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

Mutations in the p53 gene are one of the commonest specific genetic changes found in human cancer. The p53 gene is not required for normal development but lack of p53 function confers an enormously elevated risk of developing cancer, thus it seems truly to act as a tumour suppressor gene. The p53 protein is normally present in minute amounts in cells but when cells are exposed to genotoxic stimuli p53 levels rise rapidly and initiate a programme of cell death, probably by means of transcriptional regulation. This response is lost in many tumour cells as they have either inactivated their p53 genes by mutation or blocked the activity of p53 through the production of proteins that bind to it and neutralise it. Mutant p53 proteins accumulate to high levels in many cancer cells and the p53 protein and the p53 response to DNA damage represent key points for therapeutic intervention.
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PMID:p53 and human cancers. 798 42

We report that the expression of murine or human mutant p53 proteins in cells with no endogenous p53 proteins confers new or additional phenotypes upon these cells. Mutant p53 proteins expressed in cell lines lacking p53 resulted in either enhanced tumorigenic potential in nude mice ((10)3 cells) or enhanced plating efficiency in agar cell culture (human SAOS-2 cells). Also, mutant human p53 alleles, unlike the wild-type p53 protein, could also enhance the expression of a test gene regulated by the multi-drug resistance enhancer-promoter element. These data demonstrate a gain of function associated with p53 mutations in addition to the loss of function shown previously to be associated with mutations in this tumour suppressor gene.
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PMID:Gain of function mutations in p53. 809 41

The Li-Fraumeni cancer syndrome is a rare autosomal dominant syndrome, characterised by the occurrence of diverse mesenchymal and epithelial neoplasms at multiple sites. It has recently been shown that some of these individuals have a germ line mutation of the p53 tumour suppressor gene. The case of one member of such a family who has now developed three separate primary malignant tumours is reported. All three tumours expressed mutant p53 protein.
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PMID:p53 expression in three separate tumours from a patient with Li-Fraumeni's syndrome. 815 61

Cellular senescence is thought to be a key restraint on the progression of human tumours, escape from which involves loss of function of tumour suppressor genes. The number and nature of the genes involved however is uncertain, in particular the role of p53 mutation, which is commonly correlated with tumour progression. To address this question, we used the novel approach of directly assessing the effect of mutant p53 on 'pre-aged' human diploid fibroblasts (HDF), thereby avoiding the uncertainty of additional cooperating events, inherent in transgenic models. HDF were passaged till near-senescent and then infected with an amphotropic retroviral vector encoding an ala143 human mutant p53. The results show conclusively that p53 mutation alone is sufficient to extend the proliferative lifespan of normal fibroblasts by approximately 17 population doublings, but has no phenotypic effect on 'young' fibroblasts. We conclude that a key tumour-limiting function of wild-type p53 is to mediate growth arrest after a given number of cell divisions, in agreement with data implicating a p53-regulated gene, WAF-1/sdi-1, in cellular senescence. This may be reconciled with its 'guardian of the genome' role, if telomere erosion, a key change in senescence, is perceived by the cell as a form of DNA 'damage'.
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PMID:Escape from senescence in human diploid fibroblasts induced directly by mutant p53. 820 34

Mutations of the p53 detected in human hepatocellular carcinomas suggest that its inactivation is a critical step in hepatocellular carcinogenesis. In order to test whether the expression of p53 is compatible with the transformed phenotype of hepatoma cells, we transfected Hep 3B cell line with p53 expression vectors. This cell line, which contains integrated hepatitis B virus sequences, is a good model to study whether the wild-type p53 can function as a tumour suppressor gene in virus-related hepatocellular carcinoma. Wild-type and mutant p53 (Ala143)-expression vectors containing a neoR gene were used. The number of antibiotic-resistant colonies was six times lower after transfection with wild-type p53 vector as compared to the mutant vector. As measured by a specific radioimmunoassay, six of eight (75%) colonies randomly selected after mutant p53 transfections expressed the transfected mutant p53 protein. In contrast, out of eight colonies from wild-type p53-transfections, none expressed detectable p53 protein. The absence of p53 protein was due to the selective deletion of transfected wild-type p53 cDNA sequences. These studies demonstrate that the growth of hepatocellular carcinoma cells is not compatible with the expression of wild-type p53. Therefore, p53 should be considered as a tumour suppressor gene in hepatocytes.
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PMID:p53 as a growth suppressor gene in HBV-related hepatocellular carcinoma cells. 838 Dec 23

Wild-type human p53 protein is able to self-associate and consists predominantly of homotetramers in solution. In earlier work we identified the protein sequence motifs involved in p53 quaternary structure and showed that while monomeric p53 protein retains tumour suppressor function, monomeric tumour mutant p53 lacks dominant transforming activity. In this report we use point mutated and truncated cDNA genes encoding self-association defective human p53 proteins to investigate the relationship between p53 protein quaternary structure and the associated activities of transcription transactivation and target specific DNA binding. We show that p53 binds to a target oligonucleotide as a protein homodimer and that p53 dimerisation is required for detectable DNA binding. We found no evidence for p53 tetramer: DNA complexes and we suggest that the quaternary structure status of p53 may regulate a DNA binding associated activity. Monomeric p53 proteins failed to bind DNA in these assays but exhibited increased transactivating activity. Thus, both transcription transactivation and tumour suppressor functions act independently of p53 protein self-association and DNA binding. We propose that our results validate the p53 dimerisation motif as a target for rational anticancer drug design. We predict that compounds able to block p53 dimer assembly would inhibit the dominant transforming activities of mutant p53 in tumours retaining expression of a mutant allele, while leaving intact the wild-type p53 associated activities of transcription transactivation and transformation suppression in unaffected tissue.
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PMID:Human p53 binds DNA as a protein homodimer but monomeric variants retain full transcription transactivation activity. 841 20

Alterations of tumour suppressor genes are considered crucial steps in the development of human cancers. Expressions of p53 protein, a product of the tumour suppressor gene altered most commonly in human cancers examined so far, were investigated immunohistochemically in 18 osteosarcomas and 40 other malignant and benign lesions of bone. A monoclonal antibody clone PAb240, which recognizes a common conformational epitope of mutant p53 proteins, stained nuclei of tumour cells in 12 of 18 osteosarcomas (67%). Six tumours (33%) particularly showed positive immunoreactions in more than half of the tumour cells. PAb240 also stained tumour cells in a small number of other malignant bone tumours, such as malignant fibrous histiocytoma, chondrosarcoma, and Ewing's sarcomas. Furthermore, a small number of cells of giant-cell tumours were positively stained. In contrast, PAb240 was completely negative in 21 benign bone tumours and reactive lesions examined. Another monoclonal antibody clone PAb1801, which reacts with both wild- and mutant-type p53 protein, reacted in nuclei of tumour cells of 7 osteosarcomas (39%). Most of those also reacted with PAb240. PAb1801 was expressed much more frequently in other malignant bone tumours and giant-cell tumours. In addition, PAb1801 showed intranuclear positive reactions in tumour cells of a benign chondroblastoma, and reactive cells such as actively proliferating preosteoblasts in a myositis ossificans and osteoclast-like giant cells in a giant-cell tumour. The immunoelectron-microscopic observation that p53 protein was localized in euchromatic areas of nuclei of osteosarcoma cells supported the specificity of immunoreaction for p53 protein, indicating an active role of p53 protein in the regulation of DNA synthesis and transcription. These findings suggest that point mutation of the p53 gene is frequently involved in the development of osteosarcomas. PAb240 may be a useful tool not only in screening point mutations of the p53 gene in osteosarcomas but also in the differential diagnosis between osteosarcomas and reactive bone-forming lesions. Expressions of mutant p53 protein were not correlated with any clinical or pathological factors examined, although the results should be confirmed in studies of a large number of osteosarcomas.
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PMID:Analysis of mutant P53 protein in osteosarcomas and other malignant and benign lesions of bone. 841 91

Overexpression of the tumour suppressor gene p53 was investigated immunohistochemically in 96 primary gastric carcinomas and 26 corresponding metastatic perigastric lymph nodes. Abnormalities in p53 expression were found in 52 (54%) of the 96 primary carcinomas. Tumours stained positively for p53 frequently metastasised to lymph nodes (the metastatic rate: 85%) compared to findings in those with negative p53 staining (64%, P < 0.05). Ninety-two percent (24/26) of the malignant cells in the lymph nodes stained positively for p53. When the DNA ploidy pattern of the tumour was determined by flow cytometry, the aneuploid tumours in p53 positive and negative groups accounted for 69% and 45%, respectively (P < 0.05). Proliferative activity of the tumour, as measured by Ki-67 labelling, was significantly higher (30.6 +/- 12.0%) in the p53 positive group than that (25.1 +/- 10.7%) in the p53 negative group (P < 0.05). Thus, gastric cancer with a mutant p53 has high proliferative activity and metastasis to lymph nodes will probably occur.
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PMID:Gastric cancer with p53 overexpression has high potential for metastasising to lymph nodes. 843 9

Mutations in the p53 tumour suppressor gene are amongst the most frequent genetic abnormalities acquired in tumours. Recent studies in vitro suggest that mutant p53 destabilises the genome and facilitates development of aneuploidy. Here, in a study of 83 colorectal carcinomas, we demonstrate that alterations in p53 (detected by immunocytochemical stabilisation) precede and apparently facilitate divergence of aneuploid sub-clones. Aneuploidy in these tumours (but not those with normal p53) is predominantly in the subtetraploid range, suggesting that endoreduplication is important in its origin. This association with a specific phase of carcinoma progression is not shared by other commonly acquired genetic abnormalities in these tumours. These observations highlight the critical role of p53 in the regulation of abnormal chromosome replication and afford an explanation for the association between p53 abnormalities, aneuploidy and biological aggression in cancer.
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PMID:Stabilised p53 facilitates aneuploid clonal divergence in colorectal cancer. 847 57

The tumour suppressor gene p53 is frequently mutated in neoplasia. Since mutant p53 protein is often over-expressed, mutation can be indirectly detected by immunocytochemical techniques. As microwave antigen retrieval is becoming a widespread method for increasing the antigenicity of paraffin sections, we investigated the application of this technique to p53 immunohistochemical staining of oral mucosa specimens. Paraffin sections of 22 squamous cell carcinomas (SCC) and 36 benign lesions were immunohistochemically stained with and without antigen retrieval. Without antigen retrieval p53 over-expression was observed in 6/22 SCC and 1/36 benign lesions. Following antigen retrieval positive staining was observed in 15/22 SCC and 35/36 benign lesions. Staining in benign lesions was confined to basal and parabasal cells and could reflect normal functioning of wild-type p53. We conclude that antigen retrieval increases the sensitivity of p53 immunoreactivity, but such staining is not specific for malignancy and should be interpreted with caution.
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PMID:The use of antigen retrieval for immunohistochemical detection of p53 over-expression in malignant and benign oral mucosa: a cautionary note. 866 57


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