen-activated protein kinase signal transduction cascades during early pregnancy.

    Science.gov (United States)

    Jeong, Wooyoung; Kim, Jinyoung; Bazer, Fuller W; Song, Gwonhwa

    2013-12-01

    For successful implantation and establishment of early epitheliochorial placentation, porcine conceptuses require histotroph, including nutrients and growth factors, secreted by or transported into the lumen of the uterus. Epidermal growth factor (EGF), an essential component of histotroph, is known to have potential growth-promoting activities on the conceptus and uterine endometrium. However, little is known about its effects to transactivate cell signaling cascades responsible for proliferation, growth and differentiation of conceptus trophectoderm. In the present study, therefore, we determined that EGFR mRNA and protein were abundant in endometrial luminal and glandular epithelia, stratum compactum stroma and conceptus trophectoderm on days 13-14 of pregnancy, but not in any other cells of the uterus or conceptus. In addition, primary porcine trophectoderm (pTr) cells treated with EGF exhibited increased abundance of phosphorylated (p)-AKT1, p-ERK1/2 MAPK and p-P90RSK over basal levels within 5min, and effect that was maintained to between 30 and 120min. Immunofluorescence microscopy revealed abundant amounts of p-ERK1/2 MAPK and p-AKT1 proteins in the nucleus and, to a lesser extent, in the cytoplasm of pTr cells treated with EGF as compared to control cells. Furthermore, the abundance of p-AKT1 and p-ERK1/2 MAPK proteins was inhibited in control and EGF-treated pTr cells transfected with EGFR siRNA. Compared to the control siRNA transfected pTr cells, pTr cells transfected with EGFR siRNA exhibited an increase in expression of IFND and TGFB1, but there was no effect of expression of IFNG. Further, EGF stimulated proliferation and migration of pTr cells through activation of the PI3K-AKT1 and ERK1/2 MAPK-P90RSK cell signaling pathways. Collectively, these results support the hypothesis that EGF coordinately activates multiple cell signaling pathways critical to proliferation, migration and survival of trophectoderm cells that are critical to development of

  1. Increased entropy of signal transduction in the cancer metastasis phenotype

    Directory of Open Access Journals (Sweden)

    Teschendorff Andrew E

    2010-07-01

    Full Text Available Abstract Background The statistical study of biological networks has led to important novel biological insights, such as the presence of hubs and hierarchical modularity. There is also a growing interest in studying the statistical properties of networks in the context of cancer genomics. However, relatively little is known as to what network features differ between the cancer and normal cell physiologies, or between different cancer cell phenotypes. Results Based on the observation that frequent genomic alterations underlie a more aggressive cancer phenotype, we asked if such an effect could be detectable as an increase in the randomness of local gene expression patterns. Using a breast cancer gene expression data set and a model network of protein interactions we derive constrained weighted networks defined by a stochastic information flux matrix reflecting expression correlations between interacting proteins. Based on this stochastic matrix we propose and compute an entropy measure that quantifies the degree of randomness in the local pattern of information flux around single genes. By comparing the local entropies in the non-metastatic versus metastatic breast cancer networks, we here show that breast cancers that metastasize are characterised by a small yet significant increase in the degree of randomness of local expression patterns. We validate this result in three additional breast cancer expression data sets and demonstrate that local entropy better characterises the metastatic phenotype than other non-entropy based measures. We show that increases in entropy can be used to identify genes and signalling pathways implicated in breast cancer metastasis and provide examples of de-novo discoveries of gene modules with known roles in apoptosis, immune-mediated tumour suppression, cell-cycle and tumour invasion. Importantly, we also identify a novel gene module within the insulin growth factor signalling pathway, alteration of which may

  2. The cytoplasmic and the transmembrane domains are not sufficient for class I MHC signal transduction.

    Science.gov (United States)

    Gur, H; Geppert, T D; Wacholtz, M C; Lipsky, P E

    1999-02-01

    Class I MHC molecules deliver activation signals to T cells. To analyze the role of the cytoplasmic and the transmembrane (TM) domains of class I MHC molecules in T cell activation, Jurkat cells were transfected with genes for truncated class I MHC molecules which had only four intracytoplasmic amino acids and no potential phosphorylation sites or native molecules or both. Cross-linking either the native or the truncated molecules induced IL-2 production even under limiting stimulation conditions of low engagement of the stimulating mAb. Moreover, direct comparison of transfected truncated and native class I MHC molecules expressed on the same cell revealed significant stimulation induced by cross-linking the truncated molecules, despite low expression. In addition, truncated class I MHC molecules were as able to synergize with CD3, CD2, or CD28 initiated IL-2 production as native molecules. In further experiments, hybrid constructs made of the extracellular portion of the murine CD8 alpha chain and of the TM and the intracytoplasmic domains of H-2Kk class I MHC molecule were transfected into Jurkat T cells. The expression of the transfected hybrid molecules was comparable to that of the native HLA-B7 molecules. Cross-linking the intact monomorphic HLA-A,B,C epitope or the polymorphic HLA-B7 epitope induced IL-2 production upon costimulation with PMA. In contrast, cross-linking the hybrid molecules generated neither an increase in intracellular calcium concentration ([Ca2+]i) nor stimulated IL-2 production. By contrast, cross-linking intact murine class I MHC molecules induced [Ca2+]i, signal and IL-2 production in transfected Jurkat cells. The data therefore indicate that unlike many other signaling molecules, signaling via class I MHC molecules does not involve the cytoplasmic and the TM portions of the molecule, but rather class I MHC signal transduction is likely to be mediated by the extracellular domain of the molecule.

  3. Abscisic acid signaling: thermal stability shift assays as tool to analyze hormone perception and signal transduction.

    Directory of Open Access Journals (Sweden)

    Fen-Fen Soon

    Full Text Available Abscisic acid (ABA is a plant hormone that plays important roles in growth and development. ABA is also the central regulator to protect plants against abiotic stresses, such as drought, high salinity, and adverse temperatures, and ABA signaling is therefore a promising biotechnological target for the generation of crops with increased stress resistance. Recently, a core signal transduction pathway has been established, in which ABA receptors, type 2C protein phosphatases, and AMPK-related protein kinases control the regulation of transcription factors, ion channels, and enzymes. Here we use a simple protein thermal stability shift assay to independently validate key aspects of this pathway and to demonstrate the usefulness of this technique to detect and characterize very weak (Kd ≥ 50 µM interactions between receptors and physiological and synthetic agonists, to determine and analyze protein-protein interactions, and to screen small molecule inhibitors.

  4. 受体的适应性变化及细胞信号转导规律与运动的联系%Association of receptor adaptative change and cell signal transduction with exercise

    Institute of Scientific and Technical Information of China (English)

    李宏伟; 狄朝晖

    2011-01-01

    背景:受体调控和转换信号并启动细胞内信号转导,使靶细胞产生生物学效应.受体调节是机体对运动适应的重要调节方式.目的:总结运动对受体的影响、受体的适应性变化及运动受体细胞信号转导规律.方法:由第一作者用计算机检索中国期刊全文数据库(CNKI:2000/2010)和Medline数据库(2000/2010),检索词分别为"受体,运动,适应"和"receptor regulation,exercise,adaption".共检索到137篇文章,按纳入和排除标准对文献进行筛选,共纳入37篇文章.从受体概念、受体的分类和功能,受体的功能与调节,运动对受体的影响等方面进行总结,对受体在运动中的适应性变化和调节机制等方面进行探讨.结果与结论:运动训练引起瘦素受体和胰岛素受体上调,使瘦素和胰岛素分泌发生适应性改变.适宜运动使雄激素受体结合容量和受体数量提高,长期大运动量训练和力竭使雄激素受体结合容量和受体数量下降,意味着保护细胞免受过量或长期刺激而导致生理功能紊乱.急性应激使机体各组织中糖皮质激素受体含量减少,对于防止物质代谢和能量代谢紊乱,维持机体内环境稳定有重要意义.%BACKGROUND: The receptor regulates and switches signal and starts intracellular signal transduction, which causes target cellsto produce biological effects. Receptor regulation is an important regulation mode for organism to motor adaptation.OBJECTIVE: To summarize the effects of motor on receptor, the adaptati ve change of receptor, and signal transduction rule ofmotor receptor cells.METHODS: A computer-based retrieval was performed by the first author to search manuscripts in the CNKI (2000/2010) andMedline database (2000/2010) with the key word “receptor regulation, exercise, adaption”. A total of 137 manuscripts wereincluded. According to inclusion and exclusion criteria, totally 37 manuscripts were included in the final analysis. The

  5. Role of relaxation time scale in noisy signal transduction.

    Science.gov (United States)

    Maity, Alok Kumar; Chaudhury, Pinaki; Banik, Suman K

    2015-01-01

    Intra-cellular fluctuations, mainly triggered by gene expression, are an inevitable phenomenon observed in living cells. It influences generation of phenotypic diversity in genetically identical cells. Such variation of cellular components is beneficial in some contexts but detrimental in others. To quantify the fluctuations in a gene product, we undertake an analytical scheme for studying few naturally abundant linear as well as branched chain network motifs. We solve the Langevin equations associated with each motif under the purview of linear noise approximation and derive the expressions for Fano factor and mutual information in close analytical form. Both quantifiable expressions exclusively depend on the relaxation time (decay rate constant) and steady state population of the network components. We investigate the effect of relaxation time constraints on Fano factor and mutual information to indentify a time scale domain where a network can recognize the fluctuations associated with the input signal more reliably. We also show how input population affects both quantities. We extend our calculation to long chain linear motif and show that with increasing chain length, the Fano factor value increases but the mutual information processing capability decreases. In this type of motif, the intermediate components act as a noise filter that tune up input fluctuations and maintain optimum fluctuations in the output. For branched chain motifs, both quantities vary within a large scale due to their network architecture and facilitate survival of living system in diverse environmental conditions. PMID:25955500

  6. Role of relaxation time scale in noisy signal transduction.

    Directory of Open Access Journals (Sweden)

    Alok Kumar Maity

    Full Text Available Intra-cellular fluctuations, mainly triggered by gene expression, are an inevitable phenomenon observed in living cells. It influences generation of phenotypic diversity in genetically identical cells. Such variation of cellular components is beneficial in some contexts but detrimental in others. To quantify the fluctuations in a gene product, we undertake an analytical scheme for studying few naturally abundant linear as well as branched chain network motifs. We solve the Langevin equations associated with each motif under the purview of linear noise approximation and derive the expressions for Fano factor and mutual information in close analytical form. Both quantifiable expressions exclusively depend on the relaxation time (decay rate constant and steady state population of the network components. We investigate the effect of relaxation time constraints on Fano factor and mutual information to indentify a time scale domain where a network can recognize the fluctuations associated with the input signal more reliably. We also show how input population affects both quantities. We extend our calculation to long chain linear motif and show that with increasing chain length, the Fano factor value increases but the mutual information processing capability decreases. In this type of motif, the intermediate components act as a noise filter that tune up input fluctuations and maintain optimum fluctuations in the output. For branched chain motifs, both quantities vary within a large scale due to their network architecture and facilitate survival of living system in diverse environmental conditions.

  7. Nonselective block by La3+ of Arabidopsis ion channels involved in signal transduction

    Science.gov (United States)

    Lewis, B. D.; Spalding, E. P.; Evans, M. L. (Principal Investigator)

    1998-01-01

    Lanthanide ions such as La3+ are frequently used as blockers to test the involvement of calcium channels in plant and animal signal transduction pathways. For example, the large rise in cytoplasmic Ca2+ concentration triggered by cold shock in Arabidopsis seedlings is effectively blocked by 10 mM La3+ and we show here that the simultaneous large membrane depolarization is similarly blocked. However, a pharmacological tool is only as useful as it is selective and the specificity of La3+ for calcium channels was brought into question by our finding that it also blocked a blue light (BL)-induced depolarization that results from anion channel activation and believed not to involve calcium channels. This unexpected inhibitory effect of La3+ on the BL-induced depolarization is explained by our finding that 10 mM La3+ directly and completely blocked the BL-activated anion channel when applied to excised patches. We have investigated the ability of La3+ to block noncalcium channels in Arabidopsis. In addition to the BL-activated anion channel, 10 mM La3+ blocked a cation channel and a stretch-activated channel in patches of plasma membrane excised from hypocotyl cells. In root cells, 10 mM La3+ inhibited the activity of an outward-rectifying potassium channel at the whole cell and single-channel level by 47% and 58%, respectively. We conclude that La3+ is a nonspecific blocker of multiple ionic conductances in Arabidopsis and may disrupt signal transduction processes independently of any effect on Ca2+ channels.

  8. Signal perception, transduction, and response in gravity resistance. Another graviresponse in plants

    Science.gov (United States)

    Hoson, T.; Saito, Y.; Soga, K.; Wakabayashi, K.

    Resistance to the gravitational force is a serious problem that plants have had to solve to survive on land. Mechanical resistance to the pull of gravity is thus a principal graviresponse in plants, comparable to gravitropism. Nevertheless, only limited information has been obtained for this gravity response. We have examined the mechanism of gravity-induced mechanical resistance using hypergravity conditions produced by centrifugation. As a result, we have clarified the outline of the sequence of events leading to the development of mechanical resistance. The gravity signal may be perceived by mechanoreceptors (mechanosensitive ion channels) on the plasma membrane and it appears that amyloplast sedimentation in statocytes is not involved. Transformation and transduction of the perceived signal may be mediated by the structural or physiological continuum of microtubule-cell membrane-cell wall. As the final step in the development of mechanical resistance, plants construct a tough body by increasing cell wall rigidity. The increase in cell wall rigidity is brought about by modification of the metabolism of certain wall constituents and modification of the cell wall environment, especially pH. We need to clarify the details of each step by future space and ground-based experiments.

  9. Neuro-protective effects of CNTF on hippocampal neurons via an unknown signal transduction pathway

    Institute of Scientific and Technical Information of China (English)

    2006-01-01

    In our previous study, we proposed that there may be an unknown pathway in the upper stream of the known signal transduction pathway of Ciliary neurotrophic factor (CNTF) that mediates the neuro-protective function of CNTF. In the present experiment, we observed that the neuro-protective function of the non-classic signal transduction pathway in a L-NMDA (a glutamic acid ion type receptor atagonist) induced hippocampal neuron injury model, using primary culture rat hippocampal neurons, continuous photography and gp130 immunohistochemical assay. The results showed that L-NMDA induced injurious reaction of hippocampal neurons, and CNTF was able to inhibit the toxic action of L-NMDA on hippocampal neurons. Additionally, when JAK/STATs in the known classic signal transduction pathway of CNTF were blocked by PTPi-2, the protective effect of CNTF against L-NMDA injury still existed. L-NMDA caused a rapid increase in the concentration of hippocampal intracellular free [Ca2+]i. CNTF was able to attenuate L-NMDA-induced elevation of [Ca2+]i, and blocking JAK/STATs in the known classic signal trans- duction pathway of CNTF did not affect L-NMDA- induced elevation of [Ca2+]i, indicating that, apart from the known classic signal transduction pathway, there may be some other transduction pathways for CNTF to exert the protective effect on hippocampal neurons, and this pathway is related to [Ca2+].

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

  11. Nitric oxide-mediated bystander signal transduction induced by heavy-ion microbeam irradiation

    Science.gov (United States)

    Tomita, Masanori; Matsumoto, Hideki; Funayama, Tomoo; Yokota, Yuichiro; Otsuka, Kensuke; Maeda, Munetoshi; Kobayashi, Yasuhiko

    2015-07-01

    In general, a radiation-induced bystander response is known to be a cellular response induced in non-irradiated cells after receiving bystander signaling factors released from directly irradiated cells within a cell population. Bystander responses induced by high-linear energy transfer (LET) heavy ions at low fluence are an important health problem for astronauts in space. Bystander responses are mediated via physical cell-cell contact, such as gap-junction intercellular communication (GJIC) and/or diffusive factors released into the medium in cell culture conditions. Nitric oxide (NO) is a well-known major initiator/mediator of intercellular signaling within culture medium during bystander responses. In this study, we investigated the NO-mediated bystander signal transduction induced by high-LET argon (Ar)-ion microbeam irradiation of normal human fibroblasts. Foci formation by DNA double-strand break repair proteins was induced in non-irradiated cells, which were co-cultured with those irradiated by high-LET Ar-ion microbeams in the same culture plate. Foci formation was suppressed significantly by pretreatment with an NO scavenger. Furthermore, NO-mediated reproductive cell death was also induced in bystander cells. Phosphorylation of NF-κB and Akt were induced during NO-mediated bystander signaling in the irradiated and bystander cells. However, the activation of these proteins depended on the incubation time after irradiation. The accumulation of cyclooxygenase-2 (COX-2), a downstream target of NO and NF-κB, was observed in the bystander cells 6 h after irradiation but not in the directly irradiated cells. Our findings suggest that Akt- and NF-κB-dependent signaling pathways involving COX-2 play important roles in NO-mediated high-LET heavy-ion-induced bystander responses. In addition, COX-2 may be used as a molecular marker of high-LET heavy-ion-induced bystander cells to distinguish them from directly irradiated cells, although this may depend on the time

  12. Gene network homology in prokaryotes using a similarity search approach: queries of quorum sensing signal transduction.

    Directory of Open Access Journals (Sweden)

    David N Quan

    Full Text Available Bacterial cell-cell communication is mediated by small signaling molecules known as autoinducers. Importantly, autoinducer-2 (AI-2 is synthesized via the enzyme LuxS in over 80 species, some of which mediate their pathogenicity by recognizing and transducing this signal in a cell density dependent manner. AI-2 mediated phenotypes are not well understood however, as the means for signal transduction appears varied among species, while AI-2 synthesis processes appear conserved. Approaches to reveal the recognition pathways of AI-2 will shed light on pathogenicity as we believe recognition of the signal is likely as important, if not more, than the signal synthesis. LMNAST (Local Modular Network Alignment Similarity Tool uses a local similarity search heuristic to study gene order, generating homology hits for the genomic arrangement of a query gene sequence. We develop and apply this tool for the E. coli lac and LuxS regulated (Lsr systems. Lsr is of great interest as it mediates AI-2 uptake and processing. Both test searches generated results that were subsequently analyzed through a number of different lenses, each with its own level of granularity, from a binary phylogenetic representation down to trackback plots that preserve genomic organizational information. Through a survey of these results, we demonstrate the identification of orthologs, paralogs, hitchhiking genes, gene loss, gene rearrangement within an operon context, and also horizontal gene transfer (HGT. We found a variety of operon structures that are consistent with our hypothesis that the signal can be perceived and transduced by homologous protein complexes, while their regulation may be key to defining subsequent phenotypic behavior.

  13. Effect of the opioid methionine enkephalinamide on signal transduction in human T-lymphocytes

    DEFF Research Database (Denmark)

    Sørensen, A N; Claesson, Mogens Helweg

    1998-01-01

    control experiments, we found that a fraction (20-40%) of the individual sets of Met-Enk experiments responded significantly different when compared to PBS-controls. In this fraction of experiments the increase in [Ca2+]i after ligation of the TCR/CD3 complex was extremely slow compared to controls....... Moreover, the levels of [Ca2+]i in this particular fraction were lower than control levels prior to ligation of the TCR/CD3 complex. The data support the idea that signal transduction in T cells can be influenced by endogenous opioid. The data therefore give credit to the evolving hypothesis...... of a functional relationship between the neuroendocrine system and the immune system....

  14. Thermodynamic and Kinetic Analysis of Sensitivity Amplification in Biological Signal Transduction

    CERN Document Server

    Qian, H

    2003-01-01

    Based on a thermodynamic analysis of the kinetic model for the protein phosphorylation-dephosphorylation cycle, we study the ATP (or GTP) energy utilization of this ubiquitous biological signal transduction process. It was shown that the free energy from hydrolysis inside cells, Delta G (phosphorylation potential), controls the amplification and sensitivity of the switch-like cellular module; the response coefficient of the sensitivity amplification approaches the optimal 1 and the Hill coefficeint increases with increasing Delta G. Futhermore, we show the high amplification in zero-order ultrasensitivity is mechanistically related to the proofreading kinetics for protein biosynthesis. Both utilize multiple kinetic cycles in time to gain temporal cooperativity, in contrast to allosteric cooperativity that utilizes multiple subunits in a protein.

  15. Architecture and signal transduction mechanism of the bacterial chemosensory array: progress, controversies, and challenges.

    Science.gov (United States)

    Falke, Joseph J; Piasta, Kene N

    2014-12-01

    Recent research has deepened our understanding of the ancient, conserved chemosensory array that detects small molecule attractants and repellents, and directs the chemotaxis of bacterial and archaeal cells towards an optimal chemical environment. Here we review advances towards a molecular description of the ultrastable lattice architecture and ultrasensitive signal transduction mechanism of the chemosensory array, as well as controversies and challenges requiring further research. Ultimately, a full molecular understanding of array structure and on-off switching will foster (i) the design of novel therapies that block pathogenic wound seeking and infection, (ii) the development of highly specific, sensitive, stable biosensors, and (iii) the elucidation of general functional principles shared by receptor patches in all branches of life.

  16. Fyn is a redox sensor involved in solar ultraviolet light-induced signal transduction in skin carcinogenesis.

    Science.gov (United States)

    Kim, J-E; Roh, E; Lee, M H; Yu, D H; Kim, D J; Lim, T-G; Jung, S K; Peng, C; Cho, Y-Y; Dickinson, S; Alberts, D; Bowden, G T; Einspahr, J; Stratton, S P; Curiel-Lewandrowski, C; Bode, A M; Lee, K W; Dong, Z

    2016-08-01

    Solar ultraviolet (UV) light is a major etiological factor in skin carcinogenesis, with solar UV-stimulated signal transduction inducing pathological changes and skin damage. The primary sensor of solar UV-induced cellular signaling has not been identified. We use an experimental system of solar simulated light (SSL) to mimic solar UV and we demonstrate that Fyn is a primary redox sensor involved in SSL-induced signal transduction. Reactive oxygen species (ROS) generated by SSL exposure directly oxidize Cys488 of Fyn, resulting in increased Fyn kinase activity. Fyn oxidation was increased in mouse skin after SSL exposure and Fyn-knockout mice formed larger and more tumors compared with Fyn wild-type mice when exposed to SSL for an extended period of time. Murine embryonic fibroblasts (MEFs) lacking Fyn and cells in which Fyn expression was knocked down were resistant to SSL-induced apoptosis. Furthermore, cells expressing mutant Fyn (C448A) were resistant to SSL-induced apoptosis. These findings suggest that Fyn acts as a regulatory nexus between solar UV, ROS and signal transduction during skin carcinogenesis.

  17. Analysis of a signal transduction pathway involved in leaf epidermis differentiation.

    Energy Technology Data Exchange (ETDEWEB)

    Philip W. Becraft

    2005-05-23

    The major objective of this study was to identify and analyze signal transduction factors that function with the CR4 receptor kinase. We pursued this analysis in Arabidopsis. Analysis of other members of the ACR4 related receptor (CRR) family produced biochemical evidence consistent with some of them functioning in ACR4 signal transduction. Yeast 2-hybrid identified six proteins that interact with the cytoplasmic domain of ACR4, representing putative downstream signal transduction components. The interactions for all 6 proteins were verified by in vitro pull down assays. Five of the interacting proteins were phosphorylated by ACR4. We also identified candidate interactors with the extracellular TNFR domain. We hypothesize this may be the ligand binding domain for ACR4. In one approach, yeast 2-hybrid was again used and five candidate proteins identified. Nine additional candidates were identified in a genome wide scan of Arabidopsis amino acid sequences that threaded onto the TNF structure.

  18. Two-Component Signal Transduction Systems in the Cyanobacterium Synechocystis sp. PCC 6803

    Institute of Scientific and Technical Information of China (English)

    LIU Xingguo; HUANG Wei; WU Qingyu

    2006-01-01

    Two-component systems are signal transduction systems which enable bacteria to regulate cellular functions in response to changing environmental conditions. The unicellular Synechocystis sp. PCC 6803 has become a model organism for a range of biochemical and molecular biology studies aiming at investigating environmental stress response. The publication of the complete genome sequence of the cyanobacterium Synechocystis sp. PCC 6803 provided a tremendous stimulus for research in this field, and at least 80 open reading frames were identified as members of the two-component signal transduction systems in this single species of cyanobacteria. To date, functional roles have been determined for only a limited number of such proteins. This review summarizes our current knowledge about the two-component signal transduction systems in Synechocystis sp. PCC 6803 and describes recent achievements in elucidating the functional roles of these systems.

  19. Signal transduction by VEGF receptors in regulation of angiogenesis and lymphangiogenesis

    International Nuclear Information System (INIS)

    The VEGF/VPF (vascular endothelial growth factor/vascular permeability factor) ligands and receptors are crucial regulators of vasculogenesis, angiogenesis, lymphangiogenesis and vascular permeability in vertebrates. VEGF-A, the prototype VEGF ligand, binds and activates two tyrosine kinase receptors: VEGFR1 (Flt-1) and VEGFR2 (KDR/Flk-1). VEGFR1, which occurs in transmembrane and soluble forms, negatively regulates vasculogenesis and angiogenesis during early embryogenesis, but it also acts as a positive regulator of angiogenesis and inflammatory responses, playing a role in several human diseases such as rheumatoid arthritis and cancer. The soluble VEGFR1 is overexpressed in placenta in preeclampsia patients. VEGFR2 has critical functions in physiological and pathological angiogenesis through distinct signal transduction pathways regulating proliferation and migration of endothelial cells. VEGFR3, a receptor for the lymphatic growth factors VEGF-C and VEGF-D, but not for VEGF-A, regulates vascular and lymphatic endothelial cell function during embryogenesis. Loss-of-function variants of VEGFR3 have been identified in lymphedema. Formation of tumor lymphatics may be stimulated by tumor-produced VEGF-C, allowing increased spread of tumor metastases through the lymphatics. Mapping the signaling system of these important receptors may provide the knowledge necessary to suppress specific signaling pathways in major human diseases

  20. The mitochondrial Ca2+ uniporter: regulation by auxiliary subunits and signal transduction pathways.

    Science.gov (United States)

    Jhun, Bong Sook; Mishra, Jyotsna; Monaco, Sarah; Fu, Deming; Jiang, Wenmin; Sheu, Shey-Shing; O-Uchi, Jin

    2016-07-01

    Mitochondrial Ca(2+) homeostasis, the Ca(2+) influx-efflux balance, is responsible for the control of numerous cellular functions, including energy metabolism, generation of reactive oxygen species, spatiotemporal dynamics of Ca(2+) signaling, and cell growth and death. Recent discovery of the molecular identity of the mitochondrial Ca(2+) uniporter (MCU) provides new possibilities for application of genetic approaches to study the mitochondrial Ca(2+) influx mechanism in various cell types and tissues. In addition, the subsequent discovery of various auxiliary subunits associated with MCU suggests that mitochondrial Ca(2+) uptake is not solely regulated by a single protein (MCU), but likely by a macromolecular protein complex, referred to as the MCU-protein complex (mtCUC). Moreover, recent reports have shown the potential role of MCU posttranslational modifications in the regulation of mitochondrial Ca(2+) uptake through mtCUC. These observations indicate that mtCUCs form a local signaling complex at the inner mitochondrial membrane that could significantly regulate mitochondrial Ca(2+) handling, as well as numerous mitochondrial and cellular functions. In this review we discuss the current literature on mitochondrial Ca(2+) uptake mechanisms, with a particular focus on the structure and function of mtCUC, as well as its regulation by signal transduction pathways, highlighting current controversies and discrepancies.

  1. Cell Wall Integrity Signaling in Saccharomyces cerevisiae

    OpenAIRE

    Levin, David E.

    2005-01-01

    The yeast cell wall is a highly dynamic structure that is responsible for protecting the cell from rapid changes in external osmotic potential. The wall is also critical for cell expansion during growth and morphogenesis. This review discusses recent advances in understanding the various signal transduction pathways that allow cells to monitor the state of the cell wall and respond to environmental challenges to this structure. The cell wall integrity signaling pathway controlled by the small...

  2. Systemic Acquired Resistance and Signal Transduction in Plant

    Institute of Scientific and Technical Information of China (English)

    ZHAO Shu-qing; GUO Jian-bo

    2003-01-01

    Systemic acquired resistance (SAR), known as the broad-spectrum, inducible plant immunity,is a defense response triggered by pathogen infection. The response starts from the recognition of plant resist-ance (R) with the corresponding avirulence (avr) gene from the pathogen. There are some genes for conver-gence of signals downstream of different R/avr interacting partners into a single signaling pathway. Salicylicacid (SA) is required for the induction of SAR and involved in transducing the signal in target tissues. The SAsignal is transduced through NPR1, a nuclear-localized protein that interacts with transcription factors thatare involved in regulating SA-mediated gene expression. Some chemicals that mimic natural signaling com-pounds can also activate SAR. The application of biochemical activators to agriculture for plant protection is anovel idea for developing green chemical pesticide.

  3. Dynamic signaling in the Hog1 MAPK pathway relies on high basal signal transduction.

    Science.gov (United States)

    Macia, Javier; Regot, Sergi; Peeters, Tom; Conde, Núria; Solé, Ricard; Posas, Francesc

    2009-01-01

    Appropriate regulation of the Hog1 mitogen-activated protein kinase (MAPK) pathway is essential for cells to survive osmotic stress. Here, we show that the two sensing mechanisms upstream of Hog1 display different signaling properties. The Sho1 branch is an inducible nonbasal system, whereas the Sln1 branch shows high basal signaling that is restricted by a MAPK-mediated feedback mechanism. A two-dimensional mathematical model of the Snl1 branch, including high basal signaling and a Hog1-regulated negative feedback, shows that a system with basal signaling exhibits higher efficiency, with faster response times and higher sensitivity to variations in external signals, than would systems without basal signaling. Analysis of two other yeast MAPK pathways, the Fus3 and Kss1 signaling pathways, indicates that high intrinsic basal signaling may be a general property of MAPK pathways allowing rapid and sensitive responses to environmental changes. PMID:19318625

  4. Systematic Prediction of Scaffold Proteins Reveals New Design Principles in Scaffold-Mediated Signal Transduction.

    Directory of Open Access Journals (Sweden)

    Jianfei Hu

    Full Text Available Scaffold proteins play a crucial role in facilitating signal transduction in eukaryotes by bringing together multiple signaling components. In this study, we performed a systematic analysis of scaffold proteins in signal transduction by integrating protein-protein interaction and kinase-substrate relationship networks. We predicted 212 scaffold proteins that are involved in 605 distinct signaling pathways. The computational prediction was validated using a protein microarray-based approach. The predicted scaffold proteins showed several interesting characteristics, as we expected from the functionality of scaffold proteins. We found that the scaffold proteins are likely to interact with each other, which is consistent with previous finding that scaffold proteins tend to form homodimers and heterodimers. Interestingly, a single scaffold protein can be involved in multiple signaling pathways by interacting with other scaffold protein partners. Furthermore, we propose two possible regulatory mechanisms by which the activity of scaffold proteins is coordinated with their associated pathways through phosphorylation process.

  5. Signal Transduction Pathways of EMT Induced by TGF-β, SHH, and WNT and Their Crosstalks

    Science.gov (United States)

    Zhang, Jingyu; Tian, Xiao-Jun; Xing, Jianhua

    2016-01-01

    Epithelial-to-mesenchymal transition (EMT) is a key step in development, wound healing, and cancer development. It involves cooperation of signaling pathways, such as transformation growth factor-β (TGF-β), Sonic Hedgehog (SHH), and WNT pathways. These signaling pathways crosstalk to each other and converge to key transcription factors (e.g., SNAIL1) to initialize and maintain the process of EMT. The functional roles of multi-signaling pathway crosstalks in EMT are sophisticated and, thus, remain to be explored. In this review, we focused on three major signal transduction pathways that promote or regulate EMT in carcinoma. We discussed the network structures, and provided a brief overview of the current therapy strategies and drug development targeted to these three signal transduction pathways. Finally, we highlighted systems biology approaches that can accelerate the process of deconstructing complex networks and drug discovery. PMID:27043642

  6. Signal Transduction Pathways of EMT Induced by TGF-β, SHH, and WNT and Their Crosstalks

    Directory of Open Access Journals (Sweden)

    Jingyu Zhang

    2016-03-01

    Full Text Available Epithelial-to-mesenchymal transition (EMT is a key step in development, wound healing, and cancer development. It involves cooperation of signaling pathways, such as transformation growth factor-β (TGF-β, Sonic Hedgehog (SHH, and WNT pathways. These signaling pathways crosstalk to each other and converge to key transcription factors (e.g., SNAIL1 to initialize and maintain the process of EMT. The functional roles of multi-signaling pathway crosstalks in EMT are sophisticated and, thus, remain to be explored. In this review, we focused on three major signal transduction pathways that promote or regulate EMT in carcinoma. We discussed the network structures, and provided a brief overview of the current therapy strategies and drug development targeted to these three signal transduction pathways. Finally, we highlighted systems biology approaches that can accelerate the process of deconstructing complex networks and drug discovery.

  7. Signal transduction around thymic stromal lymphopoietin (TSLP) in atopic asthma

    OpenAIRE

    Kuepper Michael; Borowski Andreas; Sebastian Katrin; Friedrich Karlheinz

    2008-01-01

    Abstract Thymic stromal lymphopoietin (TSLP), a novel interleukin-7-like cytokine, triggers dendritic cell-mediated inflammatory responses ultimately executed by T helper cells of the Th2 subtype. TSLP emerged as a central player in the development of allergic symptoms, especially in the airways, and is a prime regulatory cytokine at the interface of virus- or antigen-exposed epithelial cells and dendritic cells (DCs). DCs activated by epithelium-derived TSLP can promote naïve CD4+ T cells to...

  8. Inhibition of bone morphogenetic protein signal transduction prevents the medial vascular calcification associated with matrix Gla protein deficiency.

    Directory of Open Access Journals (Sweden)

    Rajeev Malhotra

    Full Text Available Matrix Gla protein (MGP is reported to inhibit bone morphogenetic protein (BMP signal transduction. MGP deficiency is associated with medial calcification of the arterial wall, in a process that involves both osteogenic transdifferentiation of vascular smooth muscle cells (VSMCs and mesenchymal transition of endothelial cells (EndMT. In this study, we investigated the contribution of BMP signal transduction to the medial calcification that develops in MGP-deficient mice.MGP-deficient mice (MGP(-/- were treated with one of two BMP signaling inhibitors, LDN-193189 or ALK3-Fc, beginning one day after birth. Aortic calcification was assessed in 28-day-old mice by measuring the uptake of a fluorescent bisphosphonate probe and by staining tissue sections with Alizarin red. Aortic calcification was 80% less in MGP(-/- mice treated with LDN-193189 or ALK3-Fc compared with vehicle-treated control animals (P<0.001 for both. LDN-193189-treated MGP(-/- mice survived longer than vehicle-treated MGP(-/- mice. Levels of phosphorylated Smad1/5 and Id1 mRNA (markers of BMP signaling did not differ in the aortas from MGP(-/- and wild-type mice. Markers of EndMT and osteogenesis were increased in MGP(-/- aortas, an effect that was prevented by LDN-193189. Calcification of isolated VSMCs was also inhibited by LDN-193189.Inhibition of BMP signaling leads to reduced vascular calcification and improved survival in MGP(-/- mice. The EndMT and osteogenic transdifferentiation associated with MGP deficiency is dependent upon BMP signaling. These results suggest that BMP signal transduction has critical roles in the development of vascular calcification in MGP-deficient mice.

  9. Nitric oxide agents impair insulin-mediated signal transduction in rat skeletal muscle

    Directory of Open Access Journals (Sweden)

    Ragoobirsingh Dalip

    2006-05-01

    Full Text Available Abstract Background Evidence demonstrates that exogenously administered nitric oxide (NO can induce insulin resistance in skeletal muscle. We have investigated the modulatory effects of two NO donors, S-nitroso-N-acetyl-D, L-penicillamine (SNAP and S-nitrosoglutathione (GSNO on the early events in insulin signaling in rat skeletal myocytes. Results Skeletal muscle cells from 6–8 week old Sprague-Dawley rats were treated with SNAP or GSNO (25 ng/ml in the presence or absence of glucose (25 mM and insulin (100 nM. Cellular insulin receptor-β levels and tyrosine phosphorylation in IRS-1 were significantly reduced, while serine phosphorylation in IRS-1 was significantly increased in these cells, when compared to the insulin-stimulated control. Reversal to near normal levels was achieved using the NO scavenger, 2-(4-carboxyphenyl-4, 4, 5, 5-tetramethylimidazoline-1-oxyl 3-oxide (carboxy-PTIO. Conclusion These data suggest that NO is a potent modulator of insulin-mediated signal transduction and may play a significant role in the pathogenesis of type 2 diabetes mellitus.

  10. Intracellular calcium during signal transduction in the lymphocyte is altered by ELF magnetic and electric fields

    Energy Technology Data Exchange (ETDEWEB)

    Liburdy, R.P. (Lawrence Berkeley Lab., CA (United States))

    1992-02-26

    Research has shown that ELF magnetic and electric fields alter calcium transport in rat thymic T-lymphocytes during signal transduction initiated by mitogen. Interestingly activated T-lymphocytes display a nonlinear dose-response for this basic field interaction which scales with the induced electric field in contrast to the applied magnetic field. Specialized multiring annular well cell culture plates based on Faraday's Law of Current Induction were used to demonstrate that the electric field associated with the magnetic field is the exposure metric of biological interest. The first real-time measurements of (Ca{sup 2+}){sub i} were recently presented and (Ca{sup 2+}){sub i} was shown to be altered by sinusoidal 60 Hz electric fields; magnetic fields that induced comparable electric fields yielded similar alterations in (Ca{sup 2+}){sub i}. The author now presents evidence that both parameters, (Ca{sup 2+}){sub i} and calcium transport, are altered by ELF fields during calcium signaling in thymocytes and scale with the induced electric field. In addition, (Ca{sup 2+}){sub i} studies have been conducted that provide evidence supporting the hypothesis that the mitogen-gated calcium channel present in the plasma cell membrane represents a specific site of interaction for ELF fields.

  11. Adaptation of signal transduction and muscle proteome in trained horses

    NARCIS (Netherlands)

    Ginneken, Mireille Maria Elisabeth van

    2006-01-01

    In the present thesis the localization and activation of signaling proteins, known from human studies, in equine muscle were investigated under conditions of rest, after an acute bout of exercise and before and after a period of (intensified) training. Proteins of interest (protein kinase C (PKC), m

  12. The emerging role of phosphoinositide clustering in intracellular trafficking and signal transduction [version 1; referees: 4 approved

    Directory of Open Access Journals (Sweden)

    Laura Picas

    2016-03-01

    Full Text Available Phosphoinositides are master regulators of multiple cellular processes: from vesicular trafficking to signaling, cytoskeleton dynamics, and cell growth. They are synthesized by the spatiotemporal regulated activity of phosphoinositide-metabolizing enzymes. The recent observation that some protein modules are able to cluster phosphoinositides suggests that alternative or complementary mechanisms might operate to stabilize the different phosphoinositide pools within cellular compartments. Herein, we discuss the different known and potential molecular players that are prone to engage phosphoinositide clustering and elaborate on how such a mechanism might take part in the regulation of intracellular trafficking and signal transduction.

  13. Induction of host signal transduction pathways by Helicobacter pylori

    OpenAIRE

    Segal, Ellyn D.; Lange, C.; Covacci, A.; Tompkins, L S; Falkow, S

    1997-01-01

    Adherence of Helicobacter pylori to cultured gastric epithelial cells is associated with several cellular events, including the tyrosine phosphorylation of a 145-kDa host protein; the reorganization of the host cell actin and associated cellular proteins, like vasodilator-stimulated phosphoprotein, adjacent to the attached bacterial cell; and the subsequent release of the cytokine, interleukin 8 (IL-8). H. pylori isolated from patients with ulcer disease and gastric cancer contain a DNA inser...

  14. Mitogenic signal transduction in T lymphocytes in microgravity

    Science.gov (United States)

    Cogoli, A.; Bechler, B.; Cogoli-Greuter, M.; Criswell, S. B.; Joller, H.; Joller, P.; Hunzinger, E.; Muller, O.

    1993-01-01

    The activation by concanavalin A Con A of human peripheral blood lymphocytes (PBLs) in the presence of monocytes as accessory cells was investigated in cultures exposed to microgravity conditions in Spacelab. Activation of T cells was measured as incorporation of [3H]thymidine into DNA, secretion of interleukin-2 (IL-2), and interferon-gamma, and expression of IL-2 receptors. Whereas, as discovered in earlier experiments, the activation of resuspended T cells is strongly inhibited, activation of cells attached to microcarrier beads is more than doubled in microgravity. The results suggest that the depression of the activation in resuspended cells may be attributed to a malfunction of monocytes acting as accessory cells. In fact, although the ultrastructure of resuspended monocytes is not altered in microgravity, the secretion of IL-1 is strongly inhibited. Our data suggest that (1) IL-2 is produced independently of IL-1, (2) IL-1 production is triggered only when monocytes (and lymphocytes?) adhere to microcarriers, (3) the expression of IL-2 receptors depends on IL-1, and (4) provided sufficient IL-1 is available, activation is enhanced in microgravity. Finally, cultures of resuspended PBLs and monocytes in microgravity constitute a complete and natural system in which monocytes are not operational. This may be useful for studies of the role of accessory cells and cell-cell interactions in T lymphocyte activation.

  15. A mathematical model of the mating signal transduction pathway in the yeast Saccharomyces cerevisiae. Final report

    Energy Technology Data Exchange (ETDEWEB)

    Thomas Ivan Milac

    1998-09-14

    Outline of two major goals in my proposal for this fellowship. First goal having no previous training in biology, was to become knowledgeable of the paradigms, experimental techniques, and current research interests of molecular biology. Second goal was to construct a mathematical model of the mating signal transduction pathway in the yeast Saccharomyces cerevisiae.

  16. Quasi steady-state approximations in complex intracellular signal transduction networks - a word of caution

    DEFF Research Database (Denmark)

    Pedersen, Morten Gram; Bersani, A.M.; Bersani, E.

    2008-01-01

    Enzyme reactions play a pivotal role in intracellular signal transduction. Many enzymes are known to possess Michaelis-Menten (MM) kinetics and the MM approximation is often used when modeling enzyme reactions. However, it is known that the MM approximation is only valid at low enzyme...

  17. Genomic Analysis of Two-Component Signal Transduction Proteins in Basidiomycetes

    DEFF Research Database (Denmark)

    Ussery, David; Lavín, JL; Binnewies, Tim Terence;

    2010-01-01

    Two-component system (TCS) proteins are components of complex signal transduction pathways in fungi, and play essential roles in the regulation of several cellular functions and responses. Species of basidiomycetes have a marked variation in their specific physiological traits, morphological...

  18. Transduction of wound and herbivory signals in plastids

    OpenAIRE

    BONAVENTURE, GUSTAVO; Baldwin, Ian T.

    2010-01-01

    Plastids are the central orchestrators of the early and late responses to wounding and herbivory in plants. This organelle houses some of the most important enzymes involved in the biogenesis of intra and extracellular signals that mediate defense responses against these stresses. Among these enzymes are the ones initiating the biosynthesis of oxylipins [e.g., jasmonic acid (JA) and C6 volatiles], terpenoid volatiles and phenolic compounds, including both volatile [e.g., methylsalicylate (MeS...

  19. Mapping Complex Networks: Exploring Boolean Modeling of Signal Transduction Pathways

    OpenAIRE

    Bhardwaj, Gaurav; Wells, Christine P.; Albert, Reka; van Rossum, Damian B.; Patterson, Randen L

    2009-01-01

    In this study, we explored the utility of a descriptive and predictive bionetwork model for phospholipase C-coupled calcium signaling pathways, built with non-kinetic experimental information. Boolean models generated from these data yield oscillatory activity patterns for both the endoplasmic reticulum resident inositol-1,4,5-trisphosphate receptor (IP3R) and the plasma-membrane resident canonical transient receptor potential channel 3 (TRPC3). These results are specific as randomization of ...

  20. Signal transduction by the major histocompatibility complex class I molecule

    DEFF Research Database (Denmark)

    Pedersen, A E; Skov, Svend; Bregenholt, S;

    1999-01-01

    immediately after and at later intervals following MHC-I ligation. It is hypothesized that MHC-I expression, both ontogenically and in evolution, is driven by a cell-mediated selection pressure advantageous to the MHC-I-expressing cell. Accordingly, in addition to their role in T-cell selection...... and functioning, MHC-I molecules might be of importance for the maintenance of cellular homeostasis not only within the immune system, but also in the interplay between the immune system and other organ systems....

  1. Heavy metal accumulation and signal transduction in herbaceous and woody plants: Paving the way for enhancing phytoremediation efficiency.

    Science.gov (United States)

    Luo, Zhi-Bin; He, Jiali; Polle, Andrea; Rennenberg, Heinz

    2016-11-01

    Heavy metal (HM)-accumulating herbaceous and woody plants are employed for phytoremediation. To develop improved strategies for enhancing phytoremediation efficiency, knowledge of the microstructural, physiological and molecular responses underlying HM-accumulation is required. Here we review the progress in understanding the structural, physiological and molecular mechanisms underlying HM uptake, transport, sequestration and detoxification, as well as the regulation of these processes by signal transduction in response to HM exposure. The significance of genetic engineering for enhancing phytoremediation efficiency is also discussed. In herbaceous plants, HMs are taken up by roots and transported into the root cells via transmembrane carriers for nutritional ions. The HMs absorbed by root cells can be further translocated to the xylem vessels and unloaded into the xylem sap, thereby reaching the aerial parts of plants. HMs can be sequestered in the cell walls, vacuoles and the Golgi apparatuses. Plant roots initially perceive HM stress and trigger the signal transduction, thereby mediating changes at the molecular, physiological, and microstructural level. Signaling molecules such as phytohormones, reactive oxygen species (ROS) and nitric oxide (NO), modulate plant responses to HMs via differentially expressed genes, activation of the antioxidative system and coordinated cross talk among different signaling molecules. A number of genes participated in HM uptake, transport, sequestration and detoxification have been functionally characterized and transformed to target plants for enhancing phytoremediation efficiency. Fast growing woody plants hold an advantage over herbaceous plants for phytoremediation in terms of accumulation of high HM-amounts in their large biomass. Presumably, woody plants accumulate HMs using similar mechanisms as herbaceous counterparts, but the processes of HM accumulation and signal transduction can be more complex in woody plants.

  2. Heavy metal accumulation and signal transduction in herbaceous and woody plants: Paving the way for enhancing phytoremediation efficiency.

    Science.gov (United States)

    Luo, Zhi-Bin; He, Jiali; Polle, Andrea; Rennenberg, Heinz

    2016-11-01

    Heavy metal (HM)-accumulating herbaceous and woody plants are employed for phytoremediation. To develop improved strategies for enhancing phytoremediation efficiency, knowledge of the microstructural, physiological and molecular responses underlying HM-accumulation is required. Here we review the progress in understanding the structural, physiological and molecular mechanisms underlying HM uptake, transport, sequestration and detoxification, as well as the regulation of these processes by signal transduction in response to HM exposure. The significance of genetic engineering for enhancing phytoremediation efficiency is also discussed. In herbaceous plants, HMs are taken up by roots and transported into the root cells via transmembrane carriers for nutritional ions. The HMs absorbed by root cells can be further translocated to the xylem vessels and unloaded into the xylem sap, thereby reaching the aerial parts of plants. HMs can be sequestered in the cell walls, vacuoles and the Golgi apparatuses. Plant roots initially perceive HM stress and trigger the signal transduction, thereby mediating changes at the molecular, physiological, and microstructural level. Signaling molecules such as phytohormones, reactive oxygen species (ROS) and nitric oxide (NO), modulate plant responses to HMs via differentially expressed genes, activation of the antioxidative system and coordinated cross talk among different signaling molecules. A number of genes participated in HM uptake, transport, sequestration and detoxification have been functionally characterized and transformed to target plants for enhancing phytoremediation efficiency. Fast growing woody plants hold an advantage over herbaceous plants for phytoremediation in terms of accumulation of high HM-amounts in their large biomass. Presumably, woody plants accumulate HMs using similar mechanisms as herbaceous counterparts, but the processes of HM accumulation and signal transduction can be more complex in woody plants. PMID

  3. Transduction motif analysis of gastric cancer based on a human signaling network

    Energy Technology Data Exchange (ETDEWEB)

    Liu, G.; Li, D.Z.; Jiang, C.S.; Wang, W. [Fuzhou General Hospital of Nanjing Command, Department of Gastroenterology, Fuzhou, China, Department of Gastroenterology, Fuzhou General Hospital of Nanjing Command, Fuzhou (China)

    2014-04-04

    To investigate signal regulation models of gastric cancer, databases and literature were used to construct the signaling network in humans. Topological characteristics of the network were analyzed by CytoScape. After marking gastric cancer-related genes extracted from the CancerResource, GeneRIF, and COSMIC databases, the FANMOD software was used for the mining of gastric cancer-related motifs in a network with three vertices. The significant motif difference method was adopted to identify significantly different motifs in the normal and cancer states. Finally, we conducted a series of analyses of the significantly different motifs, including gene ontology, function annotation of genes, and model classification. A human signaling network was constructed, with 1643 nodes and 5089 regulating interactions. The network was configured to have the characteristics of other biological networks. There were 57,942 motifs marked with gastric cancer-related genes out of a total of 69,492 motifs, and 264 motifs were selected as significantly different motifs by calculating the significant motif difference (SMD) scores. Genes in significantly different motifs were mainly enriched in functions associated with cancer genesis, such as regulation of cell death, amino acid phosphorylation of proteins, and intracellular signaling cascades. The top five significantly different motifs were mainly cascade and positive feedback types. Almost all genes in the five motifs were cancer related, including EPOR, MAPK14, BCL2L1, KRT18, PTPN6, CASP3, TGFBR2, AR, and CASP7. The development of cancer might be curbed by inhibiting signal transductions upstream and downstream of the selected motifs.

  4. Role of Relaxation Time Scale in Noisy Signal Transduction

    OpenAIRE

    Alok Kumar Maity; Pinaki Chaudhury; Banik, Suman K

    2015-01-01

    Intra-cellular fluctuations, mainly triggered by gene expression, are an inevitable phenomenon observed in living cells. It influences generation of phenotypic diversity in genetically identical cells. Such variation of cellular components is beneficial in some contexts but detrimental in others. To quantify the fluctuations in a gene product, we undertake an analytical scheme for studying few naturally abundant linear as well as branched chain network motifs. We solve the Langevin equations ...

  5. The signal transduction mechanisms on the intestinal mucosa of rat following irradiation

    Energy Technology Data Exchange (ETDEWEB)

    You, J. H.; Kim, S. S.; Lee, K. J.; Lee, J. S. [Ewha Womans Univ., Seoul (Korea, Republic of). Coll. of Medicine

    1997-06-01

    Phospholipase C(PLC) isozymes play significant roles in signal transduction mechanism. The exact mechanisms of these signal transduction following irradiation, however, were not clearly documented. Thus, this study was planned to determine the biological significance of PLC, ras oncoprotein, EGFR, and PKC in damage and regeneration of rat intestinal mucosa following irradiation. Sixty Sprague-Dawley rats were irradiated to entire body with a single dose of 8Gy. The rats were divided into 5 groups according to the sacrifice days after irradiation. The expression of PLC, ras oncoprotein, EGRF PKC in each group were examined by the immunoblotting and immunohistochemistry. The histopathologic findings were observed using H and E stain, and the mitoses for the evidence of regeneration were counted using the light microscopy and PCNA kit. The phosphoinositide(PI) hydrolyzing activity assay was also done for the indirect evaluation of PLC-{gamma}1 activity. In the immunohistochemistry, the expression of PLC-{beta} was negative for all groups. The expression of PLC-{gamma}1 was highest in the group III followed by group II in the proliferative zone of mucosa. The expression of PKC-{delta}1 was strongly positive in group I followed by group II in the damaged surface epithelium. The above findings were also confirmed in the immunoblotting study. In the immunoblotting study, the expressions of PLC-{beta}, PLC-{gamma}1, and PLC-{delta}1 were the same as the results of immunohistochemistry. The expression of ras oncoprotein was weakly positive in groups II, III and IV and the expression of PKC was weakly positive in the group II and III. PLC-{gamma}1 mediated signal transduction including ras oncoprotein, EGFR, and PKC play a significant role in mucosal regeneration after irradiation. PLC-{delta}1 mediated signal transduction might have an important role in mucosal damage after irradiation. Further studies will be necessary to confirm the signal transduction mediating the PLC

  6. Involvement of nitric oxide in the signal transduction of salicylic acid regulating stomatal movement

    Institute of Scientific and Technical Information of China (English)

    2003-01-01

    The effects and the relationship between salicylic acid (SA) and nitric oxide (NO) on Vicia faba L. stomatal movement were studied. The results here showed that exogenous SA and NO induced stomatal closure, 100 μmol/L SA induced a rapid and striking NO increase in the cytosol of guard cells. This phenomenon was largely pre-vented by 200 μmol/L 2-phenyl-4,4,5,5-tetramethylimida-zoline-1-oxyl-3-oxide (PTIO), a specific NO scavenger, and 25 μmol/L NG-nitro-L-Arg-methyl eater (L-NAME), an in-hibitor of NO synthase (NOS) in mammalian cells that also inhibits plant NOS. In addition, SA-induced stomatal closure was largely prevented by PTIO and L-NAME. These results provide evidence that guard cells generate NO in response to SA via NOS-like activity, and that such NO production is required for full stomatal closure in response to SA. H-(1,2,4)-oxadiazole-[4,3-α]quinoxalin-1-one (ODQ), an inhibitor of guanylate cyclase, and nicotinamide, an antago-nist of cADPR production, inhibited the effects of SA- and NO-induced stomatal closure. It suggests that both cGMP and cADPR might mediate the signal transduction of SA and NO-induced stomatal closure.

  7. Role of acetylcholine on plant root-shoot signal transduction

    Institute of Scientific and Technical Information of China (English)

    2003-01-01

    The role of acetylcholine (ACh) on plant root- shoot communication was investigated using the root-split system of Vicia faba L. In the experiments, slight osmotic stress caused the decrease of ACh content in root tips and the xylem sap transported up per time unit from root tip to the shoot when the water potential of the shoot was kept unchanged. It also caused the decrease of ACh content in the abaxial epidermis. The decrease was highly correlative to the changes of transpiration rate, suggesting that the decrease of ACh content probably functions as a signal to regulate stomatal behavior. The effect of osmotic stress might be mainly through the inhibition of the ACh synthesis in root tip; thus further influences the ACh content in root tip, xylem sap and abaxial epidermis and resulting in the changes of stomatal behavior. These results provide new evidence that plants transduce positive and negative signals among roots and shoots to coordinate stomatal behavior and adapt to variable environments.

  8. Information theory and signal transduction systems: from molecular information processing to network inference.

    Science.gov (United States)

    Mc Mahon, Siobhan S; Sim, Aaron; Filippi, Sarah; Johnson, Robert; Liepe, Juliane; Smith, Dominic; Stumpf, Michael P H

    2014-11-01

    Sensing and responding to the environment are two essential functions that all biological organisms need to master for survival and successful reproduction. Developmental processes are marshalled by a diverse set of signalling and control systems, ranging from systems with simple chemical inputs and outputs to complex molecular and cellular networks with non-linear dynamics. Information theory provides a powerful and convenient framework in which such systems can be studied; but it also provides the means to reconstruct the structure and dynamics of molecular interaction networks underlying physiological and developmental processes. Here we supply a brief description of its basic concepts and introduce some useful tools for systems and developmental biologists. Along with a brief but thorough theoretical primer, we demonstrate the wide applicability and biological application-specific nuances by way of different illustrative vignettes. In particular, we focus on the characterisation of biological information processing efficiency, examining cell-fate decision making processes, gene regulatory network reconstruction, and efficient signal transduction experimental design.

  9. Plant Genes Involved in Symbiotic Sinal Perception/Signal Transduction

    DEFF Research Database (Denmark)

    Binder, A; Soyano, T; Hayashi, H;

    2014-01-01

    A host genetic programme that is initiated upon recognition of specific rhizobial Nod factors governs the symbiosis of legumes with nitrogen-fixing bacteria. This programme coordinates two major developmental processes that run in parallel in legume roots: de novo cortical cell division leading t...

  10. Multidrug resistance and retroviral transduction potential in human small cell lung cancer cell lines

    DEFF Research Database (Denmark)

    Theilade, M D; Gram, G J; Jensen, P B;

    1999-01-01

    blue colonies after X-Gal staining of the cells grown in soft agar. All examined SCLC cell lines were transducible with either vector. Transduction efficiencies varied from 5.7% to 33.5% independent of the presence of MDR. These results indicate that MDR does not severely impair transduction of SCLC......Multidrug resistance (MDR) remains a major problem in the successful treatment of small cell lung cancer (SCLC). New treatment strategies are needed, such as gene therapy specifically targeting the MDR cells in the tumor. Retroviral LacZ gene-containing vectors that were either pseudotyped for the...... gibbon ape leukemia virus (GALV-1) receptor or had specificity for the amphotropic murine leukemia virus (MLV-A) receptor were used for transduction of five SCLC cell lines differing by a range of MDR mechanisms. Transduction efficiencies in these cell lines were compared by calculating the percentage of...

  11. Multidrug resistance and retroviral transduction potential in human small cell lung cancer cell lines

    DEFF Research Database (Denmark)

    Theilade, M D; Gram, G J; Jensen, P B;

    1999-01-01

    Multidrug resistance (MDR) remains a major problem in the successful treatment of small cell lung cancer (SCLC). New treatment strategies are needed, such as gene therapy specifically targeting the MDR cells in the tumor. Retroviral LacZ gene-containing vectors that were either pseudotyped...... for the gibbon ape leukemia virus (GALV-1) receptor or had specificity for the amphotropic murine leukemia virus (MLV-A) receptor were used for transduction of five SCLC cell lines differing by a range of MDR mechanisms. Transduction efficiencies in these cell lines were compared by calculating the percentage...... of blue colonies after X-Gal staining of the cells grown in soft agar. All examined SCLC cell lines were transducible with either vector. Transduction efficiencies varied from 5.7% to 33.5% independent of the presence of MDR. These results indicate that MDR does not severely impair transduction of SCLC...

  12. A feedback control perspective on models of apoptosis signal transduction

    International Nuclear Information System (INIS)

    Apoptosis is a key regulator for replacing unused, old and damaged cells. Here we analyse three models of apoptosis. We deconstruct these models by linearising the models about the life steady state and applying methods from linear control theory. This control viewpoint uncovers a decentralised control scheme with a clear separation of plant and controller and reveals that the caspase inhibitors act as decentralised phase lead controllers

  13. Nanomechanoelectronic signal transduction scheme with metal-oxide-semiconductor field-effect transistor-embedded microcantilevers

    Science.gov (United States)

    Tark, Soo-Hyun; Srivastava, Arvind; Chou, Stanley; Shekhawat, Gajendra; Dravid, Vinayak P.

    2009-03-01

    We explore various metal-oxide-semiconductor field-effect transistor (MOSFET)-embedded microcantilever designs to assess their performance as an efficient nanomechanoelectronic signal transduction platform for monitoring deflection in microcantilever-based phenomena such as biochemical sensing and actuation. The current-voltage characteristics of embedded MOSFETs show current noise in the nanoampere range with a large signal-to-noise ratio sufficient to provide measureable output signal. The change in drain current with cantilever deflection is consistent with the effect of stress on carrier mobility and drain current reported in previous studies, validating that the MOSFET cantilevers can directly transduce deflection of a microcantilever into reproducible change in electrical signal.

  14. Modelling and simulation of signal transductions in an apoptosis pathway by using timed Petri nets

    Indian Academy of Sciences (India)

    Chen Li; Qi-Wei Ge; Mitsuru Nakata; Hiroshi Matsuno; Satoru Miyano

    2007-01-01

    This paper first presents basic Petri net components representing molecular interactions and mechanisms of signalling pathways, and introduces a method to construct a Petri net model of a signalling pathway with these components. Then a simulation method of determining the delay time of transitions, by using timed Petri nets – i.e. the time taken in firing of each transition – is proposed based on some simple principles that the number of tokens flowed into a place is equivalent to the number of tokens flowed out. Finally, the availability of proposed method is confirmed by observing signalling transductions in biological pathways through simulation experiments of the apoptosis signalling pathways as an example.

  15. Crystal structure of Pseudomonas aeruginosa bacteriophytochrome: Photoconversion and signal transduction

    Energy Technology Data Exchange (ETDEWEB)

    Yang, Xiaojing; Kuk, Jane; Moffat, Keith (UC)

    2008-11-12

    Phytochromes are red-light photoreceptors that regulate light responses in plants, fungi, and bacteria via reversible photoconversion between red (Pr) and far-red (Pfr) light-absorbing states. Here we report the crystal structure at 2.9 {angstrom} resolution of a bacteriophytochrome from Pseudomonas aeruginosa with an intact, fully photoactive photosensory core domain in its dark-adapted Pfr state. This structure reveals how unusual interdomain interactions, including a knot and an 'arm' structure near the chromophore site, bring together the PAS (Per-ARNT-Sim), GAF (cGMP phosphodiesterase/adenyl cyclase/FhlA), and PHY (phytochrome) domains to achieve Pr/Pfr photoconversion. The PAS, GAF, and PHY domains have topologic elements in common and may have a single evolutionary origin. We identify key interactions that stabilize the chromophore in the Pfr state and provide structural and mutational evidence to support the essential role of the PHY domain in efficient Pr/Pfr photoconversion. We also identify a pair of conserved residues that may undergo concerted conformational changes during photoconversion. Modeling of the full-length bacteriophytochrome structure, including its output histidine kinase domain, suggests how local structural changes originating in the photosensory domain modulate interactions between long, cross-domain signaling helices at the dimer interface and are transmitted to the spatially distant effector domain, thereby regulating its histidine kinase activity.

  16. Neural signal transduction aided by noise in multisynaptic excitatory and inhibitory pathways with saturation

    Science.gov (United States)

    Duan, Fabing; Chapeau-Blondeau, François; Abbott, Derek

    2011-08-01

    We study the stochastic resonance phenomenon in saturating dynamical models of neural signal transduction, at the synaptic stage, wherein the noise in multipathways enhances the processing of neuronal information integrated by excitatory and inhibitory synaptic currents. For an excitatory synaptic pathway, the additive intervention of an inhibitory pathway reduces the stochastic resonance effect. However, as the number of synaptic pathways increases, the signal transduction is greatly improved for parallel multipathways that feature both excitation and inhibition. The obtained results lead us to the realization that the collective property of inhibitory synapses assists neural signal transmission, and a parallel array of neurons can enhance their responses to multiple synaptic currents by adjusting the contributions of excitatory and inhibitory currents.

  17. Mechanical Signal Transduction in Countermeasures to Muscle Atrophy

    Science.gov (United States)

    Tidball, James G.; Chu, Amy (Technical Monitor)

    2002-01-01

    We have shown that modifications in muscle use result in changes in the expression and activity of calpains and nitric oxide synthase (NOS). Although muscle unloading for 10 days produced no change in the concentrations of calpain 1 or 2 and no change in calpain activation, muscle reloading produced a 90% increase in calpain 2 concentration. We developed an in vitro model to test our hypothesis that nitric oxide can inhibit cytoskeletal breakdown in skeletal muscle cells by inhibiting calpain cleavage of talin. Talin was selected because it is a well-characterized calpain substrate and it is codistributed with calpain in muscle cells. We found that intermittant loading during hindlimb suspension that is sufficient to prevent muscle mass loss that occurs during muscle unloading is also sufficient to prevent the decrease in NOS expression that normally occurs during hindlimb unloading. These findings indicate that therapeutics directed toward regulating the calpain/calpastatin system may be beneficial in preventing muscle mass loss in muscle injury, unloading and disease.

  18. Signal transduction through p53-dependent pathway after low-dose ionizing radiation

    Energy Technology Data Exchange (ETDEWEB)

    Ohnishi, T.; Matsumoto, H.; Wang Xinjiang [Nara Medical Univ., Nara (Japan)

    1995-12-31

    In the study of cell-cycle events, recent attention has focused on the signal transduction pathway in which a tumor-suppressor protein, wild-type (wt) p53 protein, acts as the key protein. A major advance in recent years has been the partial elucidation of the G{sub 1}-arrest mechanism. However, the transcriptional regulation mechanisms of components of the cell-cycle machinery remain unknown. We have investigated the induction of p53, WAF1, and cdk2 after gamma-ray irradiation using two human glioblastoma cell lines, U-87MG bearing the wt p53 gene and the other, T98G, a mutant gene. After the cells have been irradiated with gamma rays at 3 Gy, the level of p53 and WAF1 mRNAs in U-87MG increased gradually for up to 10 h, whereas these mRNAs were overexpressed in T98G, and these levels remained relatively stable after irradiation. In an attempt to examine the induction of cdk2 after gamma-ray irradiation, we analyzed the level of cdk2 mRNA using the reverse transcriptase-polymerase chain reaction (RT-PCR) technique. We calculated the amounts of cdk2 mRNA relative to that of b-actin mRNA in both cell lines, then plotted them against those in nonirradiated cells. After irradiation, the level of cdk2 mRNA in U-87MG gradually increased more than twofold by 10 h after gamma-ray irradiation, whereas the level of the mRNA in T98G remained relatively stable after irradiation. This result demonstrates that wtp53 induces the expression of not only WAF1 but also cdk2. The induction of wt p53 protein accumulation in rats exposed to x radiation is also discussed.

  19. Cellular release of and response to ATP as key determinants of the set-point of signal transduction pathways.

    Science.gov (United States)

    Ostrom, R S; Gregorian, C; Insel, P A

    2000-04-21

    The determinants of "basal" activity of signaling pathways regulating cellular responses are poorly defined. One possibility is that cells release factors to establish the set-point of such pathways. Here we show that treatment of Madin-Darby canine kidney cells with the nucleotidase apyrase decreases basal arachidonic acid release and cAMP production 30-40% and that inhibitors of P2Y receptor action also affect basal and forskolin-stimulated cAMP accumulation. Changing medium prominently increases extracellular levels of ATP in Madin-Darby canine kidney, COS-7, and HEK-293 cells. Mechanical stimulation of ATP release likely occurs in virtually every experimental protocol with cultured cells, implicating such release and P2Y receptor activation as critical in establishing the set-point for signal transduction pathways. PMID:10766795

  20. Interplay of Specific Trans- and Juxtamembrane Interfaces in Plexin A3 Dimerization and Signal Transduction.

    Science.gov (United States)

    Barton, Rachael; Khakbaz, Pouyan; Bera, Indrani; Klauda, Jeffery B; Iovine, M Kathryn; Berger, Bryan W

    2016-09-01

    Plexins are transmembrane proteins that serve as guidance receptors during angiogenesis, lymphangiogenesis, neuronal development, and zebrafish fin regeneration, with a putative role in cancer metastasis. Receptor dimerization or clustering, induced by extracellular ligand binding but modulated in part by the plexin transmembrane (TM) and juxtamembrane (JM) domains, is thought to drive plexin activity. Previous studies indicate that isolated plexin TM domains interact through a conserved, small-x3-small packing motif, and the cytosolic JM region interacts through a hydrophobic heptad repeat; however, the roles and interplay of these regions in plexin signal transduction remain unclear. Using an integrated experimental and simulation approach, we find disruption of the small-x3-small motifs in the Danio rerio Plexin A3 TM domain enhances dimerization of the TM-JM domain by enhancing JM-mediated dimerization. Furthermore, mutations of the cytosolic JM heptad repeat that disrupt dimerization do so even in the presence of TM domain mutations. However, mutations to the small-x3-small TM interfaces also disrupt Plexin A3 signaling in a zebrafish axonal guidance assay, indicating the importance of this TM interface in signal transduction. Collectively, our experimental and simulation results demonstrate that multiple TM and JM interfaces exist in the Plexin A3 homodimer, and these interfaces independently regulate dimerization that is important in Plexin A3 signal transduction.

  1. prpC-related signal transduction is influenced by copper, membrane integrity and the alpha cleavage site

    Institute of Scientific and Technical Information of China (English)

    Cathryn L Haigh; Victoria A Lewis; Laura J Vella; Colin L Masters; Andrew F Hill; Victoria A Lawson; Steven J Collins

    2009-01-01

    The copper-binding, membrane-anchored, cellular prion protein (PrPC) has two constitutive cleavage sites pro-ducing distinct N- and C-terminal fragments (N1/C1 and N2/C2). Using RKI3 cells expressing either human PrPC, mouse PrPC or mouse PrPC carrying the 3F4 epitope, this study explored the influence of the PrPC primary sequence on endoproteolytic cleavage and one putative PrPC function, MAP kinase signal transduction, in response to exoge-nous copper with or without a perturbed membrane environment. PrPC primary sequence, especially that around the N1/C1 cleavage site, appeared to influence basal levels of proteolysis at this location and extracellular signal-regulat-ed kinase 1/2 (ERK1/2) phosphorylation, with increased processing demonstrating an inverse relationship with basal ERK1/2 activation. Human PrPC showed increased N1/C1 cleavage in response to copper alone, accompanied by spe-cific p38 and JNK/SAPK phosphorylation. Combined exposure to copper plus the cholesterol-sequestering antibiotic filipin resulted in a mouse PrPC-specific substantial increase in signal protein phosphorylation, accompanied by an increase in N1/C1 cleavage. Mouse PrPC harboring the human N1/C1 cleavage site assumed more human-like profiles basally and in response to copper and altered membrane environments. Our results demonstrate that the PrPC pri-mary sequence around the N1/C1 cleavage site influences endoproteolytic processing at this location, which appears linked to MAP kinase signal transduction both basally and in response to copper. Further, the primary sequence ap-pears to confer a mutual dependence of N1/C1 cleavage and membrane integrity on the fidelity of prpC-related signal transduction in response to exogenous stimuli.

  2. Ubiquitin-Related Roles of β-Arrestins in Endocytic Trafficking and Signal Transduction.

    Science.gov (United States)

    Jean-Charles, Pierre-Yves; Rajiv, Vishwaesh; Shenoy, Sudha K

    2016-10-01

    The non-visual arrestins, β-arrestin1, and β-arrestin2 were originally identified as proteins that bind to seven-transmembrane receptors (7TMRs, also called G protein-coupled receptors, GPCRs) and block heterotrimeric G protein activation, thus leading to desensitization of transmembrane signaling. However, as subsequent discoveries have continually demonstrated, their functionality is not constrained to desensitization. They are now recognized for their critical roles in mediating intracellular trafficking of 7TMRs, growth factor receptors, ion transporters, ion channels, nuclear receptors, and non-receptor proteins. Additionally, they function as crucial mediators of ubiquitination of 7TMRs as well as other receptors and non-receptor proteins. Recently, emerging studies suggest that a class of proteins with predicted structural features of β-arrestins regulate substrate ubiquitination in yeast and higher mammals, lending support to the idea that the adaptor role of β-arrestins in protein ubiquitination is evolutionarily conserved. β-arrestins also function as scaffolds for kinases and transduce signals from 7TMRs through pathways that do not require G protein activation. Remarkably, the endocytic and scaffolding functions of β-arrestin are intertwined with its ubiquitination status; the dynamic and site specific ubiquitination on β-arrestin plays a critical role in stabilizing β-arrestin-7TMR association and the formation of signalosomes. This review summarizes the current findings on ubiquitin-dependent regulation of 7TMRs as well as β-arrestins and the potential role of reversible ubiquitination as a "biological switch" in signal transduction. J. Cell. Physiol. 231: 2071-2080, 2016. © 2016 Wiley Periodicals, Inc.

  3. Role of functionality in two-component signal transduction: A stochastic study

    Science.gov (United States)

    Maity, Alok Kumar; Bandyopadhyay, Arnab; Chaudhury, Pinaki; Banik, Suman K.

    2014-03-01

    We present a stochastic formalism for signal transduction processes in a bacterial two-component system. Using elementary mass action kinetics, the proposed model takes care of signal transduction in terms of a phosphotransfer mechanism between the cognate partners of a two-component system, viz., the sensor kinase and the response regulator. Based on the difference in functionality of the sensor kinase, the noisy phosphotransfer mechanism has been studied for monofunctional and bifunctional two-component systems using the formalism of the linear noise approximation. Steady-state analysis of both models quantifies different physically realizable quantities, e.g., the variance, the Fano factor (variance/mean), and mutual information. The resultant data reveal that both systems reliably transfer information of extracellular environment under low external stimulus and in a high-kinase-and-phosphatase regime. We extend our analysis further by studying the role of the two-component system in downstream gene regulation.

  4. The LisRK Signal Transduction System Determines the Sensitivity of Listeria monocytogenes to Nisin and Cephalosporins

    OpenAIRE

    Cotter, Paul D.; Guinane, Caitriona M.; Hill, Colin

    2002-01-01

    The Listeria monocytogenes two-component signal transduction system, LisRK, initially identified in strain LO28, plays a significant role in the virulence potential of this important food-borne pathogen. Here, it is shown that, in addition to its major contribution in responding to ethanol, pH, and hydrogen peroxide stresses, LisRK is involved in the ability of the cell to tolerate important antimicrobials used in food and in medicine, e.g., the lantibiotic nisin and the cephalosporin family ...

  5. TIP30 regulates apoptosis-related genes in its apoptotic signal transduction pathway

    Institute of Scientific and Technical Information of China (English)

    Mei Shi; Xia Zhang; Ping Wang; Hong-Wei Zhang; Bai-He Zhang; Meng-Chao Wu

    2005-01-01

    levels by TIP30 might be a pre-requisite for Bax and Bax/Bcl-xl ratio increase. We hypothesized that TIP30 might regulate Bax gene partly through p53, which sensitizes cells to apoptosis by involving a p53 apoptosis signal transduction pathway.CONCLUSION: TIP30 plays an important role in predisposing hepatoblastoma cells to apoptosis through regulating expression levels of these genes. Ad-TIP30carrying exogenous TIP30-anti-tumor genes may be regarded as a potential candidate for the treatment of hepatocellular carcinoma.

  6. Development of automated high throughput single molecular microfluidic detection platform for signal transduction analysis

    Science.gov (United States)

    Huang, Po-Jung; Baghbani Kordmahale, Sina; Chou, Chao-Kai; Yamaguchi, Hirohito; Hung, Mien-Chie; Kameoka, Jun

    2016-03-01

    Signal transductions including multiple protein post-translational modifications (PTM), protein-protein interactions (PPI), and protein-nucleic acid interaction (PNI) play critical roles for cell proliferation and differentiation that are directly related to the cancer biology. Traditional methods, like mass spectrometry, immunoprecipitation, fluorescence resonance energy transfer, and fluorescence correlation spectroscopy require a large amount of sample and long processing time. "microchannel for multiple-parameter analysis of proteins in single-complex (mMAPS)"we proposed can reduce the process time and sample volume because this system is composed by microfluidic channels, fluorescence microscopy, and computerized data analysis. In this paper, we will present an automated mMAPS including integrated microfluidic device, automated stage and electrical relay for high-throughput clinical screening. Based on this result, we estimated that this automated detection system will be able to screen approximately 150 patient samples in a 24-hour period, providing a practical application to analyze tissue samples in a clinical setting.

  7. Functional characterization of WalRK: A two-component signal transduction system from Bacillus anthracis

    Directory of Open Access Journals (Sweden)

    Alisha Dhiman

    2014-01-01

    Full Text Available Two-component signal transduction systems (TCS, consisting of a sensor histidine protein kinase and its cognate response regulator, are an important mode of environmental sensing in bacteria. Additionally, they have been found to regulate virulence determinants in several pathogens. Bacillus anthracis, the causative agent of anthrax and a bioterrorism agent, harbours 41 pairs of TCS. However, their role in its pathogenicity has remained largely unexplored. Here, we show that WalRK of B. anthracis forms a functional TCS which exhibits some species-specific functions. Biochemical studies showed that domain variants of WalK, the histidine kinase, exhibit classical properties of autophosphorylation and phosphotransfer to its cognate response regulator WalR. Interestingly, these domain variants also show phosphatase activity towards phosphorylated WalR, thereby making WalK a bifunctional histidine kinase/phosphatase. An in silico regulon determination approach, using a consensus binding sequence from Bacillus subtilis, provided a list of 30 genes that could form a putative WalR regulon in B. anthracis. Further, electrophoretic mobility shift assay was used to show direct binding of purified WalR to the upstream regions of three putative regulon candidates, an S-layer protein EA1, a cell division ABC transporter FtsE and a sporulation histidine kinase KinB3. Our work lends insight into the species-specific functions and mode of action of B. anthracis WalRK.

  8. Signal transduction pathways mediating parathyroid hormone regulation of osteoblastic gene expression

    Science.gov (United States)

    Partridge, N. C.; Bloch, S. R.; Pearman, A. T.

    1994-01-01

    Parathyroid hormone (PTH) plays a central role in regulation of calcium metabolism. For example, excessive or inappropriate production of PTH or the related hormone, parathyroid hormone related protein (PTHrP), accounts for the majority of the causes of hypercalcemia. Both hormones act through the same receptor on the osteoblast to elicit enhanced bone resorption by the osteoclast. Thus, the osteoblast mediates the effect of PTH in the resorption process. In this process, PTH causes a change in the function and phenotype of the osteoblast from a cell involved in bone formation to one directing the process of bone resorption. In response to PTH, the osteoblast decreases collagen, alkaline phosphatase, and osteopontin expression and increases production of osteocalcin, cytokines, and neutral proteases. Many of these changes have been shown to be due to effects on mRNA abundance through either transcriptional or post-transcriptional mechanisms. However, the signal transduction pathway for the hormone to cause these changes is not completely elucidated in any case. Binding of PTH and PTHrP to their common receptor has been shown to result in activation of protein kinases A and C and increases in intracellular calcium. The latter has not been implicated in any changes in mRNA of osteoblastic genes. On the other hand activation of PKA can mimic all the effects of PTH; protein kinase C may be involved in some responses. We will discuss possible mechanisms linking PKA and PKC activation to changes in gene expression, particularly at the nuclear level.

  9. Requirement of JIP scaffold proteins for NMDA-mediated signal transduction

    OpenAIRE

    Kennedy, Norman J.; Martin, Gilles; Ehrhardt, Anka G.; Cavanagh-Kyros, Julie; Kuan, Chia-Yi; Rakic, Pasko; Richard A Flavell; Treistman, Steven N.; Davis, Roger J

    2007-01-01

    JIP scaffold proteins are implicated in the regulation of protein kinase signal transduction pathways. To test the physiological role of these scaffold proteins, we examined the phenotype of compound mutant mice that lack expression of JIP proteins. These mice were found to exhibit severe defects in N-methyl-D-aspartic acid (NMDA) receptor function, including decreased NMDA-evoked current amplitude, cytoplasmic Ca++, and gene expression. The decreased NMDA receptor activity in JIP-deficient n...

  10. Screening and identification of key signal transduction pathways in pulmonary silicotic fibrosis

    Institute of Scientific and Technical Information of China (English)

    薛荣

    2014-01-01

    Objective To investigate the differential gene expression profile of the lung tissues in experimental silicosis rats and to screen for and identify the key signal transduction pathways in pulmonary silicotic fibrosis.Methods A total of 80 rats were randomly divided into control group(n=40)and silica-instilled group(n=40).Each group was equally divided into five subgroups,and each subgroup was treated at 1,7,14,21,

  11. Signal transduction of erythrocytes after specific binding of ecdysterone and cholesterol immobilized on nanodispersed magnetite

    Energy Technology Data Exchange (ETDEWEB)

    Mykhaylyk, O.M. E-mail: helek@iptelecom.net.ua; Kotzuruba, A.V.; Buchanevich, O.M.; Korduban, A.M.; Meged, E.F.; Gulaya, N.M

    2001-07-01

    Concurrent binding of cholesterol and ecdysterone immobilized on nanodispersed magnetite to intact rat erythrocytes was investigated. Several binding components on erythrocyte plasma membrane with different affinities were revealed in the range of 10{sup -15}-10{sup -8} M. The specific binding modulates signal transduction through adenylate cyclase and guanylate cyclase systems as manifested by the decrease in cAMP and increase in cGMP second messenger production.

  12. Signal transduction by erythrocytes on specific binding of doxorubicin immobilized on nanodispersed magnetite

    Energy Technology Data Exchange (ETDEWEB)

    Mykhaylyk, Olga [Institute Applied Problems Physics and Biophysics, NAS, Sluzhbova 3, UA-03142 Kyiv (Ukraine)]. E-mail: Olga.Mykhaylyk@gmx.net; Kotzuruba, Anatoliy [Institute of Biochemistry, NAS, Leontovicha 9, UA-01030 Kyiv (Ukraine); Dudchenko, Nataliya [Institute Applied Problems Physics and Biophysics, NAS, Sluzhbova 3, UA-03142 Kyiv (Ukraine); Toerok, Gyula [Research Institute for Solid State Physics and Optics, H-1525 Budapest, P.O. Box 49 (Hungary)

    2005-05-15

    Two specific binding sites for doxorubicin were revealed at the plasma membrane of human erythrocytes on investigation of the binding of doxorubicin magnetic nanoconjugates. Free and conjugated doxorubicins modulated signal transduction in erythrocytes in a similar way. Both up-regulated nitric oxide and cyclic GMP (cGMP) and down-regulated cyclic AMP (cAMP) production and stabilize the membranes of damaged erythrocytes.

  13. INOH: ontology-based highly structured database of signal transduction pathways

    OpenAIRE

    Yamamoto, Satoko; Sakai, Noriko; Nakamura, Hiromi; Fukagawa, Hiroshi; Fukuda, Ken; Takagi, Toshihisa

    2011-01-01

    The Integrating Network Objects with Hierarchies (INOH) database is a highly structured, manually curated database of signal transduction pathways including Mammalia, Xenopus laevis, Drosophila melanogaster, Caenorhabditis elegans and canonical. Since most pathway knowledge resides in scientific articles, the database focuses on curating and encoding textual knowledge into a machine-processable form. We use a hierarchical pathway representation model with a compound graph, and every pathway c...

  14. Calcium and protein phosphorylation in the transduction of gravity signal in corn roots

    Science.gov (United States)

    Friedmann, M.; Poovaiah, B. W.

    1991-01-01

    The involvement of calcium and protein phosphorylation in the transduction of gravity signal was studied using corn roots of a light-insensitive variety (Zea mays L., cv. Patriot). The gravitropic response was calcium-dependent. Horizontal placement of roots preloaded with 32P for three minutes resulted in changes in protein phosphorylation of polypeptides of 32 and 35 kD. Calcium depletion resulted in decreased phosphorylation of these phosphoproteins and replenishment of calcium restored the phosphorylation.

  15. Prion Infection of Mouse Brain Reveals Multiple New Upregulated Genes Involved in Neuroinflammation or Signal Transduction

    OpenAIRE

    Carroll, James A.; Striebel, James F.; Race, Brent; Phillips, Katie; Chesebro, Bruce

    2014-01-01

    Gliosis is often a preclinical pathological finding in neurodegenerative diseases, including prion diseases, but the mechanisms facilitating gliosis and neuronal damage in these diseases are not understood. To expand our knowledge of the neuroinflammatory response in prion diseases, we assessed the expression of key genes and proteins involved in the inflammatory response and signal transduction in mouse brain at various times after scrapie infection. In brains of scrapie-infected mice at pre...

  16. Postsynaptic Signal Transduction Models for Long-Term Potentiation and Depression

    OpenAIRE

    Manninen, Tiina; Hituri, Katri; Kotaleski, Jeanette Hellgren; Blackwell, Kim T; Linne, Marja-Leena

    2010-01-01

    More than a hundred biochemical species, activated by neurotransmitters binding to transmembrane receptors, are important in long-term potentiation (LTP) and long-term depression (LTD). To investigate which species and interactions are critical for synaptic plasticity, many computational postsynaptic signal transduction models have been developed. The models range from simple models with a single reversible reaction to detailed models with several hundred kinetic reactions. In this study, mor...

  17. Characterization of the human oncogene SCL/TAL1 interrupting locus (Stil) mediated Sonic hedgehog (Shh) signaling transduction in proliferating mammalian dopaminergic neurons

    Energy Technology Data Exchange (ETDEWEB)

    Sun, Lei [Department of Biological Sciences, University of Notre Dame, Notre Dame, IN 46556 (United States); Department of Physiology, Nankai University School of Medicine, Tianjin 300071 (China); Carr, Aprell L. [Department of Biological Sciences, University of Notre Dame, Notre Dame, IN 46556 (United States); Center for Zebrafish Research, University of Notre Dame, Notre Dame, IN 46556 (United States); Li, Ping; Lee, Jessica; McGregor, Mary [Department of Biological Sciences, University of Notre Dame, Notre Dame, IN 46556 (United States); Li, Lei, E-mail: Li.78@nd.edu [Department of Biological Sciences, University of Notre Dame, Notre Dame, IN 46556 (United States); Center for Zebrafish Research, University of Notre Dame, Notre Dame, IN 46556 (United States)

    2014-07-11

    Highlights: • Stil is a human oncogene that is conserved in vertebrate species. • Stil functions in the Shh pathway in mammalian cells. • The expression of Stil is required for mammalian dopaminergic cell proliferation. - Abstract: The human oncogene SCL/TAL1 interrupting locus (Stil) is highly conserved in all vertebrate species. In humans, the expression of Stil is involved in cancer cell survival, apoptosis and proliferation. In this research, we investigated the roles of Stil expression in cell proliferation of mammalian dopaminergic (DA) PC12 cells. Stil functions through the Sonic hedgehog (Shh) signal transduction pathway. Co-immunoprecipitation tests revealed that STIL interacts with Shh downstream components, which include SUFU and GLI1. By examining the expression of Stil, Gli1, CyclinD2 (cell-cycle marker) and PCNA (proliferating cell nuclear antigen), we found that up-regulation of Stil expression (transfection with overexpression plasmids) increased Shh signaling transduction and PC12 cell proliferation, whereas down-regulation of Stil expression (by shRNA) inhibited Shh signaling transduction, and thereby decreased PC12 cell proliferation. Transient transfection of PC12 cells with Stil knockdown or overexpression plasmids did not affect PC12 cell neural differentiation, further indicating the specific roles of Stil in cell proliferation. The results from this research suggest that Stil may serve as a bio-marker for neurological diseases involved in DA neurons, such as Parkinson’s disease.

  18. Structural insights of homotypic interaction domains in the ligand-receptor signal transduction of tumor necrosis factor (TNF)

    Science.gov (United States)

    Park, Young-Hoon; Jeong, Mi Suk; Jang, Se Bok

    2016-01-01

    Several members of tumor necrosis factor receptor (TNFR) superfamily that these members activate caspase-8 from death-inducing signaling complex (DISC) in TNF ligand-receptor signal transduction have been identified. In the extrinsic pathway, apoptotic signal transduction is induced in death domain (DD) superfamily; it consists of a hexahelical bundle that contains 80 amino acids. The DD superfamily includes about 100 members that belong to four subfamilies: death domain (DD), caspase recruitment domain (CARD), pyrin domain (PYD), and death effector domain (DED). This superfamily contains key building blocks: with these blocks, multimeric complexes are formed through homotypic interactions. Furthermore, each DD-binding event occurs exclusively. The DD superfamily regulates the balance between death and survival of cells. In this study, the structures, functions, and unique features of DD superfamily members are compared with their complexes. By elucidating structural insights of DD superfamily members, we investigate the interaction mechanisms of DD domains; these domains are involved in TNF ligand-receptor signaling. These DD superfamily members play a pivotal role in the development of more specific treatments of cancer. [BMB Reports 2016; 49(3): 159-166] PMID:26615973

  19. 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.)

  20. Progress in the participation of Ca2+-calmodulin in heat shock signal transduction

    Institute of Scientific and Technical Information of China (English)

    Rengang Zhou; Bing Li; Hongtao Liu; Daye Sun

    2009-01-01

    A novel heat shock (HS) signal transduction pathway in plants for the participation of Ca2+-calmodulin (CAM) in HS signal trans-duction was identified. HS induces a rapid increase in intracellular free calcium ion levels ([Ca2+]i), and the involvement of phospholipase C-inositol 1,4,5-trisphosphate is one of the factors leading to elevation in [Ca2+]i induced by HS. HS also increases the expression of the CaM gene and the accumulation of the CaM protein. The CaM isoform, AtCaM3, in Arabidopsis is a key member in the HS signal trans-duction pathway. AtCaM3 regulates the activity of CaM-binding protein kinase (AtCBK3) or protein phosphatase (AtPP7), promoting the activation of the HS transcription factor, AtHSFA1a, by phosphorylation/dephosphorylation and the expression of heat shock pro-tein genes, then improving heat tolerance in plants.

  1. THE ENHANCED GREEN FLUORESCENT PROTEIN AS A MARKER FOR HUMAN TUMOR CELLS LABELLED BY RETROVIRAL TRANSDUCTION

    Institute of Scientific and Technical Information of China (English)

    傅建新; 王玮; 白霞; 卢大儒; 阮长耿; 陈子兴

    2002-01-01

    Objective: To investigate the feasibility of marking the human tumor cells with enhanced green fluorescent protein (EGFP) in vitro. Methods: The retroviral vector LGSN encoding EGFP was constructed and three human tumor cell lines were infected with LGSN amphotropic virus. Tumor cell lines that stably express EGFP were selected with G418. The integration and expression of EGFP gene were analyzed by polymerase chain reaction, and flow cytometry (FCM). Results: After gene transfection and ping-pong transduction, amphotropic producer line Am12/LGSN was generated with a stable green fluorescence signal readily detectable by FCM in up to 97% of examined cells. The viral titer in the supernatants was up to 8.2×105CFU/ml. After transduction and selection, G418-resistant leukemia K562, mammary carcinoma MCF-7, and bladder cancer 5637 cells were developed, in which the integration of both EGFP and neomycin resistance gene was confirmed by DNA amplification. In comparison with uninfected cells, FCM analysis revealed EGFP expression in up to 90% (range 85.5%~90.0%) of tumor cells containing LGSN provirus. Conclusion: The retroviral vector LGSN can effectively mark the human tumor cells with a stably EGFP expression which may be in studying tumor growth, metastasis and angiogenesis.

  2. Transfer functions for protein signal transduction: application to a model of striatal neural plasticity.

    Science.gov (United States)

    Scheler, Gabriele

    2013-01-01

    We present a novel formulation for biochemical reaction networks in the context of protein signal transduction. The model consists of input-output transfer functions, which are derived from differential equations, using stable equilibria. We select a set of "source" species, which are interpreted as input signals. Signals are transmitted to all other species in the system (the "target" species) with a specific delay and with a specific transmission strength. The delay is computed as the maximal reaction time until a stable equilibrium for the target species is reached, in the context of all other reactions in the system. The transmission strength is the concentration change of the target species. The computed input-output transfer functions can be stored in a matrix, fitted with parameters, and even recalled to build dynamical models on the basis of state changes. By separating the temporal and the magnitudinal domain we can greatly simplify the computational model, circumventing typical problems of complex dynamical systems. The transfer function transformation of biochemical reaction systems can be applied to mass-action kinetic models of signal transduction. The paper shows that this approach yields significant novel insights while remaining a fully testable and executable dynamical model for signal transduction. In particular we can deconstruct the complex system into local transfer functions between individual species. As an example, we examine modularity and signal integration using a published model of striatal neural plasticity. The modularizations that emerge correspond to a known biological distinction between calcium-dependent and cAMP-dependent pathways. Remarkably, we found that overall interconnectedness depends on the magnitude of inputs, with higher connectivity at low input concentrations and significant modularization at moderate to high input concentrations. This general result, which directly follows from the properties of individual transfer

  3. Transfer functions for protein signal transduction: application to a model of striatal neural plasticity.

    Directory of Open Access Journals (Sweden)

    Gabriele Scheler

    Full Text Available We present a novel formulation for biochemical reaction networks in the context of protein signal transduction. The model consists of input-output transfer functions, which are derived from differential equations, using stable equilibria. We select a set of "source" species, which are interpreted as input signals. Signals are transmitted to all other species in the system (the "target" species with a specific delay and with a specific transmission strength. The delay is computed as the maximal reaction time until a stable equilibrium for the target species is reached, in the context of all other reactions in the system. The transmission strength is the concentration change of the target species. The computed input-output transfer functions can be stored in a matrix, fitted with parameters, and even recalled to build dynamical models on the basis of state changes. By separating the temporal and the magnitudinal domain we can greatly simplify the computational model, circumventing typical problems of complex dynamical systems. The transfer function transformation of biochemical reaction systems can be applied to mass-action kinetic models of signal transduction. The paper shows that this approach yields significant novel insights while remaining a fully testable and executable dynamical model for signal transduction. In particular we can deconstruct the complex system into local transfer functions between individual species. As an example, we examine modularity and signal integration using a published model of striatal neural plasticity. The modularizations that emerge correspond to a known biological distinction between calcium-dependent and cAMP-dependent pathways. Remarkably, we found that overall interconnectedness depends on the magnitude of inputs, with higher connectivity at low input concentrations and significant modularization at moderate to high input concentrations. This general result, which directly follows from the properties of

  4. 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

  5. Identification of intracellular domains in the growth hormone receptor involved in signal transduction

    Energy Technology Data Exchange (ETDEWEB)

    Billestrup, N.; Allevato, G.; Moldrup, A. [Hagedorn Research Lab., Gentofte (Denmark)] [and others

    1994-12-31

    The growth hormone (GH) receptor belongs to the GH/prolactin/cytokine super-family of receptors. The signal transduction mechanism utilized by this class of receptors remains largely unknown. In order to identify functional domains in the intracellular region of the GH receptor we generated a number of GH receptor mutants and analyzed their function after transfection into various cell lines. A truncated GH receptor missing 184 amino acids at the C-terminus was unable to medite GH effects on transcription of the Spi 2.1 and insulin genes. However, this mutant was fully active in mediating GH-stimulated metabolic effects such as protein synthesis and lipolysis. Furthermore, this mutant GH receptor internalized rapidly following GH binding. Another truncated GH receptor lacking all but five amino acids of the cytoplasmic domain could not mediate any effects of GH nor did it internalize. Deletion of the proline-rich region or changing the four prolines to alanines also resulted in a GH receptor deficient in signaling. Mutation of phenylalanine 346 to alanine resulted in a GH receptor which did not internalize rapidly; however, this mutant GH receptor was capable of mediating GH-stimulated transcription as well as metabolic effects. These results indicate that the intracellular part of the GH receptor can be divided into at least three functional domains: (1) for transcriptional activity, two domains are involved, one located in the C-terminal 184 amino acids and the other in the proline-rich domain; (2) for metabolic effects, a domain located in or near the proline-rich region is of importance; and (3) for internalization, phenylalanine 346 is necessary. 28 refs., 1 fig.

  6. Towards biochemical filters with a sigmoidal response to pH changes: buffered biocatalytic signal transduction

    Science.gov (United States)

    Pita, Marcos; Privman, Vladimir; Arugula, Mary A.; Melnikov, Dmitriy; Bocharova, Vera; Katz, Evgeny

    We realize a biochemical filtering process by introducing a buffer in a biocatalytic signal-transduction logic system based on the function of an enzyme, esterase. The input, ethyl butyrate, is converted into butyric acid-the output signal, which in turn is measured by the drop in the pH value. The developed approach offers a versatile "network element" for increasing the complexity of biochemical information processing systems. Evaluation of an optimal regime for quality filtering is accomplished in the framework of a kinetic rate-equation model.

  7. Synaptic signal transduction aided by noise in a dynamical saturating model

    Science.gov (United States)

    Chapeau-Blondeau, François; Duan, Fabing; Abbott, Derek

    2010-02-01

    A generic dynamical model with saturation for neural signal transduction at the synaptic stage is presented. Analysis of this model of a synaptic pathway demonstrates its ability to give rise to stochastic resonance or improvement by noise, at this stage of signal transmission. Beyond the case of the intrinsic threshold nonlinearity of the neuron response, the results extend the feasibility of stochastic resonance to neural saturating dynamics at the synaptic stage. The present results also constitute the exposition of a new type of nonlinear (saturating) dynamics capable of stochastic resonance.

  8. Towards biochemical filters with a sigmoidal response to pH changes: buffered biocatalytic signal transduction.

    Science.gov (United States)

    Pita, Marcos; Privman, Vladimir; Arugula, Mary A; Melnikov, Dmitriy; Bocharova, Vera; Katz, Evgeny

    2011-03-14

    We realize a biochemical filtering process by introducing a buffer in a biocatalytic signal-transduction logic system based on the function of an enzyme, esterase. The input, ethyl butyrate, is converted into butyric acid--the output signal, which in turn is measured by the drop in the pH value. The developed approach offers a versatile "network element" for increasing the complexity of biochemical information processing systems. Evaluation of an optimal regime for quality filtering is accomplished in the framework of a kinetic rate-equation model.

  9. Enrichment of human hematopoietic stem/progenitor cells facilitates transduction for stem cell gene therapy.

    Science.gov (United States)

    Baldwin, Kismet; Urbinati, Fabrizia; Romero, Zulema; Campo-Fernandez, Beatriz; Kaufman, Michael L; Cooper, Aaron R; Masiuk, Katelyn; Hollis, Roger P; Kohn, Donald B

    2015-05-01

    Autologous hematopoietic stem cell (HSC) gene therapy for sickle cell disease has the potential to treat this illness without the major immunological complications associated with allogeneic transplantation. However, transduction efficiency by β-globin lentiviral vectors using CD34-enriched cell populations is suboptimal and large vector production batches may be needed for clinical trials. Transducing a cell population more enriched for HSC could greatly reduce vector needs and, potentially, increase transduction efficiency. CD34(+) /CD38(-) cells, comprising ∼1%-3% of all CD34(+) cells, were isolated from healthy cord blood CD34(+) cells by fluorescence-activated cell sorting and transduced with a lentiviral vector expressing an antisickling form of beta-globin (CCL-β(AS3) -FB). Isolated CD34(+) /CD38(-) cells were able to generate progeny over an extended period of long-term culture (LTC) compared to the CD34(+) cells and required up to 40-fold less vector for transduction compared to bulk CD34(+) preparations containing an equivalent number of CD34(+) /CD38(-) cells. Transduction of isolated CD34(+) /CD38(-) cells was comparable to CD34(+) cells measured by quantitative PCR at day 14 with reduced vector needs, and average vector copy/cell remained higher over time for LTC initiated from CD34(+) /38(-) cells. Following in vitro erythroid differentiation, HBBAS3 mRNA expression was similar in cultures derived from CD34(+) /CD38(-) cells or unfractionated CD34(+) cells. In vivo studies showed equivalent engraftment of transduced CD34(+) /CD38(-) cells when transplanted in competition with 100-fold more CD34(+) /CD38(+) cells. This work provides initial evidence for the beneficial effects from isolating human CD34(+) /CD38(-) cells to use significantly less vector and potentially improve transduction for HSC gene therapy.

  10. Cloning of a two-component signal transduction system of Xanthomonas campestris pv. phaseoli var. fuscans strain BXPF65

    DEFF Research Database (Denmark)

    Chan, JWYF; Maynard, Scott; Goodwin, PH

    1998-01-01

    A putative two-component signal transduction system was amplified and cloned from the plant pathogenic bacterium Xanthomonas campestris pv. phaseoli var. fuscans isolate BXPF65. The 620 bp amplified fragment was sequenced and analyzed with the BLAST Enhanced Alignment Utility (BEAUTY). BEAUTY...... analysis indicates that the putative xanthomonad response regulator contains regions which matched to an ATP phosphorylation site, a s54-factor interaction domain, and the “receiver” domains of various transcriptional regulators of the two-component signal transduction systems. Similar analysis indicates...... that the putative histidine kinase has homology with conserved “transmitter” domains of sensor proteins in two-component signal transduction systems. RFLP analysis using the putative signal transduction system showed polymorphisms among the strains....

  11. FUS3 represses CLN1 and CLN2 and in concert with KSS1 promotes signal transduction.

    OpenAIRE

    Elion, E A; Brill, J A; Fink, G. R.

    1991-01-01

    FUS3 is functionally redundant with KSS1, a homologous yeast protein kinase, for a step(s) in signal transduction between the beta subunit of the guanine nucleotide binding protein (G protein), STE4, and the mating type-specific transcriptional activator, STE12. Either FUS3 or KSS1 can execute this function; when neither gene encoding these protein kinases is present, signal transduction is blocked, causing sterility. This functional redundancy is strain dependent; some standard laboratory st...

  12. Arm-in-Arm Response Regulator Dimers Promote Intermolecular Signal Transduction

    Science.gov (United States)

    Baker, Anna W.; Satyshur, Kenneth A.; Moreno Morales, Neydis

    2016-01-01

    ABSTRACT Bacteriophytochrome photoreceptors (BphPs) and their cognate response regulators make up two-component signal transduction systems which direct bacteria to mount phenotypic responses to changes in environmental light quality. Most of these systems utilize single-domain response regulators to transduce signals through unknown pathways and mechanisms. Here we describe the photocycle and autophosphorylation kinetics of RtBphP1, a red light-regulated histidine kinase from the desert bacterium Ramlibacter tataouinensis. RtBphP1 undergoes red to far-red photoconversion with rapid thermal reversion to the dark state. RtBphP1 is autophosphorylated in the dark; this activity is inhibited under red light. The RtBphP1 cognate response regulator, the R. tataouinensis bacteriophytochrome response regulator (RtBRR), and a homolog, AtBRR from Agrobacterium tumefaciens, crystallize unexpectedly as arm-in-arm dimers, reliant on a conserved hydrophobic motif, hFWAhL (where h is a hydrophobic M, V, L, or I residue). RtBRR and AtBRR dimerize distinctly from four structurally characterized phytochrome response regulators found in photosynthetic organisms and from all other receiver domain homodimers in the Protein Data Bank. A unique cacodylate-zinc-histidine tag metal organic framework yielded single-wavelength anomalous diffraction phases and may be of general interest. Examination of the effect of the BRR stoichiometry on signal transduction showed that phosphorylated RtBRR is accumulated more efficiently than the engineered monomeric RtBRR (RtBRRmon) in phosphotransfer reactions. Thus, we conclude that arm-in-arm dimers are a relevant signaling intermediate in this class of two-component regulatory systems. IMPORTANCE BphP histidine kinases and their cognate response regulators comprise widespread red light-sensing two-component systems. Much work on BphPs has focused on structural understanding of light sensing and on enhancing the natural infrared fluorescence of these

  13. Stimulatory Effects of Coumestrol on Embryonic and Fetal Development Through AKT and ERK1/2 MAPK Signal Transduction.

    Science.gov (United States)

    Lim, Whasun; Song, Gwonhwa

    2016-12-01

    Successful establishment of pregnancy is required for fetal-maternal interactions regulating implantation, embryonic development and placentation. A uterine environment with insufficient growth factors and nutrients increases the incidence of intrauterine growth restriction (IUGR) leading to an impaired uterine environment. In the present study, we demonstrated the effects of the phytoestrogen coumestrol on conceptus development in the pig that is regarded as an excellent biomedical animal model for research on IUGR. Results of this study indicated that coumestrol induced migration of porcine trophectoderm (pTr) cells in a concentration-dependent manner. In response to coumestrol, the phosphorylation of AKT, P70S6K, S6, ERK1/2 MAPK, and P90RSK proteins were activated in pTr cells and ERK1/2 MAPK and P90RSK phosphorylation was prolonged for a longer period than for the other proteins. To identify the signal transduction pathway induced by coumestrol, pharmacological inhibitors U0126 (an ERK1/2 inhibitor) and LY294002 (a PI3K inhibitor) were used to pretreat pTr cells. The results showed that coumestrol-induced phosphorylation of ERK1/2 MAPK and P90RSK was blocked by U0126. In addition, the increased phosphorylation in response to coumestrol was completely inhibited following pre-treatment incubation of pTr cells in the presence of LY294002 and U0126. Furthermore, these two inhibitors suppressed the ability of coumestrol to induce migration of pTr cells. Collectively, these findings suggest that coumestrol affects embryonic development through activation of the PI3K/AKT and ERK1/2 MAPK cell signal transduction pathways and improvement in the uterine environment through coumestrol supplementation may provide beneficial effects of enhancing embryonic and fetal survival and development. J. Cell. Physiol. 231: 2733-2740, 2016. © 2016 Wiley Periodicals, Inc.

  14. Stimulatory Effects of Coumestrol on Embryonic and Fetal Development Through AKT and ERK1/2 MAPK Signal Transduction.

    Science.gov (United States)

    Lim, Whasun; Song, Gwonhwa

    2016-12-01

    Successful establishment of pregnancy is required for fetal-maternal interactions regulating implantation, embryonic development and placentation. A uterine environment with insufficient growth factors and nutrients increases the incidence of intrauterine growth restriction (IUGR) leading to an impaired uterine environment. In the present study, we demonstrated the effects of the phytoestrogen coumestrol on conceptus development in the pig that is regarded as an excellent biomedical animal model for research on IUGR. Results of this study indicated that coumestrol induced migration of porcine trophectoderm (pTr) cells in a concentration-dependent manner. In response to coumestrol, the phosphorylation of AKT, P70S6K, S6, ERK1/2 MAPK, and P90RSK proteins were activated in pTr cells and ERK1/2 MAPK and P90RSK phosphorylation was prolonged for a longer period than for the other proteins. To identify the signal transduction pathway induced by coumestrol, pharmacological inhibitors U0126 (an ERK1/2 inhibitor) and LY294002 (a PI3K inhibitor) were used to pretreat pTr cells. The results showed that coumestrol-induced phosphorylation of ERK1/2 MAPK and P90RSK was blocked by U0126. In addition, the increased phosphorylation in response to coumestrol was completely inhibited following pre-treatment incubation of pTr cells in the presence of LY294002 and U0126. Furthermore, these two inhibitors suppressed the ability of coumestrol to induce migration of pTr cells. Collectively, these findings suggest that coumestrol affects embryonic development through activation of the PI3K/AKT and ERK1/2 MAPK cell signal transduction pathways and improvement in the uterine environment through coumestrol supplementation may provide beneficial effects of enhancing embryonic and fetal survival and development. J. Cell. Physiol. 231: 2733-2740, 2016. © 2016 Wiley Periodicals, Inc. PMID:26991852

  15. Do signal transduction cascades influence survival in triple-negative breast cancer? A preliminary study

    Science.gov (United States)

    Mumm, Jan-Niclas; Kölbl, Alexandra C; Jeschke, Udo; Andergassen, Ulrich

    2016-01-01

    Background Triple-negative breast cancer (TNBC) is a rather aggressive form of breast cancer, comprised by early metastasis formation and reduced overall survival of the affected patients. Steroid hormone receptors and the human epidermal growth factor receptor 2 are not overexpressed, limiting therapeutic options. Therefore, new treatment options have to be investigated. The aim of our preliminary study was to detect coherences between some molecules of intracellular signal transduction pathways and survival of patients with TNBC, in order to obtain some hints for new therapeutical solutions. Methods Thirty-one paraffin-embedded tumor tissue samples, which were determined to be negative for steroid hormone receptors as well as human epidermal growth factor receptor 2, were immunohistochemically stained for a number of signal transduction molecules from several signaling pathways. β-Catenin, HIF1α, MCL, Notch1, LRP6, XBP1, and FOXP3 were stained with specific antibodies, and their staining was correlated with patient survival by Kaplan–Meier analyses. Results Only two of the investigated molecules have shown correlation with overall survival. Cytoplasmic staining of HIF1α and centro-tumoral lymphocyte FOXP3 staining showed statistically significant correlations with survival. Conclusion The coherence of signal transduction molecules with survival of patients with TNBC is still controversially discussed in the literature. Our study comprises one more mosaic stone in the elucidation of these intracellular processes and their influences on patient outcome. Lots of research still has to be done in this field, but it would be worthwhile as it may offer new therapeutic targets for a group of patients with breast cancer, which is still hard to treat. PMID:27307757

  16. Linear models of activation cascades: analytical solutions and coarse-graining of delayed signal transduction.

    Science.gov (United States)

    Beguerisse-Díaz, Mariano; Desikan, Radhika; Barahona, Mauricio

    2016-08-01

    Cellular signal transduction usually involves activation cascades, the sequential activation of a series of proteins following the reception of an input signal. Here, we study the classic model of weakly activated cascades and obtain analytical solutions for a variety of inputs. We show that in the special but important case of optimal gain cascades (i.e. when the deactivation rates are identical) the downstream output of the cascade can be represented exactly as a lumped nonlinear module containing an incomplete gamma function with real parameters that depend on the rates and length of the cascade, as well as parameters of the input signal. The expressions obtained can be applied to the non-identical case when the deactivation rates are random to capture the variability in the cascade outputs. We also show that cascades can be rearranged so that blocks with similar rates can be lumped and represented through our nonlinear modules. Our results can be used both to represent cascades in computational models of differential equations and to fit data efficiently, by reducing the number of equations and parameters involved. In particular, the length of the cascade appears as a real-valued parameter and can thus be fitted in the same manner as Hill coefficients. Finally, we show how the obtained nonlinear modules can be used instead of delay differential equations to model delays in signal transduction.

  17. Linear models of activation cascades: analytical solutions and coarse-graining of delayed signal transduction

    Science.gov (United States)

    Desikan, Radhika

    2016-01-01

    Cellular signal transduction usually involves activation cascades, the sequential activation of a series of proteins following the reception of an input signal. Here, we study the classic model of weakly activated cascades and obtain analytical solutions for a variety of inputs. We show that in the special but important case of optimal gain cascades (i.e. when the deactivation rates are identical) the downstream output of the cascade can be represented exactly as a lumped nonlinear module containing an incomplete gamma function with real parameters that depend on the rates and length of the cascade, as well as parameters of the input signal. The expressions obtained can be applied to the non-identical case when the deactivation rates are random to capture the variability in the cascade outputs. We also show that cascades can be rearranged so that blocks with similar rates can be lumped and represented through our nonlinear modules. Our results can be used both to represent cascades in computational models of differential equations and to fit data efficiently, by reducing the number of equations and parameters involved. In particular, the length of the cascade appears as a real-valued parameter and can thus be fitted in the same manner as Hill coefficients. Finally, we show how the obtained nonlinear modules can be used instead of delay differential equations to model delays in signal transduction. PMID:27581482

  18. Partial Decay of Thiamine Signal Transduction Pathway Alters Growth Properties of Candida glabrata

    Science.gov (United States)

    Shaik, Noor F.; Neal, Erin M.; Leone, Sarah G.; Cali, Brian J.; Peel, Michael T.; Grannas, Amanda M.; Wykoff, Dennis D.

    2016-01-01

    The phosphorylated form of thiamine (Vitamin B1), thiamine pyrophosphate (TPP) is essential for the metabolism of amino acids and carbohydrates in all organisms. Plants and microorganisms, such as yeast, synthesize thiamine de novo whereas animals do not. The thiamine signal transduction (THI) pathway in Saccharomyces cerevisiae is well characterized. The ~10 genes required for thiamine biosynthesis and uptake are transcriptionally upregulated during thiamine starvation by THI2, THI3, and PDC2. Candida glabrata, a human commensal and opportunistic pathogen, is closely related to S. cerevisiae but is missing half of the biosynthetic pathway, which limits its ability to make thiamine. We investigated the changes to the THI pathway in C. glabrata, confirming orthologous functions. We found that C. glabrata is unable to synthesize the pyrimidine subunit of thiamine as well as the thiamine precursor vitamin B6. In addition, THI2 (the gene encoding a transcription factor) is not present in C. glabrata, indicating a difference in the transcriptional regulation of the pathway. Although the pathway is upregulated by thiamine starvation in both species, C. glabrata appears to upregulate genes involved in thiamine uptake to a greater extent than S. cerevisiae. However, the altered regulation of the THI pathway does not alter the concentration of thiamine and its vitamers in the two species as measured by HPLC. Finally, we demonstrate potential consequences to having a partial decay of the THI biosynthetic and regulatory pathway. When the two species are co-cultured, the presence of thiamine allows C. glabrata to rapidly outcompete S. cerevisiae, while absence of thiamine allows S. cerevisiae to outcompete C. glabrata. This simplification of the THI pathway in C. glabrata suggests its environment provides thiamine and/or its precursors to cells, whereas S. cerevisiae is not as reliant on environmental sources of thiamine. PMID:27015653

  19. Partial Decay of Thiamine Signal Transduction Pathway Alters Growth Properties of Candida glabrata.

    Directory of Open Access Journals (Sweden)

    Christine L Iosue

    Full Text Available The phosphorylated form of thiamine (Vitamin B1, thiamine pyrophosphate (TPP is essential for the metabolism of amino acids and carbohydrates in all organisms. Plants and microorganisms, such as yeast, synthesize thiamine de novo whereas animals do not. The thiamine signal transduction (THI pathway in Saccharomyces cerevisiae is well characterized. The ~10 genes required for thiamine biosynthesis and uptake are transcriptionally upregulated during thiamine starvation by THI2, THI3, and PDC2. Candida glabrata, a human commensal and opportunistic pathogen, is closely related to S. cerevisiae but is missing half of the biosynthetic pathway, which limits its ability to make thiamine. We investigated the changes to the THI pathway in C. glabrata, confirming orthologous functions. We found that C. glabrata is unable to synthesize the pyrimidine subunit of thiamine as well as the thiamine precursor vitamin B6. In addition, THI2 (the gene encoding a transcription factor is not present in C. glabrata, indicating a difference in the transcriptional regulation of the pathway. Although the pathway is upregulated by thiamine starvation in both species, C. glabrata appears to upregulate genes involved in thiamine uptake to a greater extent than S. cerevisiae. However, the altered regulation of the THI pathway does not alter the concentration of thiamine and its vitamers in the two species as measured by HPLC. Finally, we demonstrate potential consequences to having a partial decay of the THI biosynthetic and regulatory pathway. When the two species are co-cultured, the presence of thiamine allows C. glabrata to rapidly outcompete S. cerevisiae, while absence of thiamine allows S. cerevisiae to outcompete C. glabrata. This simplification of the THI pathway in C. glabrata suggests its environment provides thiamine and/or its precursors to cells, whereas S. cerevisiae is not as reliant on environmental sources of thiamine.

  20. Partial Decay of Thiamine Signal Transduction Pathway Alters Growth Properties of Candida glabrata.

    Science.gov (United States)

    Iosue, Christine L; Attanasio, Nicholas; Shaik, Noor F; Neal, Erin M; Leone, Sarah G; Cali, Brian J; Peel, Michael T; Grannas, Amanda M; Wykoff, Dennis D

    2016-01-01

    The phosphorylated form of thiamine (Vitamin B1), thiamine pyrophosphate (TPP) is essential for the metabolism of amino acids and carbohydrates in all organisms. Plants and microorganisms, such as yeast, synthesize thiamine de novo whereas animals do not. The thiamine signal transduction (THI) pathway in Saccharomyces cerevisiae is well characterized. The ~10 genes required for thiamine biosynthesis and uptake are transcriptionally upregulated during thiamine starvation by THI2, THI3, and PDC2. Candida glabrata, a human commensal and opportunistic pathogen, is closely related to S. cerevisiae but is missing half of the biosynthetic pathway, which limits its ability to make thiamine. We investigated the changes to the THI pathway in C. glabrata, confirming orthologous functions. We found that C. glabrata is unable to synthesize the pyrimidine subunit of thiamine as well as the thiamine precursor vitamin B6. In addition, THI2 (the gene encoding a transcription factor) is not present in C. glabrata, indicating a difference in the transcriptional regulation of the pathway. Although the pathway is upregulated by thiamine starvation in both species, C. glabrata appears to upregulate genes involved in thiamine uptake to a greater extent than S. cerevisiae. However, the altered regulation of the THI pathway does not alter the concentration of thiamine and its vitamers in the two species as measured by HPLC. Finally, we demonstrate potential consequences to having a partial decay of the THI biosynthetic and regulatory pathway. When the two species are co-cultured, the presence of thiamine allows C. glabrata to rapidly outcompete S. cerevisiae, while absence of thiamine allows S. cerevisiae to outcompete C. glabrata. This simplification of the THI pathway in C. glabrata suggests its environment provides thiamine and/or its precursors to cells, whereas S. cerevisiae is not as reliant on environmental sources of thiamine. PMID:27015653

  1. Plant gravitropic signal transduction: A network analysis leads to gene discovery

    Science.gov (United States)

    Wyatt, Sarah

    Gravity plays a fundamental role in plant growth and development. Although a significant body of research has helped define the events of gravity perception, the role of the plant growth regulator auxin, and the mechanisms resulting in the gravity response, the events of signal transduction, those that link the biophysical action of perception to a biochemical signal that results in auxin redistribution, those that regulate the gravitropic effects on plant growth, remain, for the most part, a “black box.” Using a cold affect, dubbed the gravity persistent signal (GPS) response, we developed a mutant screen to specifically identify components of the signal transduction pathway. Cloning of the GPS genes have identified new proteins involved in gravitropic signaling. We have further exploited the GPS response using a multi-faceted approach including gene expression microarrays, proteomics analysis, and bioinformatics analysis and continued mutant analysis to identified additional genes, physiological and biochemical processes. Gene expression data provided the foundation of a regulatory network for gravitropic signaling. Based on these gene expression data and related data sets/information from the literature/repositories, we constructed a gravitropic signaling network for Arabidopsis inflorescence stems. To generate the network, both a dynamic Bayesian network approach and a time-lagged correlation coefficient approach were used. The dynamic Bayesian network added existing information of protein-protein interaction while the time-lagged correlation coefficient allowed incorporation of temporal regulation and thus could incorporate the time-course metric from the data set. Thus the methods complemented each other and provided us with a more comprehensive evaluation of connections. Each method generated a list of possible interactions associated with a statistical significance value. The two networks were then overlaid to generate a more rigorous, intersected

  2. Expression analysis of taste signal transduction molecules in the fungiform and circumvallate papillae of the rhesus macaque, Macaca mulatta.

    Directory of Open Access Journals (Sweden)

    Yoshiro Ishimaru

    Full Text Available The molecular mechanisms of the mammalian gustatory system have been examined in many studies using rodents as model organisms. In this study, we examined the mRNA expression of molecules involved in taste signal transduction in the fungiform papillae (FuP and circumvallate papillae (CvP of the rhesus macaque, Macaca mulatta, using in situ hybridization. TAS1R1, TAS1R2, TAS2Rs, and PKD1L3 were exclusively expressed in different subsets of taste receptor cells (TRCs in the FuP and CvP. This finding suggests that TRCs sensing different basic taste modalities are mutually segregated in macaque taste buds. Individual TAS2Rs exhibited a variety of expression patterns in terms of the apparent level of expression and the number of TRCs expressing these genes, as in the case of human TAS2Rs. GNAT3, but not GNA14, was expressed in TRCs of FuP, whereas GNA14 was expressed in a small population of TRCs of CvP, which were distinct from GNAT3- or TAS1R2-positive TRCs. These results demonstrate similarities and differences between primates and rodents in the expression profiles of genes involved in taste signal transduction.

  3. Aluminum—induced apoptosis in cultured cortical neurons and its effects on SAPK/JNK signal transduction pathway

    Institute of Scientific and Technical Information of China (English)

    FuHJ; DongSZ

    2002-01-01

    Aluminum (Al) exposure and apoptotic cell death have been implicated in several neurodegenerative diseases.the mechanisms by which Al interacts with the nervous system are only partly understood.In this study,we used cultured cortical neurons to investigate the ability of Al to induce the apoptosis of neurons and to explore the role of SAPK/JNK signal transduction pathway on the apoptosis induced by Al.It was found that Al-induced degeneration of cortical neurons involved the DNA fragmentation characteristic of apoptosis.The rate of apoptosis increased significantly,which was measured by TdT-mediated dUTKP nick end labeling.Westerm blot analysis showed that SAPK/JNK activities of cortical neurons varied when the dose and exposure time of AlCl3 were different.Our study demonstrates that Al can induce the apoptosis of cortical neurons and SAPK/JNK signal transduction pathway may play a great role in the apoptosis.

  4. Azelastine hydrochloride (Azeptin) inhibits peplomycin (PLM)-induced pulmonary fibrosis by contradicting the up-regulation of signal transduction.

    Science.gov (United States)

    Yoneda, K; Yamamoto, T; Ueta, E; Osaki, T

    1997-10-01

    Inhibition of peplomycin (PLM)-induced pulmonary fibrosis by azelastine hydrochloride (Azeptin) was examined using ICR mice, and the effects of both drugs on signal transduction were investigated. Microscopically, Azeptin (a total of 56 mg/kg for 28 days) suppressed pulmonary fibrosis in mice which received an i.p. injection of a total of 60 or 75 mg/kg PLM. In parallel with the microscopic findings, smaller amounts of collagen were synthesized in the lungs of Azeptin-injected mice. PLM enhanced the expression of interleukin-1 beta- and transforming growth factor-beta-mRNA in lungs. In contrast, Azeptin suppressed the expression. Compatible with these in vivo results, Azeptin and PLM contradictively regulated protein tyrosine phosphorylation and c-myc mRNA expression in human gingival and mouse pulmonary fibroblasts. In addition, NF-kappa B was activated by fibroblast treatment with 5 micrograms/ml PLM for 1 h, but intranuclear NF-kappa B was decreased by cell treatment with 10(-5) M Azeptin. From these results, it is concluded that Azeptin inhibits PLM-induced pulmonary fibrosis by antagonizing the up-regulation of signal transduction.

  5. Do certain signal transduction mechanisms explain the comorbidity of epilepsy and mood disorders?

    Science.gov (United States)

    Rocha, Luisa; Alonso-Vanegas, Mario; Orozco-Suárez, Sandra; Alcántara-González, David; Cruzblanca, Humberto; Castro, Elena

    2014-09-01

    It is well known that mood disorders are highly prevalent in patients with epilepsy. Although several studies have aimed to characterize alterations in different types of receptors associated with both disturbances, there is a lack of studies focused on identifying the causes of this comorbidity. Here, we described some changes at the biochemical level involving serotonin, dopamine, and γ-aminobutyric acid (GABA) receptors as well as signal transduction mechanisms that may explain the coexistence of both epilepsy and mood disorders. Finally, the identification of common pathophysiological mechanisms associated with receptor-receptor interaction (heterodimers) could allow designing new strategies for treatment of patients with epilepsy and comorbid mood disorders.

  6. A model for signal transduction during quorum sensing in Vibrio harveyi

    Science.gov (United States)

    Banik, Suman K.; Fenley, Andrew T.; Kulkarni, Rahul V.

    2009-12-01

    We present a framework for analyzing luminescence regulation during quorum sensing in the bioluminescent bacterium Vibrio harveyi. Using a simplified model for signal transduction in the quorum sensing pathway, we identify key dimensionless parameters that control the system's response. These parameters are estimated using experimental data on luminescence phenotypes for different mutant strains. The corresponding model predictions are consistent with results from other experiments which did not serve as input for determining model parameters. Furthermore, the proposed framework leads to novel testable predictions for luminescence phenotypes and for responses of the network to different perturbations.

  7. Cellerator: extending a computer algebra system to include biochemical arrows for signal transduction simulations

    Science.gov (United States)

    Shapiro, Bruce E.; Levchenko, Andre; Meyerowitz, Elliot M.; Wold, Barbara J.; Mjolsness, Eric D.

    2003-01-01

    Cellerator describes single and multi-cellular signal transduction networks (STN) with a compact, optionally palette-driven, arrow-based notation to represent biochemical reactions and transcriptional activation. Multi-compartment systems are represented as graphs with STNs embedded in each node. Interactions include mass-action, enzymatic, allosteric and connectionist models. Reactions are translated into differential equations and can be solved numerically to generate predictive time courses or output as systems of equations that can be read by other programs. Cellerator simulations are fully extensible and portable to any operating system that supports Mathematica, and can be indefinitely nested within larger data structures to produce highly scaleable models.

  8. Genomic Targets and Features of BarA-UvrY (-SirA) Signal Transduction Systems

    OpenAIRE

    Zere, Tesfalem R.; Vakulskas, Christopher A.; Yuanyuan Leng; Archana Pannuri; Potts, Anastasia H.; Raquel Dias; Dongjie Tang; Bryan Kolaczkowski; Dimitris Georgellis; Ahmer, Brian M. M.; Tony Romeo

    2015-01-01

    The two-component signal transduction system BarA-UvrY of Escherichia coli and its orthologs globally regulate metabolism, motility, biofilm formation, stress resistance, virulence of pathogens and quorum sensing by activating the transcription of genes for regulatory sRNAs, e.g. CsrB and CsrC in E. coli. These sRNAs act by sequestering the RNA binding protein CsrA (RsmA) away from lower affinity mRNA targets. In this study, we used ChIP-exo to identify, at single nucleotide resolution, genom...

  9. Measurement of the formation of complexes in tyrosine kinase-mediated signal transduction

    Energy Technology Data Exchange (ETDEWEB)

    Ladbury, John E., E-mail: j.ladbury@biochem.ucl.ac.uk [Department of Biochemistry and Molecular Biology, University College London, Gower Street, London WC1E 6BT (United Kingdom)

    2007-01-01

    The use of isothermal titration calorimetry (ITC) provides a full thermodynamic characterization of an interaction in one experiment. The determination of the affinity is an important value; however, the additional layer of information provided by the change in enthalpy and entropy can help in understanding the biology. This is demonstrated with respect to tyrosine kinase-mediated signal transduction. Isothermal titration calorimetry (ITC) provides highly complementary data to high-resolution structural detail. An overview of the methodology of the technique is provided. Ultimately, the correlation of the thermodynamic parameters determined by ITC with structural perturbation observed on going from the free to the bound state should be possible at an atomic level. Currently, thermodynamic data provide some insight as to potential changes occurring on complex formation. Here, this is demonstrated in the context of in vitro quantification of intracellular tyrosine kinase-mediated signal transduction and the issue of specificity of the important interactions. The apparent lack of specificity in the interactions of domains of proteins involved in early signalling from membrane-bound receptors is demonstrated using data from ITC.

  10. An Efficient Method to Identify Conditionally Activated Transcription Factors and their Corresponding Signal Transduction Pathway Segments

    Directory of Open Access Journals (Sweden)

    Haiyan Hu

    2009-11-01

    Full Text Available A signal transduction pathway (STP is a cascade composed of a series of signal transferring steps, which often activate one or more transcription factors (TFs to control the transcription of target genes. Understanding signaling pathways is important to our understanding of the molecular mechanisms of disease. Many condition-annotated pathways have been deposited in public databases. However, condition-annotated pathways are far from complete, considering the large number of possible conditions. Computational methods to assist in the identification of conditionally activated pathways are greatly needed. In this paper, we propose an efficient method to identify conditionally activated pathway segments starting from the identification of conditionally activated TFs, by incorporating protein-DNA binding data, gene expression data and protein interaction data. Applying our methods on several microarray datasets, we have discovered many significantly activated TFs and their corresponding pathway segments, which are supported by evidence in the literature.

  11. Endocytosis of pro-inflammatory cytokine receptors and its relevance for signal transduction.

    Science.gov (United States)

    Hermanns, Heike M; Wohlfahrt, Julia; Mais, Christine; Hergovits, Sabine; Jahn, Daniel; Geier, Andreas

    2016-08-01

    The pro-inflammatory cytokines tumor necrosis factor (TNF), interleukin-1 (IL-1) and interleukin-6 (IL-6) are key players of the innate and adaptive immunity. Their activity needs to be tightly controlled to allow the initiation of an appropriate immune response as defense mechanism against pathogens or tissue injury. Excessive or sustained signaling of either of these cytokines leads to severe diseases, including rheumatoid arthritis, inflammatory bowel diseases (Crohn's disease, ulcerative colitis), steatohepatitis, periodic fevers and even cancer. Studies carried out in the last 30 years have emphasized that an elaborate control system for each of these cytokines exists. Here, we summarize what is currently known about the involvement of receptor endocytosis in the regulation of these pro-inflammatory cytokines' signaling cascades. Particularly in the last few years it was shown that this cellular process is far more than a mere feedback mechanism to clear cytokines from the circulation and to shut off their signal transduction. PMID:27071147

  12. Cell signalling and phospholipid metabolism. Final report

    Energy Technology Data Exchange (ETDEWEB)

    Boss, W.F.

    1990-12-31

    These studies explored whether phosphoinositide (PI) has a role in plants analogous to its role in animal cells. Although no parallel activity of PI in signal transduction was found in plant cells, activity of inositol phospholipid kinase was found to be modulated by light and by cell wall degrading enzymes. These studies indicate a major role for inositol phospholipids in plant growth and development as membrane effectors but not as a source of second messengers.

  13. Signal transduction across cellular membranes can be mediated by coupling of the clustering of anchored proteins in both leaflets

    Science.gov (United States)

    Yue, Tongtao; Zhang, Xianren

    2012-01-01

    One key question in signal transduction is how the signal is relayed from the outer leaflet of a cellular membrane to the inner leaflet. Using a simulation model, a mechanism for the mediation of signal transduction is proposed here in which the coupling between membrane proteins in different leaflets can be achieved by the clustering of anchored proteins, without recruiting transmembrane proteins. Depending on the hydrophobic length of the anchored proteins, three coupling patterns, including face-to-face clustering, interdigitated clustering, and weak-coupled clustering, are observed in this work. This observation provides a possible explanation of how a particular downstream signaling pathway is selected.

  14. Signal transduction and Nobel Prize%信号转导与诺贝尔奖

    Institute of Scientific and Technical Information of China (English)

    郭晓强; 王跃民

    2013-01-01

    Signal transduction is one of frontiers in life sciences, and many achievements in this field were awarded Nobel Prize. From the initial signal molecular to the subsequent second messenger and reversible phosphorylation, to the G-protein and receptor, and until today signal network system, these researches had greatly expanded the understanding of the phenomenon of life and provided new alternative for a lot of diseases. In this article, the brief history of signal transduction is reviewed according to the research course of classical signaling pathway. It is comprehensively introduced including background, history, significance and utilization of Nobel Prize-related achievements.%信号转导是生命科学前沿领域之一,至今已有多项成果荣获诺贝尔奖。从最初的信号分子,到第二信使和可逆磷酸化,再到G蛋白和G蛋白偶联受体,直到今天的信号网络系统,这些研究极大地拓展了人们对生命现象的理解和认识,从而为多种疾病的治疗提供了新的选择。笔者以经典信号通路研究历程为主线,回顾了信号转导研究的发展简史,全面地介绍了诺贝尔奖相关成果的研究背景、历程、意义和应用。

  15. P2CS: a two-component system resource for prokaryotic signal transduction research

    Directory of Open Access Journals (Sweden)

    Méjean Vincent

    2009-07-01

    Full Text Available Abstract Background With the escalation of high throughput prokaryotic genome sequencing, there is an ever-increasing need for databases that characterise, catalogue and present data relating to particular gene sets and genomes/metagenomes. Two-component system (TCS signal transduction pathways are the dominant mechanisms by which micro-organisms sense and respond to external as well as internal environmental changes. These systems respond to a wide range of stimuli by triggering diverse physiological adjustments, including alterations in gene expression, enzymatic reactions, or protein-protein interactions. Description We present P2CS (Prokaryotic 2-Component Systems, an integrated and comprehensive database of TCS signal transduction proteins, which contains a compilation of the TCS genes within 755 completely sequenced prokaryotic genomes and 39 metagenomes. P2CS provides detailed annotation of each TCS gene including family classification, sequence features, functional domains, as well as genomic context visualization. To bypass the generic problem of gene underestimation during genome annotation, we also constituted and searched an ORFeome, which improves the recovery of TCS proteins compared to searches on the equivalent proteomes. Conclusion P2CS has been developed for computational analysis of the modular TCSs of prokaryotic genomes and metagenomes. It provides a complete overview of information on TCSs, including predicted candidate proteins and probable proteins, which need further curation/validation. The database can be browsed and queried with a user-friendly web interface at http://www.p2cs.org/.

  16. Two-Component Signal Transduction System SaeRS Positively Regulates Staphylococcus epidermidis Glucose Metabolism

    Directory of Open Access Journals (Sweden)

    Qiang Lou

    2014-01-01

    Full Text Available Staphylococcus epidermidis, which is a causative pathogen of nosocomial infection, expresses its virulent traits such as biofilm and autolysis regulated by two-component signal transduction system SaeRS. In this study, we performed a proteomic analysis of differences in expression between the S. epidermidis 1457 wild-type and saeRS mutant to identify candidates regulated by saeRS using two-dimensional gel electrophoresis (2-DE combined with matrix-assisted laser desorption/lonization mass spectrometry (MALDI-TOF-MS. Of 55 identified proteins that significantly differed in expression between the two strains, 15 were upregulated and 40 were downregulated. The downregulated proteins included enzymes related to glycolysis and TCA cycle, suggesting that glucose is not properly utilized in S. epidermidis when saeRS was deleted. The study will be helpful for treatment of S. epidermidis infection from the viewpoint of metabolic modulation dependent on two-component signal transduction system SaeRS.

  17. Mutations at the SPINDLY locus of Arabidopsis alter gibberellin signal transduction.

    Science.gov (United States)

    Jacobsen, S E; Olszewski, N E

    1993-08-01

    Three independent recessive mutations at the SPINDLY (SPY) locus of Arabidopsis confer resistance to the gibberellin (GA) biosynthesis inhibitor paclobutrazol. Relative to wild type, spy mutants exhibit longer hypocotyls, leaves that are a lighter green color, increased stem elongation, early flowering, parthenocarpy, and partial male sterility. All of these phenotypes are also observed when wild-type Arabidopsis plants are repeatedly treated with gibberellin A3 (GA3). The spy-1 allele is partially epistatic to the ga1-2 mutation, which causes GA deficiency. In addition, the spy-1 mutation can simultaneously suppress the effects of the ga1-2 mutation and paclobutrazol treatment, which inhibit different steps in the GA biosynthesis pathway. This observation suggests that spy-1 activates a basal level of GA signal transduction that is independent of GA. Furthermore, results from GA3 dose-response experiments suggest that GA3 and spy-1 interact in an additive manner. These results are consistent with models in which the SPY gene product regulates a portion of the GA signal transduction pathway. PMID:8400871

  18. Insulin signal transduction in skeletal muscle from glucose-intolerant relatives of type 2 diabetic patients [corrected

    DEFF Research Database (Denmark)

    Storgaard, H; Song, X M; Jensen, C B;

    2001-01-01

    To determine whether defects in the insulin signal transduction cascade are present in skeletal muscle from prediabetic individuals, we excised biopsies from eight glucose-intolerant male first-degree relatives of patients with type 2 diabetes (IGT relatives) and nine matched control subjects...... in signal transduction noted for IRS-1 and PI 3-kinase may be attributed to elevated basal phosphorylation/activity of these parameters, because absolute phosphorylation/activity under insulin-stimulated conditions was similar between IGT relatives and control subjects. Insulin increased Akt serine......, the elevated basal activity of these signaling intermediates and the lack of a strong correlation between these parameters to glucose metabolism suggests that other defects of insulin signal transduction and/or downstream components of glucose metabolism may play a greater role in the development of insulin...

  19. Signal transduction by M3 muscarinic acetylcholine receptor in prostate cancer

    Science.gov (United States)

    GUO, LIQIANG; LIU, YUQIANG; DING, ZHIBO; SUN, WENDONG; YUAN, MINGZHEN

    2016-01-01

    The present study aimed to investigate the potential mechanisms used during signal transduction by M3 muscarinic acetylcholine receptor (CHRM3) in prostate cancer. The microarray datasets of GSE3325, including 5 clinically localized primary prostate cancers and 4 benign prostate tissues, were downloaded from the Gene Expression Omnibus database. The differentially-expressed genes (DEGs) in primary prostate cancer tissues compared with benign controls were screened using the Limma package. Gene Ontology and pathway enrichment analyses were performed using the Database for Annotation Visualization and Integrated Discovery. Next, a protein-protein interaction (PPI) network was constructed. Additionally, microRNAs (miRNAs) associated with DEGs were predicted and miRNA-target DEG analysis was performed using a Web-based Gene Set Analysis Toolkit. Finally, the PPI network and the miRNA-target DEG network were integrated using Cytoscape. In total, 224 DEGs were screened in the prostate cancer tissues, including 113 upregulated and 111 downregulated genes. CHRM3 and epidermal growth factor (EGF) were enriched in the regulation of the actin cytoskeleton. EGF and v-myc avian myelocytomatosis viral oncogene homolog (Myc) were enriched in the mitogen-activated protein kinase (MAPK) signaling pathway. EGF with the highest degree of connectivity was the hub node in the PPI network, and miR-34b could interact with Myc directly in the miRNA-target DEG network. EGF and Myc may exhibit significant roles in the progression of prostate cancer via regulation of the actin cytoskeleton and the MAPK signaling pathway. CHRM3 may activate these two pathways in prostate cancer progression. Thus, these two key factors and pathways may be crucial mechanisms during signal transduction by CHRM3 in prostate cancer. PMID:26870222

  20. Systems Perturbation Analysis of a Large-Scale Signal Transduction Model Reveals Potentially Influential Candidates for Cancer Therapeutics

    Science.gov (United States)

    Puniya, Bhanwar Lal; Allen, Laura; Hochfelder, Colleen; Majumder, Mahbubul; Helikar, Tomáš

    2016-01-01

    Dysregulation in signal transduction pathways can lead to a variety of complex disorders, including cancer. Computational approaches such as network analysis are important tools to understand system dynamics as well as to identify critical components that could be further explored as therapeutic targets. Here, we performed perturbation analysis of a large-scale signal transduction model in extracellular environments that stimulate cell death, growth, motility, and quiescence. Each of the model’s components was perturbed under both loss-of-function and gain-of-function mutations. Using 1,300 simulations under both types of perturbations across various extracellular conditions, we identified the most and least influential components based on the magnitude of their influence on the rest of the system. Based on the premise that the most influential components might serve as better drug targets, we characterized them for biological functions, housekeeping genes, essential genes, and druggable proteins. The most influential components under all environmental conditions were enriched with several biological processes. The inositol pathway was found as most influential under inactivating perturbations, whereas the kinase and small lung cancer pathways were identified as the most influential under activating perturbations. The most influential components were enriched with essential genes and druggable proteins. Moreover, known cancer drug targets were also classified in influential components based on the affected components in the network. Additionally, the systemic perturbation analysis of the model revealed a network motif of most influential components which affect each other. Furthermore, our analysis predicted novel combinations of cancer drug targets with various effects on other most influential components. We found that the combinatorial perturbation consisting of PI3K inactivation and overactivation of IP3R1 can lead to increased activity levels of apoptosis

  1. Molecular Insights into Toluene Sensing in the TodS/TodT Signal Transduction System*

    Science.gov (United States)

    Koh, Serry; Hwang, Jungwon; Guchhait, Koushik; Lee, Eun-Gyeong; Kim, Sang-Yoon; Kim, Sujin; Lee, Sangmin; Chung, Jeong Min; Jung, Hyun Suk; Lee, Sang Jun; Ryu, Choong-Min; Lee, Seung-Goo; Oh, Tae-Kwang; Kwon, Ohsuk; Kim, Myung Hee

    2016-01-01

    TodS is a sensor kinase that responds to various monoaromatic compounds, which either cause an agonistic or antagonistic effect on phosphorylation of its cognate response regulator TodT, and controls tod operon expression in Pseudomonas putida strains. We describe a molecular sensing mechanism of TodS that is activated in response to toluene. The crystal structures of the TodS Per-Arnt-Sim (PAS) 1 sensor domain (residues 43–164) and its complex with toluene (agonist) or 1,2,4-trimethylbenzene (antagonist) show a typical β2α3β3 PAS fold structure (residues 45–149), forming a hydrophobic ligand-binding site. A signal transfer region (residues 150–163) located immediately after the canonical PAS fold may be intrinsically flexible and disordered in both apo-PAS1 and antagonist-bound forms and dramatically adapt an α-helix upon toluene binding. This structural change in the signal transfer region is proposed to result in signal transmission to activate the TodS/TodT two-component signal transduction system. Site-directed mutagenesis and β-galactosidase assays using a P. putida reporter strain system verified the essential residues involved in ligand sensing and signal transfer and suggest that the Phe46 residue acts as a ligand-specific switch. PMID:26903514

  2. Signal transduction in neurons: effects of cellular prion protein on fyn kinase and ERK1/2 kinase

    Directory of Open Access Journals (Sweden)

    Tomasi Vittorio

    2010-12-01

    Full Text Available Abstract Background It has been reported that cellular prion protein (PrPc co-localizes with caveolin-1 and participates to signal transduction events by recruiting Fyn kinase. As PrPc is a secreted protein anchored to the outer surface membrane through a glycosylphosphatidylinositol (GPI anchor (secPrP and caveolin-1 is located in the inner leaflet of plasma membrane, there is a problem of how the two proteins can physically interact each other and transduce signals. Results By using the GST-fusion proteins system we observed that PrPc strongly interacts with caveolin-1 scaffolding domain and with a caveolin-1 hydrophilic C-terminal region, but not with the caveolin-1 N-terminal region. In vitro binding experiments were also performed to define the site(s of PrPc interacting with cav-1. The results are consistent with a participation of PrPc octapeptide repeats motif in the binding to caveolin-1 scaffolding domain. The caveolar localization of PrPc was ascertained by co-immunoprecipitation, by co-localization after flotation in density gradients and by confocal microscopy analysis of PrPc and caveolin-1 distributions in a neuronal cell line (GN11 expressing caveolin-1 at high levels. Conclusions We observed that, after antibody-mediated cross-linking or copper treatment, PrPc was internalized probably into caveolae. We propose that following translocation from rafts to caveolae or caveolae-like domains, secPrP could interact with caveolin-1 and induce signal transduction events.

  3. Apurinic/apyrimidinic endonuclease1/redox factor-1 (Ape1/Ref-1) is essential for IL-21-induced signal transduction through ERK1/2 pathway

    Energy Technology Data Exchange (ETDEWEB)

    Juliana, Farha M.; Nara, Hidetoshi [Department of Immunology, Yamagata University Faculty of Medicine, Yamagata (Japan); Onoda, Tadashi [Department of Immunology, Yamagata University Faculty of Medicine, Yamagata (Japan); Department of Pediatrics, Yamagata University Faculty of Medicine, Yamagata (Japan); Rahman, Mizanur; Araki, Akemi; Jin, Lianjin [Department of Immunology, Yamagata University Faculty of Medicine, Yamagata (Japan); Fujii, Hodaka [Combined Program on Microbiology and Immunology, Research Institute for Microbial Diseases, Osaka University, Suita (Japan); Tanaka, Nobuyuki [Division of Immunology, Miyagi Cancer Center Research Institute, Natori (Japan); Department of Cancer Medical Science, Tohoku University Graduate School of Medicine, Sendai (Japan); Hoshino, Tomoaki [Department of Internal Medicine 1, Kurume University School of Medicine, Kurume (Japan); Asao, Hironobu, E-mail: asao-h@med.id.yamagata-u.ac.jp [Department of Immunology, Yamagata University Faculty of Medicine, Yamagata (Japan)

    2012-04-13

    Highlights: Black-Right-Pointing-Pointer IL-21 induces nuclear accumulation of Ape1/Ref-1 protein. Black-Right-Pointing-Pointer Ape1/Ref-1 is indispensable in IL-21-induced cell proliferation and survival signal. Black-Right-Pointing-Pointer Ape1/Ref-1 is required for IL-21-induced ERK1/2 activation. -- Abstract: IL-21 is a pleiotropic cytokine that regulates T-cell and B-cell differentiation, NK-cell activation, and dendritic cell functions. IL-21 activates the JAK-STAT, ERK, and PI3K pathways. We report here that Ape1/Ref-1 has an essential role in IL-21-induced cell growth signal transduction. Overexpression of Ape1/Ref-1 enhances IL-21-induced cell proliferation, but it is suppressed by overexpressing an N-terminal deletion mutant of Ape1/Ref-1 that lacks the redox domain. Furthermore, knockdown of the Ape1/Ref-1 mRNA dramatically compromises IL-21-induced ERK1/2 activation and cell proliferation with increasing cell death. These impaired activities are recovered by the re-expression of Ape1/Ref-1 in the knockdown cells. Our findings are the first demonstration that Ape1/Ref-1 is an indispensable molecule for the IL-21-mediated signal transduction through ERK1/2 activation.

  4. Further evidence supporting a role for gs signal transduction in severe malaria pathogenesis.

    Directory of Open Access Journals (Sweden)

    Sarah Auburn

    Full Text Available With the functional demonstration of a role in erythrocyte invasion by Plasmodium falciparum parasites, implications in the aetiology of common conditions that prevail in individuals of African origin, and a wealth of pharmacological knowledge, the stimulatory G protein (Gs signal transduction pathway presents an exciting target for anti-malarial drug intervention. Having previously demonstrated a role for the G-alpha-s gene, GNAS, in severe malaria disease, we sought to identify other important components of the Gs pathway. Using meta-analysis across case-control and family trio (affected child and parental controls studies of severe malaria from The Gambia and Malawi, we sought evidence of association in six Gs pathway candidate genes: adenosine receptor 2A (ADORA2A and 2B (ADORA2B, beta-adrenergic receptor kinase 1 (ADRBK1, adenylyl cyclase 9 (ADCY9, G protein beta subunit 3 (GNB3, and regulator of G protein signalling 2 (RGS2. Our study amassed a total of 2278 cases and 2364 controls. Allele-based models of association were investigated in all genes, and genotype and haplotype-based models were investigated where significant allelic associations were identified. Although no significant associations were observed in the other genes, several were identified in ADORA2A. The most significant association was observed at the rs9624472 locus, where the G allele (approximately 20% frequency appeared to confer enhanced risk to severe malaria [OR = 1.22 (1.09-1.37; P = 0.001]. Further investigation of the ADORA2A gene region is required to validate the associations identified here, and to identify and functionally characterize the responsible causal variant(s. Our results provide further evidence supporting a role of the Gs signal transduction pathway in the regulation of severe malaria, and request further exploration of this pathway in future studies.

  5. Therapeutic effects of tyroservatide on metastasis of lung cancer and its mechanism affecting integrin–focal adhesion kinase signal transduction

    Science.gov (United States)

    Huang, Yu-ting; Zhao, Lan; Fu, Zheng; Zhao, Meng; Song, Xiao-meng; Jia, Jing; Wang, Song; Li, Jin-ping; Zhu, Zhi-feng; Lin, Gang; Lu, Rong; Yao, Zhi

    2016-01-01

    Tyroservatide (YSV) can inhibit the growth and metastasis of mouse lung cancer significantly. This study investigated the therapeutic effects of tripeptide YSV on metastasis of human lung cancer cells and explored its possible mechanism that affects integrin–focal adhesion kinase (FAK) signal transduction in tumor cells. YSV significantly inhibited the adhesion and the invasion of highly metastatic human lung cancer cell lines 95D, A549, and NCI-H1299. In addition, YSV significantly inhibited phosphorylation of FAK Tyr397 and FAK Tyr576/577 in the 95D, A549, and NCI-H1299 human lung cancer cells in vitro. And the mRNA level and protein expression of FAK in these human lung cancer cells decreased at the same time. YSV also significantly inhibited mRNA and protein levels of integrin β1 and integrin β3 in the 95D, A549, and NCI-H1299 human lung cancer cells. Our research showed that YSV inhibited adhesion and invasion of human lung cancer cells and exhibited therapeutic effects on metastasis of lung cancer. PMID:27041993

  6. The Effect of Minimally Invasive Hematoma Aspiration on the JNK Signal Transduction Pathway after Experimental Intracerebral Hemorrhage in Rats

    Science.gov (United States)

    Pei, Haitao; Jiang, Tao; Liu, Guofang; Li, Zhaoxing; Luo, Kai; An, Jingjiao; Li, Guangcheng; Guo, Yunliang

    2016-01-01

    expressions of pJNK increasing. MIHA could relieve the histo-pathological damage of nerve cells, reducing brain edema and neurological deficits, and these neuroprotective effects might be associated with suppression of JNK signal transduction pathway. PMID:27187368

  7. Adeno-associated viral vector transduction of human mesenchymal stem cells

    DEFF Research Database (Denmark)

    Stender, Stefan; Murphy, Mary; O'Brien, Tim;

    2007-01-01

    Mesenchymal stem cells (MSCs) have received considerable attention in the emerging field of regenerative medicine. One aspect of MSC research focuses on genetically modifying the cells with the aim of enhancing their regenerative potential. Adeno-associated virus (AAV) holds promise as a vector...... for human gene therapy, primarily due to its lack of pathogenicity and low risk of insertional mutagenesis. However, the existing data pertaining to AAV transduction of MSCs is limited. The objective of this work was to examine the efficiency and kinetics of in vitro transduction using AAV serotype 2...... in human MSCs and to assess whether AAV transduction affects MSC multipotentiality. The results indicated that human MSCs could indeed be transiently transduced in vitro by the AAV2 vector with efficiencies of up to 65%. The percentage of GFP-positive cells peaked at 4 days post-transduction and declined...

  8. Real-time neutron scattering investigations of biological signal transduction dynamics

    Energy Technology Data Exchange (ETDEWEB)

    May, Roland [Institut Laue-Langevinx, Grenoble Cedex (France); Hendriks, Johnny [Vrije Universiteit Amsterdam, Amsterdam (Netherlands); Crielaard, Wim [Swammerdam Institute for Life Sciences and Academic Center for Dentistry, University of Amsterdam, Amsterdam (Netherlands)

    2005-07-01

    During their catalytic cycle, proteins involved in biological signal transduction undergo unexpectedly large conformational changes, which are at the core of their biological functioning. Until now it has been extremely difficult to obtain experimental insight into the nature of these conformational changes. Mathematical modeling and time-resolved X-ray crystallography have resulted in probable routes along which these conformational changes may take place, but so far this fundamental biological phenomenon has hardly been tackled experimentally. Here, we report on an attempt to observe structural changes in Photoactive Yellow Protein with time-resolved small-angle neutron scattering using diffractometer D22 at the high-flux reactor of the Institut Laue-Langevin, Grenoble, France.

  9. Smartphone Operated Signal Transduction by Ion Nanogating (STING) Amplifier for Nanopore Sensors: Design and Analytical Application

    Science.gov (United States)

    Özel, Rıfat Emrah; Kahnemouyi, Sina; Fan, Hsinwen; Mak, Wai Han; Lohith, Akshar; Seger, Adam; Teodorescu, Mircea; Pourmand, Nader

    2016-01-01

    In this report, we demonstrated a handheld wireless voltage-clamp amplifier for current measurement of nanopore sensors. This amplifier interfaces a sensing probe and connects wirelessly with a computer or smartphone for the required stimulus input, data processing and storage. To test the proposed Signal Transduction by Ion Nanogating (STING) wireless amplifier, in the current study the system was tested with a nano-pH sensor to measure pH of standard buffer solutions and the performance was compared against the commercial voltage-clamp amplifier. To our best knowledge, STING amplifier is the first miniaturized wireless voltage-clamp platform operated with a customized smart-phone application (app). PMID:27602408

  10. Auxin as a Model for the Integration of Hormonal Signal Processing and Transduction

    Institute of Scientific and Technical Information of China (English)

    W.D.Teale; F.A.Ditengou; A.D.Dovzhenko; X.Li; A.M.Molendijk; B.Ruperti; I.Paponov; K.Palme

    2008-01-01

    The regulation of plant growth responds to many stimuli.These responses allow environmental adaptation,thereby increasing fitness.In many cases,the relay of information about a plant's environment is through plant hormones.These messengers integrate environmental information into developmental pathways to determine plant shape.This review will use,as an example,auxin in the root ofArabidopsis thaliana to illustrate the complex nature of hormonal signal processing and transduction.It will then make the case that the application of a systems-biology approach is necessary,if the relationship between a plant's environment and its growth/developmental responses is to be properly understood.

  11. Transcriptional Crosstalk between Nuclear Receptors and Cytokine Signal Transduction Pathways in Immunity

    Institute of Scientific and Technical Information of China (English)

    Lihua Wang; Xiaohu Zhang; William L. Farrar; Xiaoyi Yang

    2004-01-01

    The nuclear receptor superfamily and the transcriptional factors associated with cytokines are inherently different families of signaling molecules and activate gene transcription by binding to their respective responsive element. However, it has become increasingly clear from our works and others that nuclear receptors are important regulators of cytokine production and function through complex and varied interactions between these distinct transcriptional factors. This review provides a general overview of the mechanism of action of nuclear receptors and their transcriptional crosstalk with transcriptional factors associated with cytokine transduction pathways. One of the most important mechanistic aspects is protein to protein interaction through a direct or co-regulator-mediated indirect manner. Such crosstalk is crucially involved in physiological and therapeutic roles of nuclear receptors and their ligands in immunity,inflammation and cytokine-related tumors. Cellular & Molecular Immunology. 2004;1(6):416-424.

  12. Involvement of the p38 mitogen-activated protein kinase signal transduction pathway in burns-induced lung injury

    Institute of Scientific and Technical Information of China (English)

    CHEN Xu-lin; XIA Zhao-fan; WEI Duo; WANG Yong-jie; WANG Chang-rong

    2005-01-01

    @@ Acute lung injury (ALI) is a leading complication in extensively burned patients, especially those with inhalation injury.1 It can cause hypoxia resulting in injury of remote organs and dysfunction. P38 mitogen-activated protein kinase (p38 MAPK) is a stress activated protein kinase in the MAPK family.2 Most of the previous studies have demonstrated that p38 MAPK signal transduction pathway mediated ALI in rats with acute severe pancreatitis, sepsis etc.3-5 However, there is little information regarding the role of p38 MAPK signal transduction pathway in ALI after severe burn trauma.

  13. Chemotactic signal transduction and phosphate metabolism as adaptive strategies during citrus canker induction by Xanthomonas citri.

    Science.gov (United States)

    Moreira, Leandro Marcio; Facincani, Agda Paula; Ferreira, Cristiano Barbalho; Ferreira, Rafael Marine; Ferro, Maria Inês Tiraboshi; Gozzo, Fabio Cesar; de Oliveira, Julio Cezar Franco; Ferro, Jesus Aparecido; Soares, Márcia Regina

    2015-03-01

    The genome of Xanthomonas citri subsp. Citri strain 306 pathotype A (Xac) was completely sequenced more than 10 years; to date, few studies involving functional genomics Xac and its host compatible have been developed, specially related to adaptive events that allow the survival of Xac within the plant. Proteomic analysis of Xac showed that the processes of chemotactic signal transduction and phosphate metabolism are key adaptive strategies during the interaction of a pathogenic bacterium with its plant host. The results also indicate the importance of a group of proteins that may not be directly related to the classical virulence factors, but that are likely fundamental to the success of the initial stages of the infection, such as methyl-accepting chemotaxis protein (Mcp) and phosphate specific transport (Pst). Furthermore, the analysis of the mutant of the gene pstB which codifies to an ABC phosphate transporter subunit revealed a complete absence of citrus canker symptoms when inoculated in compatible hosts. We also conducted an in silico analysis which established the possible network of genes regulated by two-component systems PhoPQ and PhoBR (related to phosphate metabolism), and possible transcriptional factor binding site (TFBS) motifs of regulatory proteins PhoB and PhoP, detaching high degree of conservation of PhoB TFBS in 84 genes of Xac genome. This is the first time that chemotaxis signal transduction and phosphate metabolism were therefore indicated to be fundamental to the process of colonization of plant tissue during the induction of disease associated with Xanthomonas genus bacteria. PMID:25403594

  14. Effects of Low Dose Radiation on Signal Transduction of Neurons in Mouse Hypothalamus

    Institute of Scientific and Technical Information of China (English)

    2001-01-01

    Objective Effects of low dose radiation on signal transduction of neurons in mouse hypothalamus were investigated. Methods In the present study competitive protein binding assay, radioimmunoassay, in situ hybridization and immunohistochemistry were used to observe the effects of whole-body irradiation with 75 mGy X-rays on the contents of cAMP and cGMP and the expressions of c-fos mRNA, Fos protein and proopiomelanocortin (POMC) mRNA in the neurons of mouse hypothalamus. Results The results showed that cAMP content in mouse hypothalamus immediately increased significantly and reached the peak value in 15 min after irradiation, and then returned to near sham-irradiation level 1 h after irradiation, followed by a small fluctuation of increase and decrease; the changes of cGMP content were basically opposite to those of cAMP content, while the changes of cAMP/cGMP ratio were basically consistent with those of cAMP content. The expression of c-fos mRNA in the neurons of hypothalamus appeared 15 min after irradiation, reached its peak value within 1 h, began to abate 2 h with its total disappearance 8 h after irradiation; the expression of Fos protein reached its peak value 8 h after irradiation, and then gradually returned to sham-irradiation level 48 h after irradiation; the expression of POMC mRNA decreased significantly 1 h after irradiation and remained at a lower level in the observation period of 12 h. Conclusion These findings implicate that low dose radiation may potentiate the activity of the neurons in mouse hypothalamus, expedite their signal transduction, and down-regulate the functions of hypothalamus-pituitary-adrenocortical axis.

  15. Chemotactic signal transduction and phosphate metabolism as adaptive strategies during citrus canker induction by Xanthomonas citri.

    Science.gov (United States)

    Moreira, Leandro Marcio; Facincani, Agda Paula; Ferreira, Cristiano Barbalho; Ferreira, Rafael Marine; Ferro, Maria Inês Tiraboshi; Gozzo, Fabio Cesar; de Oliveira, Julio Cezar Franco; Ferro, Jesus Aparecido; Soares, Márcia Regina

    2015-03-01

    The genome of Xanthomonas citri subsp. Citri strain 306 pathotype A (Xac) was completely sequenced more than 10 years; to date, few studies involving functional genomics Xac and its host compatible have been developed, specially related to adaptive events that allow the survival of Xac within the plant. Proteomic analysis of Xac showed that the processes of chemotactic signal transduction and phosphate metabolism are key adaptive strategies during the interaction of a pathogenic bacterium with its plant host. The results also indicate the importance of a group of proteins that may not be directly related to the classical virulence factors, but that are likely fundamental to the success of the initial stages of the infection, such as methyl-accepting chemotaxis protein (Mcp) and phosphate specific transport (Pst). Furthermore, the analysis of the mutant of the gene pstB which codifies to an ABC phosphate transporter subunit revealed a complete absence of citrus canker symptoms when inoculated in compatible hosts. We also conducted an in silico analysis which established the possible network of genes regulated by two-component systems PhoPQ and PhoBR (related to phosphate metabolism), and possible transcriptional factor binding site (TFBS) motifs of regulatory proteins PhoB and PhoP, detaching high degree of conservation of PhoB TFBS in 84 genes of Xac genome. This is the first time that chemotaxis signal transduction and phosphate metabolism were therefore indicated to be fundamental to the process of colonization of plant tissue during the induction of disease associated with Xanthomonas genus bacteria.

  16. Suppression of tumorigenicity and metastatic potential of melanoma cells by transduction of interferon gene

    Directory of Open Access Journals (Sweden)

    Lykhova A. A.

    2014-01-01

    Full Text Available The aim of this study was to investigate an inhibitory effect of baculovirus-mediated transduction of the murine interferon-beta gene on mouse melanoma in vitro and in vivo. Methods. Studies were performed on B16 mouse melanoma (MM-4 cell line. Transduction, immunocytochemical and tumor cell biology approaches have been used in this study. Results. Transduction of MM-4 cells by the recombinant baculovirus with IFN-beta gene is accompanied by morphological changes of tumor cells, suppression of cell proliferation, significant inhibition of platting efficiency of cells and their colonies formation in semisolid agar. Moreover, transduction of melanoma MM-4 cells by the baculovirus IFN-transgene leads to inhibition of tumorigenicity and metastatic ability of the cells in vivo. The intravenous administration of recombinant baculovirus vector with IFN gene inhibits growth of metastases induced in the lungs of mice by intravenously injected tumor cells. Conclusions. Transduction of mouse melanoma cells by the recombinant baculovirus with murine IFN-beta gene inhibits their proliferative potential, tumorigenicity and metastatic activity.

  17. ARG1 and ARL2 contribute to gravity signal transduction in the statocytes of Arabidopsis thaliana roots and hypocotyls

    Science.gov (United States)

    Masson, Patrick; Harrison, Benjamin; Stanga, John; Otegui, Marisa; Sedbrook, John

    Gravity is an important cue that plant organs use to guide their growth. Each organ is characterized by a defined gravity set point angle that dictates its optimal orientation within the gravity field. Specialized cells, named statocytes, enable this directional growth response by perceiving gravity via the sedimentation of, and/or tension/pressure exerted by, starch-filled plastids within their cytoplasm. Located in the columella region of the cap in roots and in the endodermis of hypocotyls and stems, these cells modulate the lateral transport of auxin across the corresponding organ in a gravistimulus-dependent manner. Upon plant reorientation within the gravity field, a gravity signal transduction pathway is activated within those cells, which in roots leads to a relocalization of the PIN3 auxin efflux carrier toward the lower membrane and an alkalinization of the cytoplasm. In turn, these events appear to promote a lateral transport of auxin toward the bottom side of the stimulated organ, which promotes a curvature. We previously uncovered ARG1 and ARL2 as essential contributors to these cellular processes. Mutations in these genes result in altered root and hypocotyl gravitropism. In roots, this abnormal growth behavior is associated with a lack of PIN3 relocalization within the statocytes and an absence of preferential downward auxin transport upon gravistimulation. These two genes encode paralogous J-domain proteins that are associated with the plasma membrane and other membranes of the vesicular trafficking pathway, and appear to modulate protein trafficking within the statocytes. An analysis of the root gravitropic phenotypes associated with different double mutant configurations affecting ARG1, ARL2 and PIN3 suggest that all three proteins function in a common gravity-signaling pathway. Surprisingly, when a mutation that affects starch biosynthesis (pgm) is introgressed into an arg1-2 mutant, the gravitropic defects are dramatically enhanced relative to

  18. Mutations in the gravity persistence signal loci in Arabidopsis disrupt the perception and/or signal transduction of gravitropic stimuli

    Science.gov (United States)

    Wyatt, Sarah E.; Rashotte, Aaron M.; Shipp, Matthew J.; Robertson, Dominique; Muday, Gloria K.; Brown, C. S. (Principal Investigator)

    2002-01-01

    Gravity plays a fundamental role in plant growth and development, yet little is understood about the early events of gravitropism. To identify genes affected in the signal perception and/or transduction phase of the gravity response, a mutant screen was devised using cold treatment to delay the gravity response of inflorescence stems of Arabidopsis. Inflorescence stems of Arabidopsis show no response to gravistimulation at 4 degrees C for up to 3 h. However, when gravistimulated at 4 degrees C and then returned to vertical at room temperature (RT), stems bend in response to the previous, horizontal gravistimulation (H. Fukaki, H. Fujisawa, M. Tasaka [1996] Plant Physiology 110: 933-943). This indicates that gravity perception, but not the gravitropic response, occurs at 4 degrees C. Recessive mutations were identified at three loci using this cold effect on gravitropism to screen for gravity persistence signal (gps) mutants. All three mutants had an altered response after gravistimulation at 4 degrees C, yet had phenotypically normal responses to stimulations at RT. gps1-1 did not bend in response to the 4 degrees C gravity stimulus upon return to RT. gps2-1 responded to the 4 degrees C stimulus but bent in the opposite direction. gps3-1 over-responded after return to RT, continuing to bend to an angle greater than wild-type plants. At 4 degrees C, starch-containing statoliths sedimented normally in both wild-type and the gps mutants, but auxin transport was abolished at 4 degrees C. These results are consistent with GPS loci affecting an aspect of the gravity signal perception/transduction pathway that occurs after statolith sedimentation, but before auxin transport.

  19. 植物细胞中磷酸肌醇和磷脂酶C介导的信号转导%Signal Transduction by Phosphoinositides and Phospholipase C in Plant Cells

    Institute of Scientific and Technical Information of China (English)

    李莉; 井文; 章文华

    2015-01-01

    磷酸肌醇(PIs)是磷脂酰肌醇(PtdIns)单、双、三磷酸化产物的总称。磷脂酶C (PLC)水解磷脂酰肌醇-4,5-二磷酸[Pt-dIns(4,5)P2]产生二酰甘油(DAG)和肌醇三磷酸(InsP3),此双信使系统的靶蛋白分别是蛋白激酶C (PKC)和InsP3受体(钙通道蛋白)。此经典的信号途径是从动物细胞中发现的。到目前为止,植物中没有发现PKC或InsP3受体,但有其独特的磷酸肌醇信号组分和途径。与动物不同,植物PI含量最高的是磷脂酰肌醇-4-磷酸(PtdIns4P),最多可达PtdIns(4,5)P2的100倍;而DAG磷酸化产物磷脂酸(PA)和InsP3磷酸化产物肌醇六磷酸(InsP6)也被证明是植物中重要的信号分子。本文通过比较动、植物细胞中PI和PLC信号途径的差异,综述了植物细胞中PI和PLC途径的独特作用和调控机理。%Phosphoinositides (PIs) are mono-, bis-, or tris-phosphorylated derivatives of phosphatidylinositol (PtdIns). Phosphatidylinositol 4,5-bisphosphate [PtdIns(4,5)P2] can be hydrolyzed by phospholipase C (PLC) to produce diacylglycerol (DAG) and inositol trisphosphates (InsP3). In animal cells, DAG and InsP3 are important second messengers that activate protein kinase C (PKC) and InsP3 receptor (Ca2+ channel), respectively. How-ever, neither PKC nor InsP3 receptor has been found in plant cells. Instead, there are unique phosphoinositide signaling pathways in plant cells. In plants, PtdIns4P is the most abundant PI, and the ratio of phosphatidyli-nositol 4-phosphate (PtdIns4P) to PtdIns(4,5)P2 is as high as 100 to 1. The phosphorylated products of DAG and InsP3, phosphatidic acid (PA) and inositol hexakisphosphate (InsP6), respectively, are as signaling mole-cules in plants. This paper compared the PI and PLC signalings between plant and animal cells, and summa-rized the unique mechanism of PI and PLC pathways in plant cells.

  20. Microtubule dynamics and signal transduction at the immunological synapse: new partners and new connections

    OpenAIRE

    Lasserre, Rémi; Alcover, Andrés

    2012-01-01

    Antigen recognition induces T-cell polarization towards antigen presenting cells, generating the immunological synapse at the cell interface. Now, microtubule-mediated polarized vesicle transport is shown to be required for the organization of a signalling-competent synapse and hence T-cell activation.

  1. Novel effects of Helicobacter pylori CagA on key genes of gastric cancer signal transduction: a comparative transfection study.

    Science.gov (United States)

    Vaziri, Farzam; Peerayeh, Shahin N; Alebouyeh, Masoud; Maghsoudi, Nader; Azimzadeh, Pedram; Siadat, Seyed D; Zali, Mohammad R

    2015-04-01

    Helicobacter pylori (H. pylori) infection is now recognized as a worldwide problem. Helicobacter pylori CagA is the first bacterial oncoprotein to be identified in relation to human cancer. Helicobacter pylori CagA is noted for structural diversity in its C-terminal region (contains EPIYA motifs), with which CagA interacts with numerous host cell proteins. Deregulation of host signaling by translocated bacterial proteins provides a new aspect of microbial-host cell interaction. The aim of this study is to compare the cellular effects of two different CagA EPIYA motifs on identified signaling pathways involve in gastric carcinogenesis. To investigate the effects of CagA protein carboxyl region variations on the transcription of genes involved in gastric epithelial carcinogenesis pathways, the eukaryotic vector carrying the cagA gene (ABC and ABCCC types) was transfected into gastric cancer cell line. The 42 identified key genes of signal transduction involved in gastric cancer were analyzed at the transcription level by real-time PCR. The results of real-time PCR provide us important clue that the ABCCC oncoprotein variant can change the fate of the cell completely different from ABC type. In fact, these result proposed that the ABCCC type can induce the intestinal metaplasia, IL-8, perturbation of Crk adaptor proteins, anti-apoptotic effect and carcinogenic effect more significantly than ABC type. These data support our hypothesis of a complex interaction of host cell and these two different H. pylori effector variants that determines host cellular fate.

  2. Ensembles of signal transduction models using Pareto Optimal Ensemble Techniques (POETs).

    Science.gov (United States)

    Song, Sang Ok; Chakrabarti, Anirikh; Varner, Jeffrey D

    2010-07-01

    Mathematical modeling of complex gene expression programs is an emerging tool for understanding disease mechanisms. However, identification of large models sometimes requires training using qualitative, conflicting or even contradictory data sets. One strategy to address this challenge is to estimate experimentally constrained model ensembles using multiobjective optimization. In this study, we used Pareto Optimal Ensemble Techniques (POETs) to identify a family of proof-of-concept signal transduction models. POETs integrate Simulated Annealing (SA) with Pareto optimality to identify models near the optimal tradeoff surface between competing training objectives. We modeled a prototypical-signaling network using mass-action kinetics within an ordinary differential equation (ODE) framework (64 ODEs in total). The true model was used to generate synthetic immunoblots from which the POET algorithm identified the 117 unknown model parameters. POET generated an ensemble of signaling models, which collectively exhibited population-like behavior. For example, scaled gene expression levels were approximately normally distributed over the ensemble following the addition of extracellular ligand. Also, the ensemble recovered robust and fragile features of the true model, despite significant parameter uncertainty. Taken together, these results suggest that experimentally constrained model ensembles could capture qualitatively important network features without exact parameter information.

  3. Enhanced fluorescence cyanide detection at physiologically lethal levels: reduced ICT-based signal transduction.

    Science.gov (United States)

    Badugu, Ramachandram; Lakowicz, Joseph R; Geddes, Chris D

    2005-03-16

    Three water-soluble fluorescent probes have been specifically designed to determine free cyanide concentrations up to physiologically lethal levels, >20 microM. The probes have been designed in such a way as to afford many notable sensing features, which render them unique with regard to signal transduction, photophysical characteristics, and their application to physiological cyanide determination and safeguard. The probes are readily able to reversibly bind free aqueous cyanide with dissociation constants around 4 microM3. Subsequent cyanide binding modulates the intramolecular charge transfer within the probes, a change in the electronic properties within the probes, resulting in enhanced fluorescence optical signals as a function of increased solution cyanide concentration. The ground-state chelation with cyanide produces wavelength shifts, which also enable the probes to sense cyanide in both an excitation and emission ratiometric manner, in addition to enhanced fluorescence signaling. This has enabled a generic cyanide sensing platform to be realized that is not dependent on fluorescent probe concentration, probe photodegradation, or fluctuations in the intensity of any employed excitation sources, ideal for remote cyanide sensing applications. Further, the >600 nm fluorescence emission of the probes potentially allows for enhanced fluorescence ratiometric cyanide sensing in the optical window of tissues and blood, facilitating their use for the transdermal monitoring of cyanide for mammalian safeguard or postmortem in fire victims, both areas of active research. PMID:15755185

  4. β-arrestin 和信号转导%β-Arrestin and Signal Transduction

    Institute of Scientific and Technical Information of China (English)

    倪曙民; 叶孟; 王少敏

    2009-01-01

    β-arrestins are a family of important signaling adapter proteins and scaffold proteins. β-arrestins function not only as negative regulators of G-protein-coupled receptor (GPCR) signaling transduction, but also as scaffold proteins that promote other signaling pathways, such as Mitogen-activated protein kinase(MAPK) activated by GPCR. In addition, β-arrestin interacts with regulators of transcription factors, such as IκB and MDM2, and regulates indirectly transcription of NF-κB and p53.%β-arrestin是一类重要的信号调控蛋白和支架蛋白(scaffold).在G蛋白偶联受体(G-protein-coupled receptor,GPCR)信号转导中,β-arrestin不但可以作为GPCR信号的负性调控分子,还能作为支架蛋白促进GPCR对其他信号通路的激活,如有丝分裂原激活蛋白激酶(mitogen-activated protein kinase,MAPK)途径.另外β-arrestin还能与转录因子调节蛋白,如IKB和Mdm2相互作用间接调节NF-κB和P53介导的转录.

  5. Aberrant expression of proteins involved in signal transduction and DNA repair pathways in lung cancer and their association with clinical parameters.

    Directory of Open Access Journals (Sweden)

    Yong He

    Full Text Available BACKGROUND: Because cell signaling and cell metabolic pathways are executed through proteins, protein signatures in primary tumors are useful for identifying key nodes in signaling networks whose alteration is associated with malignancy and/or clinical outcomes. This study aimed to determine protein signatures in primary lung cancer tissues. METHODOLOGY/ PRINCIPAL FINDINGS: We analyzed 126 proteins and/or protein phosphorylation sites in case-matched normal and tumor samples from 101 lung cancer patients with reverse-phase protein array (RPPA assay. The results showed that 18 molecules were significantly different (p<0.05 by at least 30% between normal and tumor tissues. Most of those molecules play roles in cell proliferation, DNA repair, signal transduction and lipid metabolism, or function as cell surface/matrix proteins. We also validated RPPA results by Western blot and/or immunohistochemical analyses for some of those molecules. Statistical analyses showed that Ku80 levels were significantly higher in tumors of nonsmokers than in those of smokers. Cyclin B1 levels were significantly overexpressed in poorly differentiated tumors while Cox2 levels were significantly overexpressed in neuroendocrinal tumors. A high level of Stat5 is associated with favorable survival outcome for patients treated with surgery. CONCLUSIONS/ SIGNIFICANCE: Our results revealed that some molecules involved in DNA damage/repair, signal transductions, lipid metabolism, and cell proliferation were drastically aberrant in lung cancer tissues, and Stat5 may serve a molecular marker for prognosis of lung cancers.

  6. Engineering cell-cell signaling.

    Science.gov (United States)

    Blagovic, Katarina; Gong, Emily S; Milano, Daniel F; Natividad, Robert J; Asthagiri, Anand R

    2013-10-01

    Juxtacrine cell-cell signaling mediated by the direct interaction of adjoining mammalian cells is arguably the mode of cell communication that is most recalcitrant to engineering. Overcoming this challenge is crucial for progress in biomedical applications, such as tissue engineering, regenerative medicine, immune system engineering and therapeutic design. Here, we describe the significant advances that have been made in developing synthetic platforms (materials and devices) and synthetic cells (cell surface engineering and synthetic gene circuits) to modulate juxtacrine cell-cell signaling. In addition, significant progress has been made in elucidating design rules and strategies to modulate juxtacrine signaling on the basis of quantitative, engineering analysis of the mechanical and regulatory role of juxtacrine signals in the context of other cues and physical constraints in the microenvironment. These advances in engineering juxtacrine signaling lay a strong foundation for an integrative approach to utilize synthetic cells, advanced 'chassis' and predictive modeling to engineer the form and function of living tissues.

  7. Analysis of 4070A envelope levels in retroviral preparations and effect on target cell transduction efficiency.

    Science.gov (United States)

    Slingsby, J H; Baban, D; Sutton, J; Esapa, M; Price, T; Kingsman, S M; Kingsman, A J; Slade, A

    2000-07-01

    A number of stable producer cell lines for high-titer Mo-MuLV vectors have been constructed. Development has previously centered on increasing end-point titers by producing maximal levels of Mo-MuLV Gag/Pol, envelope glycoproteins, and retroviral RNA genomes. We describe the production yields and transduction efficiency characteristics of two Mo-MuLV packaging cell lines, FLYA13 and TEFLYA. Although they both produce 4070A-pseudotyped retroviral vectors reproducibly at >1 x 10(6) LFU ml(-1), the transduction efficiency of unconcentrated and concentrated virus from FLYA13 lines is poor compared with vector preparations from TEFLYA lines. A powerful inhibitor of retroviral transduction is secreted by FLYA13 packaging cells. We show that the inhibitory factor does not affect transduction of target cells by RD114-pseudotyped vectors. This suggests that the inhibitory factor functions at the level of envelope-receptor interactions. Phosphate starvation of target cells shows a two-fold increase in Pit2 receptor mRNA and causes some improvement in FLYA13 virus transduction efficiency. Western blots show that FLYA13 viral samples contain an eight-fold higher ratio of 4070A envelope to p30gag than that of virus produced by TEFLYA producer cell lines. This study correlates overexpression of 4070A envelope glycoprotein in retroviral preparations with a reduction of transduction efficiency at high multiplicities of infection. We suggest that TEFLYA packaging cells express preferable levels of 4070A compared with FLYA13, which not only enables high-titer stocks to be generated, but also facilitates a high efficiency of transduction of target cells. PMID:10910141

  8. Peroxiredoxins in Regulation of MAPK Signalling Pathways; Sensors and Barriers to Signal Transduction

    Science.gov (United States)

    Latimer, Heather R.; Veal, Elizabeth A.

    2016-01-01

    Peroxiredoxins are highly conserved and abundant peroxidases. Although the thioredoxin peroxidase activity of peroxiredoxin (Prx) is important to maintain low levels of endogenous hydrogen peroxide, Prx have also been shown to promote hydrogen peroxide-mediated signalling. Mitogen activated protein kinase (MAPK) signalling pathways mediate cellular responses to a variety of stimuli, including reactive oxygen species (ROS). Here we review the evidence that Prx can act as both sensors and barriers to the activation of MAPK and discuss the underlying mechanisms involved, focusing in particular on the relationship with thioredoxin. PMID:26813660

  9. Peroxiredoxins in Regulation of MAPK Signalling Pathways; Sensors and Barriers to Signal Transduction.

    Science.gov (United States)

    Latimer, Heather R; Veal, Elizabeth A

    2016-01-01

    Peroxiredoxins are highly conserved and abundant peroxidases. Although the thioredoxin peroxidase activity of peroxiredoxin (Prx) is important to maintain low levels of endogenous hydrogen peroxide, Prx have also been shown to promote hydrogen peroxide-mediated signalling. Mitogen activated protein kinase (MAPK) signalling pathways mediate cellular responses to a variety of stimuli, including reactive oxygen species (ROS). Here we review the evidence that Prx can act as both sensors and barriers to the activation of MAPK and discuss the underlying mechanisms involved, focusing in particular on the relationship with thioredoxin. PMID:26813660

  10. Hair cell mechano-transduction : Its influence on the gross mechanical characteristics of a hair cell sense organ

    NARCIS (Netherlands)

    vanNetten, SM

    1997-01-01

    The complex mechanical behaviour of a hair cell bundle appears to be a direct consequence of the gating forces on the individual transduction channels. The mechanical molecular interactions involved in transduction channel gating, therefore, also bear a reciprocal influence, via the hair bundles; on

  11. Design principles of nuclear receptor signaling: How complex networking improves signal transduction

    NARCIS (Netherlands)

    A.N. Kolodkin (Alexey); F.J. Bruggeman (Frank); N. Plant (Nick); M.J. Moné (Martijn); B.M. Bakker (Barbara); M.J. Campbell (Moray); J.P.T.M. van Leeuwen (Hans); C. Carlberg (Carsten); J.L. Snoep (Jacky); H.V. Westerhoff (Hans)

    2010-01-01

    textabstractThe topology of nuclear receptor (NR) signaling is captured in a systems biological graphical notation. This enables us to identify a number of design aspects of the topology of these networks that might appear unnecessarily complex or even functionally paradoxical. In realistic kinetic

  12. Design principles of nuclear receptor signaling : how complex networking improves signal transduction

    NARCIS (Netherlands)

    Kolodkin, Alexey N.; Bruggeman, Frank J.; Plant, Nick; Mone, Martijn J.; Bakker, Barbara M.; Campbell, Moray J.; van Leeuwen, Johannes P. T. M.; Carlberg, Carsten; Snoep, Jacky L.; Westerhoff, Hans V.

    2010-01-01

    The topology of nuclear receptor (NR) signaling is captured in a systems biological graphical notation. This enables us to identify a number of 'design' aspects of the topology of these networks that might appear unnecessarily complex or even functionally paradoxical. In realistic kinetic models of

  13. A Small G Protein as a Novel Component of the Rice Brassinosteroid Signal Transduction.

    Science.gov (United States)

    Zhang, Ge; Song, Xiaoguang; Guo, Hongyan; Wu, Yao; Chen, Xiaoying; Fang, Rongxiang

    2016-09-01

    Brassinosteroids (BRs) are a class of steroid hormones that are essential for plant growth and development. The BR signal transduction pathway in the dicot model plant Arabidopsis is well established, but the components connecting the BR signaling steps in rice have not been fully explored. For example, how the BR signaling is fine-tuned in rice, especially at the BR receptor level, is largely unknown. Here we show that OsPRA2, a rice small G protein, plays a repressive role in the BR signaling pathway. Lamina inclination, coleoptile elongation, and root inhibition assays indicated that rice plants with suppressed expression of OsPRA2 were more sensitive to exogenously applied brassinolide than the wild-type plants. Conversely, rice overexpressing OsPRA2 was less sensitive to exogenous brassinolide. Further study uncovered that OsPRA2 inhibited the dephosphorylation of, and thus inactivated the transcription factor BRASSINAZOLE-RESISTANT 1 (OsBZR1). More importantly, OsPRA2 was found to co-localize with and directly bind to rice BR receptor BRASSINOSTEROID-INSENSITIVE 1 (OsBRI1) at the plasma membrane. Additionally, the in vitro assays showed that OsPRA2 inhibits its autophosphorylation. This OsPRA2-OsBRI1 interaction led to the dissociation of OsBRI1 from its co-receptor OsBAK1, and abolished OsBRI1-mediated phosphorylation of OsBAK1. Together, these results reveal a possible working mechanism of OsPRA2 as a novel negative regulator on OsBRI1 and OsBZR1 and extend the knowledge about the regulatory mechanism of rice BR signaling.

  14. A Small G Protein as a Novel Component of the Rice Brassinosteroid Signal Transduction.

    Science.gov (United States)

    Zhang, Ge; Song, Xiaoguang; Guo, Hongyan; Wu, Yao; Chen, Xiaoying; Fang, Rongxiang

    2016-09-01

    Brassinosteroids (BRs) are a class of steroid hormones that are essential for plant growth and development. The BR signal transduction pathway in the dicot model plant Arabidopsis is well established, but the components connecting the BR signaling steps in rice have not been fully explored. For example, how the BR signaling is fine-tuned in rice, especially at the BR receptor level, is largely unknown. Here we show that OsPRA2, a rice small G protein, plays a repressive role in the BR signaling pathway. Lamina inclination, coleoptile elongation, and root inhibition assays indicated that rice plants with suppressed expression of OsPRA2 were more sensitive to exogenously applied brassinolide than the wild-type plants. Conversely, rice overexpressing OsPRA2 was less sensitive to exogenous brassinolide. Further study uncovered that OsPRA2 inhibited the dephosphorylation of, and thus inactivated the transcription factor BRASSINAZOLE-RESISTANT 1 (OsBZR1). More importantly, OsPRA2 was found to co-localize with and directly bind to rice BR receptor BRASSINOSTEROID-INSENSITIVE 1 (OsBRI1) at the plasma membrane. Additionally, the in vitro assays showed that OsPRA2 inhibits its autophosphorylation. This OsPRA2-OsBRI1 interaction led to the dissociation of OsBRI1 from its co-receptor OsBAK1, and abolished OsBRI1-mediated phosphorylation of OsBAK1. Together, these results reveal a possible working mechanism of OsPRA2 as a novel negative regulator on OsBRI1 and OsBZR1 and extend the knowledge about the regulatory mechanism of rice BR signaling. PMID:27375203

  15. The anaphase-promoting complex protein 5 (AnapC5 associates with A20 and inhibits IL-17-mediated signal transduction.

    Directory of Open Access Journals (Sweden)

    Allen W Ho

    Full Text Available IL-17 is the founding member of a family of cytokines and receptors with unique structures and signaling properties. IL-17 is the signature cytokine of Th17 cells, a relatively new T cell population that promotes inflammation in settings of infection and autoimmunity. Despite advances in understanding Th17 cells, mechanisms of IL-17-mediated signal transduction are less well defined. IL-17 signaling requires contributions from two receptor subunits, IL-17RA and IL-17RC. Mutants of IL-17RC lacking the cytoplasmic domain are nonfunctional, indicating that IL-17RC provides essential but poorly understood signaling contributions to IL-17-mediated signaling. To better understand the role of IL-17RC in signaling, we performed a yeast 2-hybrid screen to identify novel proteins associated with the IL-17RC cytoplasmic tail. One of the most frequent candidates was the anaphase promoting complex protein 7 (APC7 or AnapC7, which interacted with both IL-17RC and IL-17RA. Knockdown of AnapC7 by siRNA silencing exerted no detectable impact on IL-17 signaling. However, AnapC5, which associates with AnapC7, was also able to bind IL-17RA and IL-17RC. Moreover, AnapC5 silencing enhanced IL-17-induced gene expression, suggesting an inhibitory activity. Strikingly, AnapC5 also associated with A20 (TNFAIP3, a recently-identified negative feedback regulator of IL-17 signal transduction. IL-17 signaling was not impacted by knockdown of Itch or TAXBP1, scaffolding proteins that mediate A20 inhibition in the TNFα and IL-1 signaling pathways. These data suggest a model in which AnapC5, rather than TAX1BP1 and Itch, is a novel adaptor and negative regulator of IL-17 signaling pathways.

  16. Apurinic/apyrimidinic endonuclease1/redox factor-1 (Ape1/Ref-1) is essential for IL-21-induced signal transduction through ERK1/2 pathway.

    Science.gov (United States)

    Juliana, Farha M; Nara, Hidetoshi; Onoda, Tadashi; Rahman, Mizanur; Araki, Akemi; Jin, Lianjin; Fujii, Hodaka; Tanaka, Nobuyuki; Hoshino, Tomoaki; Asao, Hironobu

    2012-04-13

    IL-21 is a pleiotropic cytokine that regulates T-cell and B-cell differentiation, NK-cell activation, and dendritic cell functions. IL-21 activates the JAK-STAT, ERK, and PI3K pathways. We report here that Ape1/Ref-1 has an essential role in IL-21-induced cell growth signal transduction. Overexpression of Ape1/Ref-1 enhances IL-21-induced cell proliferation, but it is suppressed by overexpressing an N-terminal deletion mutant of Ape1/Ref-1 that lacks the redox domain. Furthermore, knockdown of the Ape1/Ref-1 mRNA dramatically compromises IL-21-induced ERK1/2 activation and cell proliferation with increasing cell death. These impaired activities are recovered by the re-expression of Ape1/Ref-1 in the knockdown cells. Our findings are the first demonstration that Ape1/Ref-1 is an indispensable molecule for the IL-21-mediated signal transduction through ERK1/2 activation.

  17. DMPD: Gram-negative endotoxin: an extraordinary lipid with profound effects oneukaryotic signal transduction. [Dynamic Macrophage Pathway CSML Database

    Lifescience Database Archive (English)

    Full Text Available 1916089 Gram-negative endotoxin: an extraordinary lipid with profound effects oneuk...ep;5(12):2652-60. (.png) (.svg) (.html) (.csml) Show Gram-negative endotoxin: an extraordinary lipid with profound effects...tive endotoxin: an extraordinary lipid with profound effects oneukaryotic signal transduction. Authors Raetz

  18. Comparative analysis of two-component signal transduction systems of Bacillus cereus, Bacillus thuringiensis and Bacillus anthracis

    NARCIS (Netherlands)

    Been, M.W.H.J. de; Francke, C.; Moezelaar, R.; Abee, T.; Siezen, R.J.

    2006-01-01

    Members of the Bacillus cereus group are ubiquitously present in the environment and can adapt to a wide range of environmental fluctuations. In bacteria, these adaptive responses are generally mediated by two-component signal transduction systems (TCSs), which consist of a histidine kinase (HK) and

  19. The human keratinocyte two-dimensional gel protein database (update 1995): mapping components of signal transduction pathways

    DEFF Research Database (Denmark)

    Celis, J E; Rasmussen, H H; Gromov, P;

    1995-01-01

    )vaccinia virus expression of full length cDNAs, and (vi) in vitro transcription/translation of full-length cDNAs. This year, special emphasis has been given to the identification of signal transduction components by using 2-D gel immunoblotting of crude keratinocyte lysates in combination with enhanced...

  20. Restoration of autophagy alleviates hepatic ER stress and impaired insulin signalling transduction in high fructose-fed male mice.

    Science.gov (United States)

    Wang, Hao; Sun, Ruo-Qiong; Zeng, Xiao-Yi; Zhou, Xiu; Li, Songpei; Jo, Eunjung; Molero, Juan C; Ye, Ji-Ming

    2015-01-01

    High-carbohydrate (mainly fructose) consumption is a major dietary factor for hepatic insulin resistance, involving endoplasmic reticulum (ER) stress and lipid accumulation. Because autophagy has been implicated in ER stress, the present study investigated the role of autophagy in high-fructose (HFru) diet-induced hepatic ER stress and insulin resistance in male C57BL/6J mice. The results show that chronic HFru feeding induced glucose intolerance and impaired insulin signaling transduction in the liver, associated with ER stress and the accumulation of lipids. Intriguingly, hepatic autophagy was suppressed as a result of activation of mammalian target of rapamycin. The suppressed autophagy was detected within 6 hours after HFru feeding along with activation of both inositol-requiring enzyme 1 and protein kinase RNA-like endoplasmic reticulum kinase pathways. These events occurred prior to lipid accumulation or lipogenesis and were sufficient to blunt insulin signaling transduction with activation of c-Jun N-terminal kinase/inhibitory-κB kinase and serine phosphorylation of insulin receptor substrate 1. The stimulation of autophagy attenuated ER stress- and c-Jun N-terminal kinase/inhibitory-κB kinase-associated impairment in insulin signaling transduction in a mammalian target of rapamycin -independent manner. Taken together, our data suggest that restoration of autophagy functions disrupted by fructose is able to alleviate ER stress and improve insulin signaling transduction.

  1. Molecular profiling reveals diversity of stress signal transduction cascades in highly penetrant Alzheimer's disease human skin fibroblasts.

    Directory of Open Access Journals (Sweden)

    Graziella Mendonsa

    Full Text Available The serious and growing impact of the neurodegenerative disorder Alzheimer's disease (AD as an individual and societal burden raises a number of key questions: Can a blanket test for Alzheimer's disease be devised forecasting long-term risk for acquiring this disorder? Can a unified therapy be devised to forestall the development of AD as well as improve the lot of present sufferers? Inflammatory and oxidative stresses are associated with enhanced risk for AD. Can an AD molecular signature be identified in signaling pathways for communication within and among cells during inflammatory and oxidative stress, suggesting possible biomarkers and therapeutic avenues? We postulated a unique molecular signature of dysfunctional activity profiles in AD-relevant signaling pathways in peripheral tissues, based on a gain of function in G-protein-coupled bradykinin B2 receptor (BKB2R inflammatory stress signaling in skin fibroblasts from AD patients that results in tau protein Ser hyperphosphorylation. Such a signaling profile, routed through both phosphorylation and proteolytic cascades activated by inflammatory and oxidative stresses in highly penetrant familial monogenic forms of AD, could be informative for pathogenesis of the complex multigenic sporadic form of AD. Comparing stimulus-specific cascades of signal transduction revealed a striking diversity of molecular signaling profiles in AD human skin fibroblasts that express endogenous levels of mutant presenilins PS-1 or PS-2 or the Trisomy 21 proteome. AD fibroblasts bearing the PS-1 M146L mutation associated with highly aggressive AD displayed persistent BKB2R signaling plus decreased ERK activation by BK, correctible by gamma-secretase inhibitor Compound E. Lack of these effects in the homologous PS-2 mutant cells indicates specificity of presenilin gamma-secretase catalytic components in BK signaling biology directed toward MAPK activation. Oxidative stress revealed a JNK-dependent survival

  2. Essential role of Her3 in two signaling transduction patterns: Her2/Her3 and MET/Her3 in proliferation of human gastric cancer.

    Science.gov (United States)

    Yun, Chen; Gang, Li; Rongmin, Gu; Xu, Wen; Xuezhi, Ming; Huanqiu, Chen

    2015-12-01

    Various receptor tyrosine kinase (RTK) pathways were verified in many cancers including gastric cancer (GC), We sought to investigate the expression of RTKs including Her2, Her3, and Met and their transduction patterns in human GC. Over-expression of Her2, Her3, and c-Met in human GC was verified by immunohistochemistry leading to constitutive activation of RTK signaling pathways. Combined RTKs expression was valuable indicators for poor prognosis of GC patients. Using ErbB2 specific inhibitor Lapatinib and c-Met specific inhibitor PHA-665752, we further demonstrated that this constitutive activation of RTK signaling is necessary for the survival of GC cells. However, various RTK pattern: Her3/Her2 and Met/Her3 were verified in the transduction growth stimulus from outside via both AKT and MAPK signaling. Moreover, the essential roles of Her3 in both two heterodimers were obtained which showed significantly attenuated growth effect due to Her3 knockdown both in vitro and in vivo. In conclusion, various molecular transduction patterns: Her2/Her3 and Met/Her3 were verified in human GC, and Her3 could serve as a potential target in GC treatment.

  3. Small Molecule Inhibition of Ligand-Stimulated RAGE-DIAPH1 Signal Transduction

    Science.gov (United States)

    Manigrasso, Michaele B.; Pan, Jinhong; Rai, Vivek; Zhang, Jinghua; Reverdatto, Sergey; Quadri, Nosirudeen; DeVita, Robert J.; Ramasamy, Ravichandran; Shekhtman, Alexander; Schmidt, Ann Marie

    2016-01-01

    The receptor for advanced glycation endproducts (RAGE) binds diverse ligands linked to chronic inflammation and disease. NMR spectroscopy and x-ray crystallization studies of the extracellular domains of RAGE indicate that RAGE ligands bind by distinct charge- and hydrophobicity-dependent mechanisms. The cytoplasmic tail (ct) of RAGE is essential for RAGE ligand-mediated signal transduction and consequent modulation of gene expression and cellular properties. RAGE signaling requires interaction of ctRAGE with the intracellular effector, mammalian diaphanous 1 or DIAPH1. We screened a library of 58,000 small molecules and identified 13 small molecule competitive inhibitors of ctRAGE interaction with DIAPH1. These compounds, which exhibit in vitro and in vivo inhibition of RAGE-dependent molecular processes, present attractive molecular scaffolds for the development of therapeutics against RAGE-mediated diseases, such as those linked to diabetic complications, Alzheimer’s disease, and chronic inflammation, and provide support for the feasibility of inhibition of protein-protein interaction (PPI). PMID:26936329

  4. Signal transduction in light–oxygen–voltage receptors lacking the adduct-forming cysteine residue

    Science.gov (United States)

    Yee, Estella F.; Diensthuber, Ralph P.; Vaidya, Anand T.; Borbat, Peter P.; Engelhard, Christopher; Freed, Jack H.; Bittl, Robert; Möglich, Andreas; Crane, Brian R.

    2015-01-01

    Light–oxygen–voltage (LOV) receptors sense blue light through the photochemical generation of a covalent adduct between a flavin-nucleotide chromophore and a strictly conserved cysteine residue. Here we show that, after cysteine removal, the circadian-clock LOV-protein Vivid still undergoes light-induced dimerization and signalling because of flavin photoreduction to the neutral semiquinone (NSQ). Similarly, photoreduction of the engineered LOV histidine kinase YF1 to the NSQ modulates activity and downstream effects on gene expression. Signal transduction in both proteins hence hinges on flavin protonation, which is common to both the cysteinyl adduct and the NSQ. This general mechanism is also conserved by natural cysteine-less, LOV-like regulators that respond to chemical or photoreduction of their flavin cofactors. As LOV proteins can react to light even when devoid of the adduct-forming cysteine, modern LOV photoreceptors may have arisen from ancestral redox-active flavoproteins. The ability to tune LOV reactivity through photoreduction may have important implications for LOV mechanism and optogenetic applications. PMID:26648256

  5. Converting mid-infrared signals to near-infrared through optomechanical transduction

    Science.gov (United States)

    Kapsalis, A.; Mesaritakis, C.; Bogris, A.; Syvridis, D.

    2015-01-01

    Mid-infrared silicon photonics emerge as the dominant technology to bridge photonics and electronics in multifunctional high-speed integrated chips. The transmission and processing of optical signals lying at the mid-infrared wavelength region is ideal for sensing, absorption-spectroscopy and free-space communications and the use of group IV materials becomes principally promising as the vehicle towards their realization. In parallel, optical forces originating from modes and cavities can reach to outstandingly large values when sizes drop into the nanoscale. In this work, we propose the exploitation of large gradient optical forces generated between suspended silicon beams and optomechanical transduction as a means of converting signals from the mid-infrared to the near-infrared region. A midinfrared signal is injected into the waveguide system so as to excite the fundamental symmetric mode. In the 2-5μm wavelength range, separation gaps in the 100nm order and waveguide widths ranging from 300-600nm, the mode is mostly guided in the air slot between the waveguides which maximizes the optomechanical coupling coefficient and optical force. The resulting attractive force deflects the waveguides and the deflection is linearly dependent on the midinfrared optical power. A simple read-out technique using 1.55μm signals with conventional waveguiding in the directional coupler formed by the two beams is analyzed. A positive conversion efficiency (<0dB) is foreseen for waveguides with suspending lengths up to 150μm. The converter could be ideal for use in sensing and spectroscopy rendering the inefficient mid-infrared detectors obsolete. The low-index unconventional guiding in mid-infrared could be a key component towards multifunctional lab-on-a-chip devices.

  6. Decitabine suspends human CD34+ cell differentiation and proliferation during lentiviral transduction.

    Science.gov (United States)

    Uchida, Naoya; Hsieh, Matthew M; Platner, Charlotte; Saunthararajah, Yogen; Tisdale, John F

    2014-01-01

    Efficient ex vivo transduction of hematopoietic stem cells (HSCs) is encumbered by differentiation which reduces engraftment. We hypothesized that inhibiting DNA methyltransferase with decitabine would block differentiation of transduced CD34+ cells under cytokine stimulation and thus improve transduction efficiency for engrafting HSCs. Human CD34+ cells in cytokine-containing media were treated with or without decitabine for 24 or 48 hours, and then these cells were transduced with a GFP-expressing lentiviral vector. Utilizing decitabine pre-treatment for 48 hours, we observed an equivalent percentage of successfully transduced cells (GFP-positivity) and a higher percentage of cells that retained CD34 positivity, compared to no decitabine exposure. Cell proliferation was inhibited after decitabine exposure. Similar results were observed among CD34+ cells from six different donors. Repopulating activity was evaluated by transplantation into NOD/SCID/IL2Rγnull mice and demonstrated an equivalent percentage of GFP-positivity in human cells from decitabine-treated samples and a trend for higher human cell engraftment (measured 20-24 weeks after transplantation), compared to no decitabine exposure. In conclusion, ex vivo decitabine exposure inhibits both differentiation and proliferation in transduced human CD34+ cells and modestly increases the engraftment ability in xenograft mice, while the transduction efficiency is equivalent in decitabine exposure, suggesting improvement of lentiviral transduction for HSCs.

  7. Decitabine suspends human CD34+ cell differentiation and proliferation during lentiviral transduction.

    Directory of Open Access Journals (Sweden)

    Naoya Uchida

    Full Text Available Efficient ex vivo transduction of hematopoietic stem cells (HSCs is encumbered by differentiation which reduces engraftment. We hypothesized that inhibiting DNA methyltransferase with decitabine would block differentiation of transduced CD34+ cells under cytokine stimulation and thus improve transduction efficiency for engrafting HSCs. Human CD34+ cells in cytokine-containing media were treated with or without decitabine for 24 or 48 hours, and then these cells were transduced with a GFP-expressing lentiviral vector. Utilizing decitabine pre-treatment for 48 hours, we observed an equivalent percentage of successfully transduced cells (GFP-positivity and a higher percentage of cells that retained CD34 positivity, compared to no decitabine exposure. Cell proliferation was inhibited after decitabine exposure. Similar results were observed among CD34+ cells from six different donors. Repopulating activity was evaluated by transplantation into NOD/SCID/IL2Rγnull mice and demonstrated an equivalent percentage of GFP-positivity in human cells from decitabine-treated samples and a trend for higher human cell engraftment (measured 20-24 weeks after transplantation, compared to no decitabine exposure. In conclusion, ex vivo decitabine exposure inhibits both differentiation and proliferation in transduced human CD34+ cells and modestly increases the engraftment ability in xenograft mice, while the transduction efficiency is equivalent in decitabine exposure, suggesting improvement of lentiviral transduction for HSCs.

  8. Ligation of MHC class I and class II molecules can lead to heterologous desensitization of signal transduction pathways that regulate homotypic adhesion in human lymphocytes.

    Science.gov (United States)

    Wagner, N; Engel, P; Vega, M; Tedder, T F

    1994-06-01

    Engagement of lymphocyte MHC class I and class II Ags activates an array of intracellular signal transduction pathways that up-regulates the activity of cell-surface adhesion receptors, resulting in homotypic cell-cell aggregation. In this study, engagement of MHC class I and class II molecules with specific mAbs was shown to also inhibit lymphocyte homotypic adhesion. Two mAbs reactive with class II Ag, homotypic adhesion blocking mAb (HAB)-2, and HAB-3, and one mAb reactive with class I Ag, HAB-4, were generated that inhibited homotypic adhesion of activated lymphocytes and B and T cell lines at concentrations as low as 0.1 microgram/ml. Binding of these mAbs resulted in heterologous desensitization of other surface signal transduction molecules as homotypic adhesion induced through class I, class II, CD19, CD20, CD39, CD40, Leu-13, and PMA was also inhibited. The spontaneous adhesion exhibited by some cell lines was also abrogated by binding of these mAbs. Abs that either induced, blocked, or had no effect on adhesion bound to distinct epitopes on class I, whereas the anti-class II mAbs recognized either distinct or overlapping epitopes. Thus, engagement of distinct epitopes on MHC molecules can result in homologous or heterologous desensitization of cell-surface signaling molecules. The induction or inhibition of homotypic adhesion through class I molecules did not require the presence of the cytoplasmic domain, as deletion of this portion of the class I molecule had no effect. In contrast, the transmembrane region was essential for signal transduction as the mAbs binding to a chimeric molecule in which the transmembrane and cytoplasmic domains of class I were exchanged with those of the HB15 molecule did not induce or inhibit homotypic adhesion. Although this report is the first demonstration that homotypic adhesion can be influenced in a negative manner through MHC molecules, these findings demonstrate a considerable level of cross-talk between MHC molecules

  9. Radiation-induced signal transduction mechanisms and consequences; Modification de la signalisation intracellulaire provoquee par l'irradiation. Mecanismes et consequences

    Energy Technology Data Exchange (ETDEWEB)

    Herrlich, P. [Karlsruhe Univ. (T.H.) (Germany); Herrlich, P.; Bender, K.; Knebel, A.; Blattner, Ch.; Rahmsdorf, H.J.; Gottlicher, M. [Forschungszentrum Karlsruhe (Germany). Inst. fuer Genetik; Bohmer, F.; Grob, S. [Research Unit Molecular Cell Biology, Klinikum der Friedrich Schiller Universitat Jena (Germany)

    1999-03-01

    Over a dose range up to 50 Gy of low-LET (linear energy transfer) ionizing radiation and up to 5 kJ/m{sup 2} UVB, mammalian cells convert molecular damage into productive response (mostly gain of function). By inactivation of negative regulatory components, such as protein tyrosine phosphatases as one mechanism discovered, the balance between restraining and stimulating influences is disturbed and an increase in signal flow results. Also DNA damage causing transcriptional arrest produces a signalling cascade of as yet unknown details. Such stimulation of the intracellular communication network can lead to apoptosis, elevated cell cycling and differentiation processes possibly including repair and recombination. The outcome likely depends on integration of all signals received which is as yet ill-understood. Although accurate determinations of low-dose inductions have not been achieved for technical reasons, the dose-response curves of induced signal transduction likely show threshold characteristics, in contrast to the direct consequences of DNA damage. (author)

  10. Signal transduction controls heterogeneous NF-κB dynamics and target gene expression through cytokine-specific refractory states

    Science.gov (United States)

    Adamson, Antony; Boddington, Christopher; Downton, Polly; Rowe, William; Bagnall, James; Lam, Connie; Maya-Mendoza, Apolinar; Schmidt, Lorraine; Harper, Claire V.; Spiller, David G.; Rand, David A.; Jackson, Dean A.; White, Michael R. H.; Paszek, Pawel

    2016-01-01

    Cells respond dynamically to pulsatile cytokine stimulation. Here we report that single, or well-spaced pulses of TNFα (>100 min apart) give a high probability of NF-κB activation. However, fewer cells respond to shorter pulse intervals (<100 min) suggesting a heterogeneous refractory state. This refractory state is established in the signal transduction network downstream of TNFR and upstream of IKK, and depends on the level of the NF-κB system negative feedback protein A20. If a second pulse within the refractory phase is IL-1β instead of TNFα, all of the cells respond. This suggests a mechanism by which two cytokines can synergistically activate an inflammatory response. Gene expression analyses show strong correlation between the cellular dynamic response and NF-κB-dependent target gene activation. These data suggest that refractory states in the NF-κB system constitute an inherent design motif of the inflammatory response and we suggest that this may avoid harmful homogenous cellular activation. PMID:27381163

  11. Phosphodiesterase 4D acts downstream of Neuropilin to control Hedgehog signal transduction and the growth of medulloblastoma.

    Science.gov (United States)

    Ge, Xuecai; Milenkovic, Ljiljana; Suyama, Kaye; Hartl, Tom; Purzner, Teresa; Winans, Amy; Meyer, Tobias; Scott, Matthew P

    2015-01-01

    Alterations in Hedgehog (Hh) signaling lead to birth defects and cancers including medulloblastoma, the most common pediatric brain tumor. Although inhibitors targeting the membrane protein Smoothened suppress Hh signaling, acquired drug resistance and tumor relapse call for additional therapeutic targets. Here we show that phosphodiesterase 4D (PDE4D) acts downstream of Neuropilins to control Hh transduction and medulloblastoma growth. PDE4D interacts directly with Neuropilins, positive regulators of Hh pathway. The Neuropilin ligand Semaphorin3 enhances this interaction, promoting PDE4D translocation to the plasma membrane and cAMP degradation. The consequent inhibition of protein kinase A (PKA) enhances Hh transduction. In the developing cerebellum, genetic removal of Neuropilins reduces Hh signaling activity and suppresses proliferation of granule neuron precursors. In mouse medulloblastoma allografts, PDE4D inhibitors suppress Hh transduction and inhibit tumor growth. Our findings reveal a new regulatory mechanism of Hh transduction, and highlight PDE4D as a promising target to treat Hh-related tumors. PMID:26371509

  12. A cytosolic juxtamembrane interface modulates plexin A3 oligomerization and signal transduction.

    Directory of Open Access Journals (Sweden)

    Rachael Barton

    Full Text Available Plexins (plxns are transmembrane (TM receptors involved in the guidance of vascular, lymphatic vessel, and neuron growth as well as cancer metastasis. Plxn signaling results in cytosolic GTPase-activating protein activity, and previous research implicates dimerization as important for activation of plxn signaling. Purified, soluble plxn extracellular and cytosolic domains exhibit only weak homomeric interactions, suggesting a role for the plxn TM and juxtamembrane regions in homooligomerization. In this study, we consider a heptad repeat in the Danio rerio PlxnA3 cytosolic juxtamembrane domain (JM for its ability to influence PlxnA3 homooligomerization in TM-domain containing constructs. Site-directed mutagenesis in conjunction with the AraTM assay and bioluminescent energy transfer (BRET² suggest an interface involving a JM heptad repeat, in particular residue M1281, regulates PlxnA3 homomeric interactions when examined in constructs containing an ectodomain, TM and JM domain. In the presence of a neuropilin-2a co-receptor and semaphorin 3F ligand, disruption to PlxnA3 homodimerization caused by an M1281F mutation is eliminated, suggesting destabilization of the PlxnA3 homodimer in the JM is not sufficient to disrupt co-receptor complex formation. In contrast, enhanced homodimerization of PlxnA3 caused by mutation M1281L remains even in the presence of ligand semaphorin 3F and co-receptor neuropilin-2a. Consistent with this pattern of PlxnA3 dimerization in the presence of ligand and co-receptor, destabilizing mutations to PlxnA3 homodimerization (M1281F are able to rescue motor patterning defects in sidetracked zebrafish embryos, whereas mutations that enhance PlxnA3 homodimerization (M1281L are not. Collectively, our results indicate the JM heptad repeat, in particular residue M1281, forms a switchable interface that modulates both PlxnA3 homomeric interactions and signal transduction.

  13. Regulation of Early Steps of GPVI Signal Transduction by Phosphatases: A Systems Biology Approach.

    Directory of Open Access Journals (Sweden)

    Joanne L Dunster

    2015-11-01

    Full Text Available We present a data-driven mathematical model of a key initiating step in platelet activation, a central process in the prevention of bleeding following Injury. In vascular disease, this process is activated inappropriately and causes thrombosis, heart attacks and stroke. The collagen receptor GPVI is the primary trigger for platelet activation at sites of injury. Understanding the complex molecular mechanisms initiated by this receptor is important for development of more effective antithrombotic medicines. In this work we developed a series of nonlinear ordinary differential equation models that are direct representations of biological hypotheses surrounding the initial steps in GPVI-stimulated signal transduction. At each stage model simulations were compared to our own quantitative, high-temporal experimental data that guides further experimental design, data collection and model refinement. Much is known about the linear forward reactions within platelet signalling pathways but knowledge of the roles of putative reverse reactions are poorly understood. An initial model, that includes a simple constitutively active phosphatase, was unable to explain experimental data. Model revisions, incorporating a complex pathway of interactions (and specifically the phosphatase TULA-2, provided a good description of the experimental data both based on observations of phosphorylation in samples from one donor and in those of a wider population. Our model was used to investigate the levels of proteins involved in regulating the pathway and the effect of low GPVI levels that have been associated with disease. Results indicate a clear separation in healthy and GPVI deficient states in respect of the signalling cascade dynamics associated with Syk tyrosine phosphorylation and activation. Our approach reveals the central importance of this negative feedback pathway that results in the temporal regulation of a specific class of protein tyrosine phosphatases in

  14. The allosteric behavior of Fur mediates oxidative stress signal transduction in Helicobacter pylori

    Directory of Open Access Journals (Sweden)

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