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1

Synthesis and stereochemical effects of pyrrolidinyl-acetylenic thieno[3,2-d]pyrimidines as EGFR and ErbB-2 inhibitors  

British Library Electronic Table of Contents (United Kingdom)

A novel class of pyrrolidinyl-acetyleneic thieno[3,2-d]pyrimidines has been identified which potently inhibit the EGFR and ErbB-2 receptor tyrosine kinases. Synthetic modifications of the pyrrolidine carbamate moiety result in a range of effects on enzyme and cellular potency. In addition, the impact of the absolute stereochemical configuration on cellular potency and oral mouse pharmacokinetics is described.

2009-01-01

2

Assessment of epidermal growth factor receptor (EGFR, ErbB1) and HER2 (ErbB2) protein expression levels and response to lapatinib (Tykerb, GW572016) in an expanded panel of human normal and tumour cell lines  

British Library Electronic Table of Contents (United Kingdom)

Abstract. Objective: Lapatinib (Tykerb, GW572016), a potent inhibitor of the catalytic activities of epidermal growth factor receptor (EGFR) and human epidermal growth factor receptor 2 (HER2) (ErbB2), inhibits population growth of selected EGFR and HER2 overexpressing cell lines. Previous studies with a small number of cell lines suggest a correlation between overexpression of EGFR and/or HER2 and sensitivity to growth inhibition by lapatinib; however, the precise determinants of lapatinib selectivity for tumour and/or other cells remain unclear. Materials and methods: To clarify the determinants of its selectivity in cultured cells, lapatinib-induced cell population growth inhibition and relative EGFR and HER2 protein expression were quantified in 61 different human tumour cell lines fro...

2007-01-01

3

Endogenous expression of HrasG12V induces developmental defects and neoplasms with copy number imbalances of the oncogene  

UK PubMed Central (United Kingdom)

We developed mice with germline endogenous expression of oncogenic Hras to study effects on development and mechanisms of tumor initiation. They had high perinatal mortality, abnormal...Full Text Available

2009-05-12

5

Oncogenic transformation produced by agents and modalities used in cancer therapy and its modulation  

International Nuclear Information System (INIS)

The long-term survival of certain patients after treatment with radiation or chemotherapeutic agents has allowed the realization that agents that effectively control cancer in the human subject may also possess an oncogenic potential, resulting in secondary malignancies in a significant proportion of surviving patients. A quantitative assessment of the oncogenic effects of these agents at a cellular level is important, as is information on conditions and agents that may effectively alter the development of the neoplastic state. Cell culture systems where the neoplastic transformation of cells can be scored after exposure to carcinogens offer powerful tools for evaluating the oncogenic potential of radiation and chemotherapeutic agents.

1982-01-01

6

Modulating factors in the expression of radiation-induced oncogenic transformation  

Energy Technology Data Exchange (ETDEWEB)

Many assays for oncogenic transformation have been developed ranging from those in established rodent cell lines where morphological alteration is scored, to those in human cells growing in nude mice where tumor invasiveness is scored. In general, systems that are most quantitaive are also the least relevant in terms of human carcinogenesis and human risk estimation. The development of cell culture systems has made it possible to assess at the cellular level the oncogenic potential of a variety of chemical, physical and viral agents. Cell culture systems afford the opportunity to identify factors and conditions that may prevent or enhance cellular transformation by radiation and chemicals. Permissive and protective factors in radiation-induced transformation include thyroid hormone and the tumor promoter TPA that increase the transformation incidence for a given dose of radiation, and retinoids, selenium, vitamin E, and 5-aminobenzamide that ...

1990-08-01

7

Modulating factors in the expression of radiation-induced oncogenic transformation  

International Nuclear Information System (INIS)

Many assays for oncogenic transformation have been developed ranging from those in established rodent cell lines where morphological alteration is scored, to those in human cells growing in nude mice where tumor invasiveness is scored. In general, systems that are most quantitaive are also the least relevant in terms of human carcinogenesis and human risk estimation. The development of cell culture systems has made it possible to assess at the cellular level the oncogenic potential of a variety of chemical, physical and viral agents. Cell culture systems afford the opportunity to identify factors and conditions that may prevent or enhance cellular transformation by radiation and chemicals. Permissive and protective factors in radiation-induced transformation include thyroid hormone and the tumor promoter TPA that increase the transformation incidence for a given dose of radiation, and retinoids, selenium, vitamin E, and 5-aminobenzamide that ...

1990-01-01

8

Regulation of Senescence in Cancer and Aging  

UK PubMed Central (United Kingdom)

Senescence is regarded as a physiological response of cells to stress, including telomere dysfunction, aberrant oncogenic activation, DNA damage, and oxidative stress. This stress response has an antagonistically...Full Text Available

9

Ras activation of genes: Mob-1 as a model.  

UK PubMed Central (United Kingdom)

The ras oncogenes function by indirectly controlling expression of a subset of yet-undefined genes that are crucial for cell growth and differentiation. In a differential display strategy, numerous...Full Text Available

1994-12-20

10

Molecular Genetics and Carcinogenesis Section  

Science.gov (United States)

The Molecular Genetics and Carcinogenesis Section conducts studies using human epithelial cells to assess: activation of proto-oncogenes by chemical and physical carcinogens; inactivation and dysregulation of tumor suppressor genes by chemical and physical

11

Dysregulation of the mevalonate pathway promotes transformation  

UK PubMed Central (United Kingdom)

The importance of cancer metabolism has been appreciated for many years, but the intricacies of how metabolic pathways interconnect with oncogenic signaling are not fully understood. With a clear understanding...Full Text Available

2010-08-24

12

Trefoil Factor 3 Is Oncogenic and Mediates Anti-Estrogen Resistance in Human Mammary Carcinoma123  

UK PubMed Central (United Kingdom)

We report herein that trefoil factor 3 (TFF3) is oncogenic and mediates anti-estrogen resistance in human mammary carcinoma. Forced expression of TFF3 in mammary carcinoma cells increased cell proliferation...Full Text Available

2010-12-01

13

Malignant transformation of diploid human fibroblasts by transfection of oncogenes  

Energy Technology Data Exchange (ETDEWEB)

This document consist of brief reports prepared by postdoctoral students supported by the project, each describing his accomplishments under the grant. Topics include (1) Malignant Transformation of MSU-1. 1 Cells by Gamma Radiation, (2) Correlation between Levels of ras Expression and Presence of Transformed Phenotypes Including Tumorigenicity, Using a Modulatable Promoter, (3) Relation between Specific rad Oncogene Expression, (4) Correlation of Genetic Changes in Fibroblastic Tumors with Malignancies, (5)Transformation of MSU-1.1 Cells by sis Oncogene, (6) Malignant Transformation of MSU-1.0 Cells, (7) Correlation of Urokinase Plasminogen Activation (mu-PA) with Malignant Phenotype, (8)Two Dimensional Gel Electrophoresis Studies of the Proteins of the Major Cell Strains of the MSU-1 Family of Cells, and (9) Correlation between Proteinase Activity Levels and Malignancy.

1992-01-01

14

Involvement of the Tpl-2/cot oncogene in MMTV tumorigenesis.  

Science.gov (United States)

We report for the first time a relationship between the Tpl-2/cot oncogene and Mouse Mammary Tumor Virus (MMTV) associated transformation of mammary gland cells. A sub-genomic library generated from a primary mammary gland tumor yielded a novel MMTV integration site which disrupted the Tpl-2/cot proto-oncogene between exons 7 and 8. Comparison of a cell line derived from normal mammary gland (comma-D) and a cell line established from an MMTV induced mammary tumor (GR) demonstrated similar rearrangements within Tpl-2/cot for the GR cells but not in the comma-D cells. These rearrangements in the cell line were accompanied by an increase in the level of Tpl-2/cot specific mRNA. This data suggests that Tpl-2/cot expression may be important in epithelial cell transformation or tumor progression. PMID:8934549

1996-11-01

15

Novel method for differentiation between Trastuzumab and host adaptive response.  

Science.gov (United States)

Humoral immune response to human epidermal growth factor receptor 2 (HER-2/neu or ErbB-2) has been detected in sera of breast cancer patients and shown to be an appropriate prognostic marker (Taylor et al., 2007). However, since Trastuzumab (Herceptin) is a widely used monoclonal antibody as cancer therapy agent for tumors over-expressing HER-2, there is a need for an efficient way to detect host-generated antibodies against HER-2 without the confounding effect of Herceptin. Here we describe a screening method developed to decipher between host antibodies against HER-2 and that of Herceptin. By producing a series of truncation mutants within the epitope of Herceptin, we were able to inhibit this binding. We demonstrated also that by a three amino acid substitution (PPF?SSS) we were able to abrogate Herceptin binding while generating a highly conserved HER-2 extracellular domain (ECD). By producing a stable cell line that expresses this mutated form of the human HER-2 ECD, we have a ...

2011-06-08

16

A radiation hybrid map of the BRCA1 region of chromosome 17q12-q21  

Energy Technology Data Exchange (ETDEWEB)

The chromosomal region 17q12-q21 contains a gene (BRCA1) conferring susceptibility to early-onset familial breast and ovarian cancer. An 8000-rad radiation-reduced hybrid (RH) panel was constructed to provide a resource for long-range mapping of this region. A large fraction of the hybrids ([approximately]90%) retained detectable human chromosome 17 sequences. The complete panel of 76 hybrids was scored for the presence or absence of 22 markers from this chromosomal region, including 14 cloned genes, seven microsatellite repeats, and one anonymous DNA segment. Statistical analysis of the marker retention data employing multipoint methods provided both comprehensive and framework maps of this chromosomal region, including distance estimates between adjacent markers. The comprehensive RH map includes 17 loci and spans 179 cRays[sub (8000)]. Likelihood ratios of at least 1000:1 support the 10-locus framework order: cen-D17S250-ERBB2-(THRA1, ...

1993-09-01

17

The protozoan parasite Theileria annulata alters the differentiation state of the infected macrophage and suppresses musculoaponeurotic fibrosarcoma oncogene (MAF) transcription factors  

UK PubMed Central (United Kingdom)

AbstractThe tick-borne protozoan parasite Theileria annulata causes a debilitating disease of cattle called Tropical Theileriosis. The parasite predominantly invades...Full Text Available

2009-08-01

18

The protein encoded by the rolB plant oncogene hydrolyses indole glucosides.  

UK PubMed Central (United Kingdom)

The rolB gene of Agrobacterium rhizogenes, whose expression stimulates the formation of roots by transformed plant tissues and other growth alterations in transgenic plants, codes for a beta-glucosidase...Full Text Available

1991-11-01

19

The plant oncogene rolC is responsible for the release of cytokinins from glucoside conjugates.  

UK PubMed Central (United Kingdom)

The rolC gene of Agrobacterium rhizogenes, which drastically affects growth and development of transgenic plants, codes for a cytokinin-beta-glucosidase. Indeed, rolC protein expressed in Escherichia...Full Text Available

1991-10-01

20

The oncogenic transforming potential of the passage of single ? particles through mammalian cell nuclei  

UK PubMed Central (United Kingdom)

Domestic, low-level exposure to radon gas is considered a major environmental lung-cancer hazard involving DNA damage to bronchial cells by α particles from radon progeny. At domestic exposure...Full Text Available

1999-01-05

 
 
 
 
21

The Zinc Finger SET Domain Gene Prdm14 Is Overexpressed in Lymphoblastic Lymphomas with Retroviral Insertions at Evi32  

UK PubMed Central (United Kingdom)

BackgroundAKXD recombinant inbred strains of mice have proven to be very useful in the identification of potential oncogenes and tumor suppressors involved in the development of...Full Text Available

22

Targeting the p53 Pathway in Ewing Sarcoma  

UK PubMed Central (United Kingdom)

The p53 tumour suppressor plays a pivotal role in the prevention of oncogenic transformation. Cancers frequently evade the potent antitumour surveillance mechanisms of p53 through mutation of the TP53...Full Text Available

2011-01-01

23

TFIIH Operates through an Expanded Proximal Promoter To Fine-Tune c-myc Expression  

UK PubMed Central (United Kingdom)

A continuous stream of activating and repressing signals is processed by the transcription complex paused at the promoter of the c-myc proto-oncogene. The general transcription factor...Full Text Available

2005-01-01

24

Shelterin complex and associated factors at human telomeres  

UK PubMed Central (United Kingdom)

The processes regulating telomere function have major impacts on fundamental issues in human cancer biology. First, active telomere maintenance is almost always required for full oncogenic transformation...Full Text Available

2011-03-01

25

Neurotensin Receptor 1 Is Expressed in Gastrointestinal Stromal Tumors but Not in Interstitial Cells of Cajal  

UK PubMed Central (United Kingdom)

Gastrointestinal stromal tumors (GIST) are thought to derive from the interstitial cells of Cajal (ICC) or an ICC precursor. Oncogenic mutations of the KIT or PDGFRA receptor tyrosine kinases are present...Full Text Available

26

Large-scale cross-species oncogenomics identifies candidate oncogenes and tumor suppressor genes  

UK PubMed Central (United Kingdom)

While genomic alterations identified in human tumors using techniques such as comparative genomic hybridisation (CGH) may be recurrent, they frequently encompass large regions, in some cases...Full Text Available

2010-02-01

27

Impact of genetic changes to the CRPV genome and their application to the study of pathogenesis in vivo  

UK PubMed Central (United Kingdom)

The cottontail rabbit papillomavirus (CRPV)/rabbit model has been used to study oncogenicity and immunogenicity of different antigens from the papillomavirus genome and has therefore served...Full Text Available

2007-02-20

28

Helicobacter pylori infection, oncogenic pathways and epigenetic mechanisms in gastric carcinogenesis  

UK PubMed Central (United Kingdom)

Chronic colonization of the human stomach by Helicobacter pylori, a Gram-negative bacterium, is the major cause of chronic gastritis, peptic ulcers and gastric cancer. Recent...Full Text Available

2010-05-01

29

HPV16 E2 could act as down-regulator in cellular genes implicated in apoptosis, proliferation and cell differentiation  

UK PubMed Central (United Kingdom)

BackgroundHuman Papillomavirus (HPV) E2 plays several important roles in the viral cycle, including the transcriptional regulation of the oncogenes E6 and E7, the regulation of the...Full Text Available

30

Functional Interactions between Retinoblastoma and c-MYC in a Mouse Model of Hepatocellular Carcinoma  

UK PubMed Central (United Kingdom)

Inactivation of the RB tumor suppressor and activation of the MYC family of oncogenes are frequent events in a large spectrum of human cancers. Loss of RB function and MYC activation are thought to...Full Text Available

31

Deficiency of Phosphoinositide 3-Kinase Enhancer Protects Mice From Diet-Induced Obesity and Insulin Resistance  

UK PubMed Central (United Kingdom)

OBJECTIVEPhosphoinositide 3-kinase enhancer A (PIKE-A) is a proto-oncogene that promotes tumor growth and transformation by enhancing Akt activity. However, the physiological functions...Full Text Available

2010-04-01

32

Chromosomal sites for hepatitis B virus integration in human hepatocellular carcinoma.  

UK PubMed Central (United Kingdom)

The discovery that hepatitis B virus (HBV) integrates into host chromosomes raises the question of whether such viral DNA integration correlates directly with the activation of specific oncogenes or...Full Text Available

1991-12-01

33

Autoantibodies to BRAF, a new family of autoantibodies associated with rheumatoid arthritis  

UK PubMed Central (United Kingdom)

IntroductionBRAF (v raf murine sarcoma viral oncogene homologue B1) is a serine-threonine kinase involved in the mitogen-activated protein kinase (MAPK) signalling pathway, known...Full Text Available

2010-01-01

34

A DNA transposon-based approach to validate oncogenic mutations in the mouse  

UK PubMed Central (United Kingdom)

Large-scale cancer genome projects will soon be able to sequence many cancer genomes to comprehensively identify genetic changes in human cancer. Genome-wide association studies have also identified...Full Text Available

2008-12-16

35

Gene rearrangement and radiation carcinogenesis  

International Nuclear Information System (INIS)

The development of leukemia and thyroid cancer is characterized by activation of the abl oncogene and ret oncogene, respectively. In order to clarify the relationship between these gene aberrations and radiation, the pro-myelogenous leukemia-derived cell line HL60 and the thyroid cancer-derived cell line 8505C, were irradiated in vitro with 100Gy of X-rays. RNA was then extracted from 10"8 cells of the respective cell lines and examined by the reverse transcription PCR method for rearrangements of abl and ret genes. Five kinds of positive bands were observed in the HL-60 cells irradiated with 100Gy of X-ray. Similarly, six positive bands were also observed in the 8505C cells irradiated with 100Gy. In vitro X-irradiation activation of oncogenes found in radiation induced cancers imply that gene rearrangement by X-rays is involved in the development of malignant tumors. Furthermore, in an experiment to detect radiation ...

1993-11-01

36

Interaction of x-rays and food pyrolysis products in producing oncogenic transformation in vitro  

International Nuclear Information System (INIS)

In recent years it has become evident from epidemiological and experimental data that a large number of environmental factors, including diet, play a role in modifying the incidence of cancer. Cell culture systems in which oncogenic transformation serves as an end point are powerful tools for evaluating these questions. Using such systems it has been shown recently that pyrolysis products from charred surfaces of broiled meat and fish can transform hamster embryo cells in vitro as well as produce tumors in the animal. Our studies in vitro have demonstrated the oncogenic potential of ionizing radiation in both hamster and human cells and have established in hamster cells the dose response relationship at doses ranging from 1 to 600 rad for x-rays and 0.1 to 150 rad for neutrons. The present work was aimed at evaluating whether there exists a cocarcinogenic interaction between a pyrolysis product and x-rays in their ability to transform hamster ...

1981-07-01

37

Genes involved in immortalization of human mammary cells  

Energy Technology Data Exchange (ETDEWEB)

Breast cancer progression is characterized by inappropriate cell growth. Normal cells cease growth after a limited number of cell divisions--a process called cellular senescence-while tumor cells may acquire the ability to proliferate indefinitely (immortality). Inappropriate expression of specific oncogenes in a key cellular signaling pathway (Ras, Raf) can promote tumorigenicity in immortal cells, while causing finite lifespan cells to undergo a rapid senescence-like arrest. We have studied when in the course of transformation of cultured human mammary epithelial cells (HMEC), the response to overexpressed oncogenic Raf changes from being tumor-suppressive to tumor enhancing, and what are the molecular underpinnings of this response. Our data indicate: (1) HMEC acquire the ability to maintain growth in the presence of oncogenic Raf not simply as a consequence of overcoming senescence, but as a result of a newly discovered ...

2001-09-27

38

Endogenous expression of Hras(G12V) induces developmental defects and neoplasms with copy number imbalances of the oncogene.  

Science.gov (United States)

We developed mice with germline endogenous expression of oncogenic Hras to study effects on development and mechanisms of tumor initiation. They had high perinatal mortality, abnormal cranial dimensions, defective dental ameloblasts, and nasal septal deviation, consistent with some of the features of human Costello syndrome. These mice developed papillomas and angiosarcomas, which were associated with Hras(G12V) allelic imbalance and augmented Hras signaling. Endogenous expression of Hras(G12V) was also associated with a higher mutation rate in vivo. Tumor initiation by Hras(G12V) likely requires augmentation of signal output, which in papillomas and angiosarcomas is achieved via increased Hras-gene copy number, which may be favored by a higher mutation frequency in cells expressing the oncoprotein. PMID:19416908

2009-04-29

39

Dietary turmeric modulates DMBA-induced p21ras, MAP kinases and AP-1/NF-?B pathway to alter cellular responses during hamster buccal pouch carcinogenesis  

British Library Electronic Table of Contents (United Kingdom)

The chemopreventive efficacy of turmeric has been established in experimental systems. However, its mechanism(s) of action are not fully elucidated in vivo. The present study investigates the mechanism of turmeric-mediated chemoprevention in 7,12-dimethylbenz(a)anthracene (DMBA)-induced hamster buccal pouch (HBP) carcinogenesis at 2, 4, 6, 10 and 12?weeks. Dietary turmeric (1%) led to decrease in DMBA-induced tumor burden and multiplicity, and enhanced the latency period in parallel, to its modulatory effects on oncogene products and various cellular responses during HBP tumorigenesis. DMBA-induced expression of ras oncogene product, p21 and downstream target, the mitogen-activated protein kinases were significantly decreased by turmeric during HBP carcinogenesis. Turmeric also diminished ...

2008-01-01

40

Roles of the TNF receptor-associated factor (TRAF)2/3 binding site in differential B cell signaling by CD40 and its viral oncogenic mimic, latent membrane protein 1 (LMP1)  

UK PubMed Central (United Kingdom)

The Epstein-Barr virus protein, LMP1, is a functional mimic of the cellular receptor CD40, but signals to B lymphocytes in an amplified and sustained manner compared to CD40. LMP1 contributes...Full Text Available

2009-09-01

 
 
 
 
41

Relationship between O6-alkylguanine-DNA alkyltransferase activity and N-methyl-N'-nitro-N-nitrosoguanidine-induced mutation, transformation, and cytotoxicity in C3H/10T1/2 cells expressing exogenous alkyltransferase genes.  

UK PubMed Central (United Kingdom)

While a great deal of evidence has directly implicated the importance of O6-alkylation of guanine in the mutagenicity of alkylating agents, evidence demonstrating the oncogenic potential of this lesion...Full Text Available

1992-12-01

42

Overexpression of eIF-5A2 in mice causes accelerated organismal aging by increasing chromosome instability  

UK PubMed Central (United Kingdom)

BackgroundAmplification of 3q26 is one of the most frequent genetic alterations in many human malignancies. Recently, we isolated a novel oncogene eIF-5A2 within...Full Text Available

43

Double minutes arise from circular extrachromosomal DNA intermediates which integrate into chromosomal sites in human HL-60 leukemia cells.  

UK PubMed Central (United Kingdom)

Amplification of oncogenes has been found to be an important prognostic factor in behavior of patients' malignancies. In this study we have used new gel electrophoresis techniques to follow the location...Full Text Available

1990-06-01

44

Transformation and radiosensitivity of human diploid skin fibroblasts transfected with activated RAS oncogene and SV40 T-antigen  

Energy Technology Data Exchange (ETDEWEB)

Three normal human diploid cell strains were transfected with an activated Ha-ras oncogene (EJ ras) or SV40 T-antigen. Multiple clones were examined for morphological alterations, growth requirements, ability to grow under anchorage independent conditions, immortality and tumorigenicity in nude mice. Clones expressing SV40 T-antigen alone or in combination with ras protein p21 were significantly radioresistant as compared with their parent cells or clones transfected with the neo gene only. This radioresistant phenotype persisted in post-crisis, immortalized cell lines. These data suggest that expression of the SV40 T-antigen but not activated Ha-ras plays an important role in the radiosensitivity of human diploid cells. The radioresistant phenotype in SV40 T transfected cells was not related to the enhanced level of genetic instability seen in pre-crisis and newly immortalized cells, nor to the process of immortalization itself. (author).

1992-08-01

45

Multistep process of neoplastic transformation of normal human fibroblasts by 60Co gamma rays and Harvey sarcoma viruses  

Energy Technology Data Exchange (ETDEWEB)

As reported previously (Namba et al., 1985), normal human fibroblasts were transformed by 60Co gamma-ray irradiation into immortal cells with abnormal karyotypes. These transformed cells (KMST-6), however, showed a low cloning efficiency in soft agar and no transplantability. However, upon treatment with Harvey murine sarcoma virus (Ha-MSV), the cells acquired elevated clonability in soft agar and transplantability in nude mice. Ha-MSV alone, however, did not convert normal human fibroblasts into either immortal or tumorigenic cells. The Ha-MSV-transformed KMST-6 cells showed an enhanced expression of the ras oncogene, but normal and 60Co gamma-ray-transformed cells did not. Our current data suggest that gamma rays worked against normal human cells as an initiator, giving rise to chromosome aberrations and immortality, and that Ha-MSV, probably through its ras oncogene, played a role in the progression of the malignant cell population to a more ...

1986-03-15

46

Molecular resemblance of an AIDS-associated lymphoma and endemic Burkitt lymphomas: Implications for their pathogenesis  

International Nuclear Information System (INIS)

Non-Hodgkin lymphoma is a common feature of AIDS. Approximately 30-40% of these tumors exhibit clinical features suggestive of endemic Burkitt lymphoma: they are aggressive malignancies that occur in association with Epstein-Barr virus infection, they arise in the setting of immunosuppression, and they carry t(8;14) translocations without detectable rearrangement of the MYC oncogene. To understand the molecular basis of these parallels, the authors analyzed a case of Epstein-Barr-positive AIDS-associated undifferentiated lymphoma. Southern blots show that the tumor exhibits immunoglobulin joining segment rearrangement but no rearrangement of the MYC oncogene. Cloning of the rearranged joining segment allowed the isolation of recombinant clones encompassing the translocation breakpoint, and sequencing of the translocation junction disclosed that the breakpoint is situated 7 base pairs from the chromosome 14 site involved in a previously ...

47

Report on NCI symposium: comparison of mechanisms of carcinogenesis by radiation and chemical agents. II. Cellular and animal models  

International Nuclear Information System (INIS)

The point at which the common final pathway for induction of cancer by chemical carcinogens and ionizing radiation has not been identified. Although common molecular targets are suggested by recent findings about the role of oncogenes, the mechanism by which the deposition of radiation energy and the formation of adducts or other DNA lesions induced by chemicals affects the changes in the relevant targets may be quite different. The damage to DNA that plays no part in the transformation events, but that influences the stability of the genome, and therefore, the probability of subsequent changes that influence tumorigenesis may be more readily induced by some agents than others. Similarly, the degree of cytotoxic effects that disrupt tissue integrity and increase the probability of expression of initiated cells may be dependent on the type of carcinogen. Also, evidence was presented that repair of the initial lesions could be demonstrated after exposure to low-LET ...

1984-05-20

48

Immortalization of human foreskin keratinocytes by various human papillomavirus DNAs corresponds to their association with cervical carcinoma  

Energy Technology Data Exchange (ETDEWEB)

Normal human foreskin keratinocytes cotransfected with the neomycin resistance gene and recombinant human papillomavirus (HPV) DNAs (types 16, 18, 31, and 33) that have a high or moderate association with cervical malignancy acquired immortality and contained integrated and transcriptionally active viral genomes. Only transcripts from the intact E6 and E7 genes were detected in at least one cell line, suggesting that one or both of these genes are responsible for immortalization. Recombinant HPV DNAs with low or no oncogenic potential for cervical cancer (HPV1a, -5, -6b, and -11) induced small G418-resistant colonies that senesced as did the nontransfected cells. These colonies contained only episomal virus DNA; therefore, integration of HPV sequences is important for immortalization of keratinocytes. This study suggests that the virus-encoded immortalization function contributes to the pathogenesis of cervical carcinoma.

1989-01-01

49

Cytoplasmic p63 immunohistochemistry is a useful marker for muscle differentiation: an immunohistochemical and immunoelectron microscopic study  

British Library Electronic Table of Contents (United Kingdom)

TP63, a member of the TP53 gene family, is a nuclear marker of myoepithelial cells. Antibody against p63 is frequently used to aid in the diagnosis of prostate carcinoma, as well as in the identification of myoepithelial cells in other tissues including the breast. p63 is also a marker for squamous cell carcinoma. Recently, it was found that all p53 family members are involved in regulating the process of muscle differentiation through the retinoblastoma (RB) protein. Ablation of these p53 family functions blocks the differentiation program and promotes malignant transformation by enabling cooperating oncogenes to transform myoblasts. We therefore studied p63 expression in a number of neoplasms with myogenic differentiation. Immunohistochemical staining for p63 was performed on paraffin se...

2011-01-01

50

Novel high-throughput screening system for identifying STAT3-SH2 antagonists  

International Nuclear Information System (INIS)

Constitutive activation of the oncogenic transcription factor STAT3 frequently occurs in various human malignancies. STAT3 activation involves dimerization via intermolecular pTyr-SH2 interaction. Thus, antagonizing this interaction is a feasible approach to inhibit STAT3 activation for cancer therapy. In order to identify selective STAT3 inhibitors, we developed a biochemical HTS system based on AlphaScreen technology, which measures the abilities of test compounds to antagonize pTyr-SH2 interactions. We screened our chemical libraries using this system and identified 5,15-diphenylporphyrin (5,15-DPP) as a selective STAT3-SH2 antagonist. Selective inhibition of STAT3 nuclear translocation and DNA biding activity was observed in cells treated with 5,15-DPP. IL-6-dependent dimerization of STAT3, c-myc promoter binding and c-myc protein expression were all suppressed by 5,15-DPP, whereas no decrement in either expression or phosphorylation level of STAT3 was ...

2009-03-13

51

Increased transcription of the c-myc oncogene in two methylcholanthrene-induced quail fibroblastic cell lines  

Energy Technology Data Exchange (ETDEWEB)

The expression of three c-onc genes (c-erb, c-myc, c-myb) was investigated in five cell lines established from fibrosarcomas induced with 20-methylcholanthrene (MCA) of Japanese quails. These cell lines showed low levels of the three c-onc genes, with the exception of two cell lines that accumulated moderate (MCAQ 1-4) and large amounts (MCAQ 3-5) of c-myc RNA. Molecular cloning and restriction endonuclease analyses indicated that expression of c-myc in these two cell lines were not associated with detectable rearrangements in the c-myc locus, that the size of the c-myc transcript (2.7 kb) in MCAQ 3-5 was similar to that of the normal c-myc messenger RNAs (mRNA) and that the transcriptional activatin observed in MCAQ 3-5 was not mediated by the LTR (long terminal repeat) of a proximate ALV (avian leukosis virus) provirus. Finally, when analyzed with the restriction enzymes Msp I and Hpa II, the c-myc locus of MCAQ 3-5 and MCAQ 1-4 was found hypomethylated as compared with that of the ...

1984-12-01

52

Chromosome mapping of human CDC25A and CDC25B phosphatases  

Energy Technology Data Exchange (ETDEWEB)

The human CDC25 tyrosine phosphatases trigger activation of CDC2 by removing inhibitory phosphates; thus the genes encoding these phosphatases may be suspected as potential oncogenes due to their role in promoting cell division. To date, three human CDC25 genes have been identified: CDC25A, B, and C. This communication describes the mapping of CDC25A to chromosome 3p21 and CDC25B to chromosome 20p13 by fluorescence in situ hybridization with confirmation by the polymerase chain reaction of hamster-human somatic cell hybrid DNA. 3p21 is near an area frequently involved in karyotypic abnormalities in renal carcinomas, small cell carcinomas of the lung, and benign tumors of the salivary gland. 20p13 does not seem to be a common area for karyotypic alteration in tumors. Mapping of these genes to their chromosomal loci may help identify tumors with abnormal regulation of CDC25 genes due to genomic alterations. 15 refs., 3 figs.

1993-10-01

53

Molecular events involved in ionizing radiation induced skin carcinogenesis  

International Nuclear Information System (INIS)

The process of mouse skin tumor formation is subdivided into three operational stages. These stages include initiation, promotion and progression. Ionizing radiation has been found to be a weak initiating agent in the production of malignant squamous cell carcinomas, a complete carcinogen and an agent effective in causing tumor progression. Four skin tumor histologies have been seen with ionizing radiation: benign papillomas, squamous (SCC) and basal (BCC) cell carcinomas and fibrosarcomas. Distinct non-ras transforming genes have been detected in radiation initiated SCCs. A benign papilloma cell line (308) was used as a model system to study ionizing radiation induced progression. A variant 308 cell line (308 10 Gy 5) derived by irradiation of the parental 308 cell has been characterized. The 308 10 Gy 5 cells unlike the parental 308 cells from malignant tumors in athymic nude mice upon subcutaneous injection. The variant 308 10 Gy 5 cells unlike the parental cells also show by ...

54

Insulin-like growth factor binding protein-7 (IGFBP7) functions as a potential tumor suppressor in hepatocellular carcinoma (HCC).  

Science.gov (United States)

PURPOSE: Hepatocellular carcinoma (HCC) is a highly virulent malignancy with no effective treatment thus requiring innovative and effective targeted therapies. The oncogene Astrocyte elevated gene-1 (AEG-1) plays a seminal role in hepatocarcinogenesis and profoundly downregulates insulin-like growth factor binding protein-7 (IGFBP7). The present study focuses on analyzing potential tumor suppressor functions of IGFBP7 in HCC and the relevance of IGFBP7 downregulation in mediating AEG-1 function.EXPERIMENTAL DESIGN: IGFBP7 expression was detected by immunohistochemistry in HCC tissue microarray and real-time PCR and ELISA in human HCC cell lines. Dual Fluorescence in situ hybridization was performed to detect loss of heterozygosity at IGFBP7 locus. Stable IGFBP7-overexpressing clones were established in the background of AEG-1-overexpressing human HCC cells and were analyzed for in vitro proliferation and senescence and in vivo tumorigenesis and ...

2011-09-16

55

Monitoring of DNA and cytogenetic damage in lymphocytes from persons with skin cancer diseases  

International Nuclear Information System (INIS)

There is a lot of interest in the studies that would help to understand whether there is a casual association between cancer and various types of molecular or cytogenetic damage detected in human cells. One major oncogenesis process is activation of proto-oncogenes by point mutations or chromosomal translocation. There are substantial evidence that indicates that the loss of heterozygosity of certain chromosomes is involved in human cancerogenesis. Our study aimed to elicit the possible association between cancer and DNA and cytogenetic abnormalities induced in lymphocytes of people bearing various categories of skin cancer cells. Fresh blood was collected by venipuncture from 25 individuals (including nine prior to cancer treatment). All patients were nonsmoking males, however 42.3 % of them were former smokers. Blood samples were divided into two parts and in the first part of samples cytogenetic studies were performed immediately, while from the second part ...

2004-11-01