Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C1326912 (tumorigenesis)
 57,481 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Platelet-derived growth factor (PDGF) is a 30 kDa protein consisting of disulfide-bonded dimers of A- and B-chains. PDGF receptors are of two types, alpha- and beta-receptors, which are members of the protein-tyrosine kinase family of receptors. The receptors are activated by ligand-induced dimerization, whereby the receptors become phosphorylated on tyrosine residues. These form attachment sites for signalling molecules, which inter alia activate the Ras.Raf pathway. PDGF has important functions in development and is required for a proper timing of oligodendrocyte differentiation. The v-sis oncogene of simian sarcoma virus (SSV) is a retroviral homolog of the B-chain gene, and induces transformation by an autocrine activation of PDGF receptors at the cell surface. SSV induces malignant glioma in experimental animals, suggesting a role for autocrine PDGF in glioma development. PDGF and PDGF receptors are frequently coexpressed in human glioma cell lines. Specific and nonspecific PDGF antagonists block the growth of some glioma cell lines in vitro and in vivo, suggesting that autocrine PDGF is involved in transformation and tumorigenesis. In situ studies of human gliomas show overexpression of alpha-receptors in glioma cells of high-grade tumors. In a few cases, overexpression is caused by receptor amplification. Since high-grade glioma cells also express the PDGF A-chain, an autocrine activation of the alpha-receptor may drive the proliferation of glioma cells in vivo.
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PMID:Platelet-derived growth factor in human glioma. 858 62

The mammalian D-type cyclins promote progression through a G1 checkpoint by phosphorylating the retinoblastoma protein (pRB), and can contribute to oncogenesis via their deregulated expression achieved through gene amplification, chromosomal rearrangement, or retroviral integration. We now report a novel mechanism of tumour-associated D-cyclin over-abundance, resulting from enhanced protein stability. In two human cell lines established from a single uterine sarcoma biopsy, pRB-positive SK-UT-1B and pRB-deficient SK-UT-1, aberrant accumulation of functional cyclins D1, and D2 and D3 occurred in the absence of gene amplification and/or elevated mRNA expression. The abundance of D-cyclin proteins remained elevated throughout the cell cycle, and pulse-chase experiments revealed six to 10-fold prolongation of their protein half-lives as compared with either diploid fibroblasts or control U-2-OS sarcoma cells. These results point to a critical regulatory role of D-type cyclin turnover, and contribute to refinement of current views of the role played by the cyclin D-CDK-p16-pRB pathway in cell cycle control and tumorigenesis.
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PMID:Enhanced protein stability: a novel mechanism of D-type cyclin over-abundance identified in human sarcoma cells. 871 Mar 82

The isolation and molecular analysis of genes which cause and/or predispose to Wilms' tumor have yielded fascinating insights into the role of tissue-specific gene regulation in both development and disease processes. Analysis of the WT1 transcription factor has clearly established its role in Wilms' tumorigenesis and a broader role in both urogenital organogenesis and mesenchymal cell differentiation events. Clearly, loss of function mutations in WT1 is correlated with aberrant function as a regulator of gene expression, ultimately resulting in neoplastic transformation in the developing kidney. A question we have pursued is whether alterations of WT1 structure and/or function can be associated with other types of malignancies, possibly reflecting WT1's broader role in mesenchymal differentiation. To this end, we have analyzed a rare solid tumor designated Intra-Abdominal Desmoplastic Small Round Cell Sarcoma (IADSRCT) which often displays a recurrent chromosomal translocation t(11;22)(p13;q12) involving the WT1 genomic locus. We have shown that the EWS1 gene fron chromosome 22q12 is fused to the WT1 gene in IADSRCT and that a fusion protein is produced which functions as a potent activator of transcription. Our results suggest that WT1 has sustained a gain-of function alteration as a results of this fusion and that the fusion gene functions as a dominant oncogene in this disease. Thus, the WT1 locus may be the target for both gain- and loss-of-function mutations resulting in different disease outcomes. A summary of our ongoing analysis of the EWS-WT1 fusion gene is presented.
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PMID:Fusion of the EWS1 and WT1 genes as a result of the t(11;22)(p13;q12) translocation in desmoplastic small round cell tumors. 882 70

Since the discovery of v-jun as the transforming protein of the sarcoma virus 17 three mammalian homologues of v-jun have been isolated. All three jun genes respond to a multitude of agents, and the encoded proteins in turn bind to and regulate, positively or negatively, the transcription of dependent genes, thereby influencing cellular fate. In addition, through transcription factor "cross-talk" Jun influences the transcription of genes regulated by different classes of transcription factors, such as steroid hormone receptors. Although the role of Jun proteins in transcriptional regulation has been thoroughly analyzed in recent years, the role of Jun proteins in oncogenesis is still poorly understood.
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PMID:Jun: transcription factor and oncoprotein. 897 16

Tissue reconstruction of various kinds of gynecologic malignant tumor cell lines was studied using the rotation-culture system. The reconstructed cell aggregates were examined histologically using both light and electron microscopy. Our established cell lines used in this study were uterine cervical epidermoid carcinoma, endometrial adenocarcinoma, ovarian malignant tumor and uterine sarcoma. All of the reconstructed aggregates from each cell line were very similar to the original tumor tissue. In the case of a well differentiated type of adenocarcinoma derived from the ovarian cancers or the endometrial cancers, papillary cell aggregates (grape-like structures) and/or hollow cell ball (gland alveolus-like) structures were observed. The individual cells were adjoined with by desmosomes and well developed microvilli protruded from the free surface of the cells. On the other hand large cell non-keratinizing squamous cell carcinoma cells formed spherical-shaped aggregates that showed a stratified structure similar to pearl formation. Sarcoma cells formed solid clusters while desmosomes or desmosome-like junctions were not detected. Rotation culture is an excellent method to reveal diagnosis of the original tumor and tumorigenesis by investigating a reconstructed tissue from peritoneal effusions because the reconstructed tissue is similar to the original tumor.
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PMID:Tissue reconstruction of gynecologic tumor cells in the rotation culture system. 943 37

Both tumor suppressor genes p53 and p16(INK4A) play a crucial role in the control of cell cycle and tumor development. In this study 19 malignant fibrous histiocytomas of the bone (MFH-b), a very rare sarcoma entity, were investigated for mutations in p53 and p16 genes by a PCR-SSCP-sequencing analysis. In the tumor samples two p53 mutations and two polymorphisms (one in the p53 gene and one in the p16 gene) were found. The occurrence rate for p53 mutations and the absence of p16 mutations in MFH-b are comparable to the findings for MFH of soft tissues (MFH-st) and osteosarcomas, suggesting that p53 rather than p16 may play a role in tumorigenesis of MFH-b.
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PMID:How is the mutational status for tumor suppressors p53 and p16(INK4A) in MFH of the bone? 948 81

Transgenic mouse models of mammary tumorigenesis and analyses of human breast tumour samples have indicated a role for Src proteins in the tumorigenic process. The downstream effectors of Src function in mammary epithelial cells are less well understood. STAT proteins constitute a family of transcription factors whose activation by cytokine and non-cytokine receptors leads to tyrosine phosphorylation, dimerization and translocation from the cytoplasm to the nucleus. In the nucleus they activate the transcription of specific genes by binding to consensus DNA elements. STATs 1 and 3 can be activated by both cytokine and non-cytokine receptors, and bind as homodimers or heterodimers to viral simian sarcoma virus (sis)-inducible elements such as that found in the c-fos promoter. Here we report that one of the downstream effectors of Src function in mammary epithelial cells is STAT3. We demonstrate that v-src expression in mammary epithelial cells induces Tyr-705 phosphorylation, nuclear translocation and DNA binding of STAT3. Furthermore, we demonstrate that v-src can induce STAT3-dependent transcription. These observations are the first direct evidence that v-src can regulate transcription through the activation of STAT proteins, and add a further level of complexity to the understanding of the mode of action of v-src.
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PMID:Expression of v-src in mammary epithelial cells induces transcription via STAT3. 953 74

Gorlin (or nevoid basal cell carcinoma) syndrome is characterized by a variety of clinical problems including generalized overgrowth of the body, cysts, developmental abnormalities of the skeleton and a predisposition to benign and malignant tumors. The syndrome results from germline mutations of the human homolog of the drosophila segment polarity gene patched (ptc). Here we report that mice heterozygous for ptc develop many of the features characteristic of Gorlin syndrome and that they exhibit a high incidence of rhabdomyosarcomas (RMS), the most common soft-tissue sarcoma in children. The downstream signalling partner of ptc, gli1, was overexpressed in all RMSs analyzed, indicating that abnormal signalling of the ptc-gli1 pathway may be common for the various tumors associated with the syndrome. igf2, implicated in the formation of RMSs, was also overexpressed, suggesting cross-talk between the ptc and igf2 pathways in tumorigenesis. Developmental defects in Gorlin syndrome resemble those induced by ionizing radiation. We show that ptc heterozygous mice exhibit increased incidence of radiation-induced teratogenesis. This suggests a role for ptc in the response to ionizing radiation and provides a model for both the systemic (developmental) and stochastic (cancer) abnormalities observed in Gorlin syndrome.
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PMID:Rhabdomyosarcomas and radiation hypersensitivity in a mouse model of Gorlin syndrome. 958 26

An understanding of the basic mechanisms responsible for the pathogenesis of liver neoplasms is needed in order to develop better therapeutic strategies. The present study utilized a pharmacogenetic mouse model to assess the role of cytochrome P4501A1 (Cyp1a1) in modulating genetic damage to oncogenic and tumor suppressor loci following in utero exposure to the polycyclic aromatic hydrocarbon, 3-methylcholanthrene (MC). Analysis of the Ha-ras, Ki-ras, INK4a and p53 genes was carried out with lysates from paraffin-embedded liver tissue from transplacentally-treated mice. The lysates were subjected to DNA amplification by the PCR technique followed by allele-specific oligonucleotide hybridization screening and SSCP analysis. All of the 26 neoplasms screened (23 hepatocellular carcinomas, two hepatocellular adenomas and one sarcoma) exhibited a GGC-->CGC (GLY13-->ARG13) transversion at the Ki-ras gene locus. None of the tumors had Ki-ras mutations at codon 12 of exon 1. Approximately 12% (3/26) of the liver tumors exhibited point mutations in exon 1 of the INK4a gene, with each of the three tumors exhibiting two point mutations. Analysis of exon 2 of the INK4a gene showed the presence of a CCG-->CTG (PRO73-->LEU73) transition in two of the 26 neoplasms. No mutations were found in exons 1 or 2 of the Ha-ras gene, or in exons 5-8 of the p53 gene. Analysis of tumor RNAs showed overexpression of Ha-ras, cip1 and c-jun in approximately 38% of the liver tumor samples. The results of this study suggest that mutagenic damage to oncogenes and tumor suppressor genes may be critical factors in mediating transplacentally-induced liver tumorigenesis. The fact that Ki-ras mutations were found in all of the tumors suggests that mutation at this gene locus may be an early event in liver tumor pathogenesis, while mutation in tumor suppressor genes may occur later during tumor progression. These combined results are consistent with the pathogenesis of cancer in humans.
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PMID:Induction of mutations in Ki-ras and INK4a in liver tumors of mice exposed in utero to 3-methylcholanthrene. 966 43

Simian virus 40 (SV40) is an oncogenic virus which induces tumors in hamsters and transforms human cells in tissue culture. Between 1955 and 1963, polio vaccines and adenovaccines were contaminated with SV40; therefore, millions of people were exposed to this oncogenic virus. The SV40 proteins responsible for in vivo oncogenesis and in vitro cell transformation are encoded by the early region of the virus. These proteins are called T (tumor) antigens (Tags), because animals with tumors induced by SV40 have antibodies against these viral proteins. Recently, we and other research laboratories have found SV40 in specific types of human tumors: mesothelioma, ependymoma and choroid plexus tumors, osteosarcoma and sarcoma. The same tumor types will develop in hamsters which have been injected systemically with SV40. SV40 causes cell transformation in tissue culture and tumors in animals, because SV40 Tag binds and inactivates the cellular tumor suppressor gene products, Rb and p53. We found that SV40 Tag binds p53 and Rb in human mesotheliomas, possibly contributing to the malignant phenotype.
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PMID:The biological activities of simian virus 40 large-T antigen and its possible oncogenic effects in humans. 968 8


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