Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P43146 (tumour suppressor)
 5,935 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Somatic cell hybrids were produced by fusion of normal human (foreskin) fibroblasts and a transformed Chinese hamster fibroblast line V79-8. Overall, approximately 30% of hybrid clones showed stable reversion to normal morphology and growth control in vitro as shown by serum and anchorage dependence. In one-third of these clones, senescence was observed after a number of generations similar to that required for the human fibroblast parent cells to senesce. The remainder appear to be immortal. Normal human chromosomes can therefore restore growth control with or without finite life-span to this transformed cell. V79 cells were found to be transfectable at an efficiency compatible with detection of single-copy gene transfer from genomic DNA. Furthermore, these cells were exceptionally sensitive to negative ("suicide") selection. Taken together, our data suggest that the V79 line represents an ideal system for isolation of human tumour suppressor genes.
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PMID:Suppression of transformation and immortality in human/Chinese hamster fibroblast hybrids--a model for suppressor gene isolation. 291 3

In a study of DNAs from 100 breast cancer patients and 100 controls, there were no differences in the frequencies of common or rare alleles at the Harvey ras (c-Ha-ras) locus on chromosome 11. However, one Ha-ras allele was deleted from the tumour DNA in 14 of 65 informative patients. Loss of a Ha-ras allele correlates with paucity of oestrogen receptor protein and with increased tumour size at presentation, but is not associated with microscopic evidence of lymph node invasion. The findings on Ha-ras and other informative loci are consistent with the possibility that a tumour suppressor gene involved in the early stages of breast cancer is located on the short arm of chromosome 11.
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PMID:Partial deletion of chromosome 11p in breast cancer correlates with size of primary tumour and oestrogen receptor level. 306 95

In response to genotoxic stress, cell cycle progression can be arrested at certain checkpoints which serve to maintain genomic integrity. We have investigated the mechanism of ultraviolet B (UVB) irradiation-induced cell cycle arrest in normal human keratinocytes and in the HaCaT keratinocyte cell line which carries mutant p53 tumour suppressor protein. While only normal keratinocytes showed a delay in G1 following sublethal UVB irradiation both cell types exhibited prolonged G2 arrest attributable to rapid inhibition of cyclin B-associated cdc2 kinase activity. This inhibition coincided with increased tyrosine phosphorylation of cdc2 and was reversed by the cdc25C phosphatase in vitro. The data indicate that UVB-induced G2 arrest in mammalian cells is mediated by inhibitory tyrosine phosphorylation of cdc2 and acts as a defense mechanism against DNA damage irrespective of the cells' p53 status.
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PMID:Ultraviolet B irradiation-induced G2 cell cycle arrest in human keratinocytes by inhibitory phosphorylation of the cdc2 cell cycle kinase. 747 36

There is now much evidence to suggest that the p53 tumour suppressor protein functions to monitor the integrity of the genome. When DNA damage is detected, p53 suppresses cell growth to allow repair or directs the cell into apoptosis. The mechanism of action of p53 is as yet unclear but recent evidence has accumulated to suggest that p53 might act by regulating gene expression. Consistent with this model, p53 can both activate and repress a number of viral and cellular promoters. p53 has also been shown to bind to the CCAAT-binding Factor and TATA-binding protein (TBP), and there is direct evidence that p53 represses in vitro transcription by preventing TBP from binding DNA. We now provide evidence that p53 can repress transcription from the SV40 promoter by disrupting DNA/protein complexes involving transcription factor Sp1.
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PMID:p53 represses SV40 transcription by preventing formation of transcription complexes. 747 50

The inducible response of the tumour suppressor gene p53 has been examined following exposure to DNA-damaging agents in Ataxia telangiectasia (AT) cell lines, an autosomal recessive disorder with multiple clinical and biological abnormalities including sensitivity to ionising radiation. The p53 induction was significantly delayed and reduced in the 8 AT cell lines examined over the 6 h following irradiation with no dose response in p53 induction being observed compared to control cells. The increase of WAF1/CIP1(p21) and GADD45 mRNA, two genes transcriptionally activated by p53, was also reduced in the AT cell lines after such treatment. In contrast, the increase in p53 protein, WAF1/CIP1(p21) and GADD45 mRNA expression following exposure to the alkylating agent methylmethane sulphonate (25 and 100 micrograms ml-1) was similar in both cell types. No alterations in the expression of EBNA-5, an EBV-encoded nuclear antigen which has been shown to bind p53 or mutations in the p53 gene (exons 4 to 8) were found in the AT cell lines studied. The AT gene product would thus appear to be involved upstream of p53, GADD45 and WAF1/CIP1 (p21) in the signalling of the presence of strand breaks produced by ionising radiation, with this defect in response contributing to the high cancer risk and radiosensitivity observed in this disorder.
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PMID:The role of the Ataxia telangiectasia gene in the p53, WAF1/CIP1(p21)- and GADD45-mediated response to DNA damage produced by ionising radiation. 747 67

A 68 year old female who presented with long-term thrombocytopenia was clinically diagnosed as having chronic idiopathic thrombocytopenia purpura (ITP). Increased levels of the tumour suppressor p53 protein were detected by immunohistochemistry in the neutrophils and some monocytes of the peripheral blood preparation using the antibody DO-1, recognizing mutant and wild type p53 protein conformations. However, no positive staining in the peripheral blood samples from 41 myelodysplasias (MDS) and six normal individuals was observed. Single-stranded conformational polymorphism analysis performed on DNA extracted from the cytospin preparations from this patient indicated no mutations in exons 5-8 of the p53 gene. This report describes the unusual detection of elevated p53 protein in a non-neoplastic condition by immunohistochemistry using the antibody DO-1. This unexpected finding raises the possibility of classifying such patients as early MDS on the basis of their p53 status.
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PMID:Elevated levels of p53 protein in the neutrophils and monocytes of a patient with chronic idiopathic thrombocytopenic purpura or possible early myelodysplasia? 750 Jun 49

Studies of the loss of allelic heterozygosity (LOH) in tumour tissues have evolved as an important tool for the identification of chromosomal regions which are likely to harbour tumour suppressor genes. The classical procedure to determine LOH has been restriction fragment length polymorphism (RFLP) analysis and Southern blotting, a time consuming method requiring radioisotopes and several micrograms of DNA. Recently, the use of highly polymorphic microsatellites of the CA-dinucleotide repeat class and polymerase chain reaction (PCR) has considerably advanced and facilitated the detection of LOH in tumour tissues. We here describe a strategy to identify LOH based on PCR amplification of CA-dinucleotide repeats, denaturing polyacrylamide gel electrophoresis (PAGE) and nucleic acid detection with a sensitive silver staining protocol. In a comparative study of 20 astrocytomas, this rapid technique was able to identify all cases of LOH on chromosome 17 p that had previously been found in these tumours by RFLP analysis and Southern blotting. This non-radioactive PCR based assay has a great potential for LOH studies in human tumours.
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PMID:A rapid and non-radioactive PCR based assay for the detection of allelic loss in human gliomas. 751 49

Mutations in a human homologue of the yeast DNA mismatch repair gene MSH2 (equivalent to bacterial MutS) cause the condition hereditary non-polyposis colorectal cancer (HNPCC). Cancers in HNPCC originate within benign neoplastic polyps termed adenomas. Adenomas are clonal and each may serve as a marker of a single initiating mutation. The progression of adenomas is marked by increasing size, dysplasia and villosity. These characteristics can be taken as the morphological counterparts of the stepwise accumulation of mutations implicating oncogenes and tumour suppressor genes. The aim of this study was to link the morphogenesis of hereditary colorectal cancer with recent insights into the role of DNA mismatch repair genes. The frequency and anatomical distribution of adenomas in at-risk members of HNPCC families was the same as in an autopsy population. This suggests that the HNPCC gene does not initiate the process of neoplastic transformation. On the other hand, adenomas in at-risk members of HNPCC families were more likely to show villosity (p < 0.001), high grade dysplasia (p = 0.002) and probably increased size (p = 0.15). These findings are consistent with the observation that the HNPCC gene causes DNA replication errors to develop and accumulate within neoplastic but not normal tissues. The effect of the HNPCC gene is to accelerate the progression of adenoma to carcinoma, but not to initiate adenoma development.
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PMID:Hereditary non-polyposis colorectal cancer--morphologies, genes and mutations. 752 76

Exposure of mammalian cells to ionizing radiation causes a delay in progression through the cycle at several checkpoints. Cells from patients with ataxia-telangiectasia (A-T) ignore these checkpoint controls postirradiation. The tumour suppressor gene product p53 plays a key role at the G1/S checkpoint preventing the progression of cells into S phase. The induction of p53 by radiation is reduced and/or delayed in A-T cells, which appears to account for the failure of delay at the G1/S checkpoint. We have investigated further this defect in radiation signal transduction in A-T. While the p53 response was defective after radiation, agents that interfered with cell cycle progression such as mimosine, aphidicolin and deprivation of serum led to a normal p53 response in A-T cells. None of these agents caused breaks in DNA, as determined by pulse-field gel electrophoresis, in order to elicit the response. Since this pathway is mediated by protein kinases, we investigated the activity of several of these enzymes in control and A-T cells. Ca+2-dependent and -independent protein kinase C activities were increased by radiation to the same extent in the two cell types, a variety of serine/threonine protein kinase activities were approximately the same and anti-tyrosine antibodies failed to reveal any differences in protein phosphorylation between A-T and control cells. It is not evident what is the nature of the defect in signal transduction in A-T cells. However, it is clear that the p53 response is normal in these cells after exposure to some agents and it is mediated through protein kinase C or another serine/threonine kinase.
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PMID:Defect in radiation signal transduction in ataxia-telangiectasia. 753 Jul 54

The transcription factor DRTF1/E2F is implicated in the control of cellular proliferation due to its interaction with key regulators of cell cycle progression, such as the retinoblastoma tumour suppressor gene product and related pocket proteins, cyclins and cyclin-dependent kinases. DRTF1/E2F DNA binding activity arises when a member of two distinct families of proteins, DP and E2F, interact as DP/E2F heterodimers. Here, we report the isolation and characterisation of a new member of the E2F family of proteins, called E2F-5. E2F-5 was isolated through a yeast two hybrid assay in which a 14.5 d.p.c. mouse embryo library was screened for molecules capable of binding to murine DP-1, but also interacts with all known members of the DP family of proteins. E2F-5 exists as a physiological heterodimer with DP-1 in the generic DRTF1/E2F DNA binding activity present in mammalian cell extracts, an interaction which results in co-operative DNA binding activity and transcriptional activation through the E2F site. A potent transcriptional activation domain, which functions in both yeast and mammalian cells and resides in the C-terminal region of E2F-5, is specifically inactivated upon pocket protein binding. Comparison of the sequence with other members of the family indicates that E2F-5 shows a greater level of similarity with E2F-4 than to E2F-1, -2 and -3. The structural and functional similarity of E2F-5 and E2F-4 defines a subfamily of E2F proteins.
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PMID:Molecular and functional characterisation of E2F-5, a new member of the E2F family. 754 60


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