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Query: UNIPROT:P04637 (p53)
 77,613 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Loss of heterozygosity is common for the short arm of chromosome 17 in medulloblastomas, and putative medulloblastoma suppressor loci have been localized to 17p13. The colocalization of the p53 tumor suppressor gene to 17p13 raises the possibility that its mutant alleles may play a role in the malignant transformation of "medulloblasts." Mutations and deletions of the p53 gene have been described in many tumor types and in the germline of some individuals with the Li-Fraumeni syndrome, but reports on the status of the p53 and mdm2 (a gene coding for a p53-associated protein reportedly amplified in human sarcomas) genes in medulloblastomas are few and an indication of their roles, if any, in the etiology of this important childhood tumor has yet to emerge. Here we have analyzed polymerase chain reaction-amplified products of exons 4-9 (95% of reported p53 mutations occur within this region) of the p53 gene in 9 medulloblastomas for potential mutations using the technique of single strand conformation polymorphism analysis and DNA sequencing. We found only one mutation, an A-T to T-A transversion involving the second base of codon 285 and resulting in the substitution of valine for glutamic acid, amplification of the mdm2 gene could be detected in zero of eight of these tumors. These findings suggest that genetic events associated with the inactivation of p53 gene occur in only a minor subset of medulloblastomas.
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PMID:p53 gene mutation and mdm2 gene amplification are uncommon in medulloblastoma. 792 11

Four genes are now known to be responsible for inherited susceptibility to breast cancer: the BRCA1 gene on chromosome 17q21, the ataxia-telangiectasia (AT) gene (11q22-q23), the TP53 gene (17p13.1) and the androgen receptor (AR) (Xq11.2-q12). These genes, however, differ dramatically in terms of the risk of breast cancer that they confer, the proportion of breast cancer incidence that they account for and the other cancers and other phenotypes with which they are associated. Genetic linkage studies have shown that some high risk breast cancer families, particularly those where breast cancer occurs in association with ovarian cancer, are due to a gene on chromosome 17q known as BRCA1. The BRCA1 gene is estimated to confer a breast cancer risk of about 70% by age 70, and may account for about 2% of overall breast cancer incidence, although a higher proportion of younger cases. Germline mutations in the TP53 gene are responsible for a high proportion of LI-Fraumeni families, in which breast cancer occurs in association with childhood sarcomas and other cancers. In such families, the risk of breast cancer is over 50% by age 50, and the risk of all cancers is nearly 100%; germline TP53 mutations are, however, probably responsible for much less than 1% of all breast cancer. By contrast, heterozygotes for the AT gene carry a much more moderate risk of breast cancer. This gene, however, is much more common in the population and may account for 7% or more of breast cancer incidence. Finally, germline mutations in the androgen receptor are known to cause male breast cancer, but this has only been demonstrated in two families. Evidence from linkage and population based studies suggests that these genes may account for about one half of the observed familial clustering of breast cancer; other breast cancer susceptibility genes therefore remain to be identified.
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PMID:Inherited susceptibility to breast cancer. 801 3

Cell cycle anomalies have been described in ataxia-telangiectasia cells after exposure to ionizing radiation. A recent report demonstrates that cells from these patients lack the ionizing radiation-induced increase in p53 protein seen in controls. We report here that an ionizing radiation-induced p53 response is reduced and/or delayed in cells from four ataxia-telangiectasia complementation groups. On the other hand, p53 induction is normal in all A-T complementation groups after exposure to UV-B light, an agent to which these cells are not hypersensitive. Specific inhibitors of protein kinase C and serine/threonine phosphatases prevented the radiation induction of p53 protein. Agents that produced double-strand breaks in DNA and/or inhibition of transcription caused an induction of p53 in the absence of radiation in control cells but not in ataxia-telangiectasia, but inhibitors of cell cycle progression such as mimosine and aphidicolin led to an increase in p53 in both cell types in the absence of radiation. These results suggest that there is more than one signal transduction pathway responsible for activation of p53, one of which is less efficient in ataxia-telangiectasia cells.
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PMID:Ionizing radiation and UV induction of p53 protein by different pathways in ataxia-telangiectasia cells. 824 33

Alterations of the TP53 tumor suppressor gene are present in various human malignancies and in the dominantly inherited Li-Fraumeni syndrome. Recently, a cell cycle checkpoint pathway involving p53 and GADD45 has been identified as defective in ataxia-telangiectasia. Using single strand conformation polymorphism analysis of PCR products, we looked for TP53 mutations in DNA of patients with AT. We did not find any mutation in 6 patients, suggesting that TP53 mutations are not directly involved in the cancer susceptibility observed in AT.
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PMID:Lack of mutations in the P53 gene exons 5 to 8 in ataxia-telangiectasia. 850 Jan 1

'Checkpoint' controls arrest the cell cycle after DNA damage, allowing repair to take place before mutations can be perpetuated. In multicellular organisms, DNA damage can also induce apoptotic cell death, protecting the organism at the expense of the individual cell. How does a cell 'choose' between cycle arrest and death? Analysis of two human tumour suppressor proteins, p53 and the ATM (ataxia-telangiectasia mutated) gene product, may provide some answers.
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PMID:Cellular responses to DNA damage: cell-cycle checkpoints, apoptosis and the roles of p53 and ATM. 853 57

The molecular basis of radiosensitivity was studied using a cDNA complementation approach to correct radiosensitivity in cells. Four cDNAs of sizes 1.6, 2.0, 2.2 and 2.5 kb were isolated that corrected several aspects of the phenotype of cells from patients with the human genetic disorder ataxia-telangiectasia, characterized by hypersensitivity to ionizing radiation. The criteria used to assess correction included cell viability, induced chromosome aberrations, G2 phase delay and induction of p53 after exposure to radiation. One cDNA (2.5 kb) was identified as the complete sequence of the RNA helicase p68, which was capable of correcting radiosensitivity based on two of the above four criteria, with p53 induction post irradiation being partially corrected. The 2.2 kb cDNA was shown to correspond to the complete sequence of arginyl tRNA synthetase and the other two cDNAs were identical to the 3' untranslated regions (UTR) of the transcription factor TFIIS (1.6 kb) and phospholipase A2 (2.0 kb) respectively. Additional transfections with the 3'UTR (198 nucleotides) of p68 RNA helicase and its inverse sequence revealed that the 3'UTR had the same complementation capacity as the full-length cDNA, whereas the inverse construct failed to complement radiosensitivity. These data provide additional support for a novel role for 3'UTRs in the regulation of gene expression.
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PMID:Genetic complementation of radiation response by 3' untranslated regions (UTR) of RNA. 861 88

Several reports have demonstrated a defective p53 response to ionizing radiation exposure in ataxia-telangiectasia (A-T) cells. On the other hand, p53 induction was normal after u.v. irradiation, an agent to which A-T cells are not hypersensitive. We show here that A-T cells are more sensitive than normal lymphoblastoid cells to cisplatin treatment but the rate of induction of p53 by cisplatin is similar in both cell types. In addition, the half-life of p53, both in the induced and uninduced forms, is the same in A-T and normal lymphoblastoid cells. The use of a reporter assay to determine the functional status of p53 confirmed the results obtained in the induction experiments with cisplatin. These results demonstrate that p53 induction status in A-T cells does not correlate with sensitivity to the inducting agent and there is no inherent defect in the turn-over of p53 in the induced or uninduced states in A-T.
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PMID:Induction of p53 and increased sensitivity to cisplatin in ataxia-telangiectasia cells. 876 Mar 8

The gene mutated in ataxia-telangiectasia (AT) patients, denoted ATM, encodes a putative protein or lipid kinase. To elucidate the functions of ATM, we disrupted the mouse ATM gene through homologous recombination in mice. Consistent with cellular defects of AT patients, the ATM-/- cells are hypersensitive to gamma-irradiation and defective in cell-cycle arrest following radiation, correlating with a defective up-regulation of p53. In addition, ATM-/- mouse thymocytes are more resistant to apoptosis induced by gamma-irradiation than normal thymocytes. ATM-/- fibroblasts are inefficient in G1 to S-phase progression following serum stimulation and senesce after only a few passages in culture. They have an increased constitutive level of p21CP1/WAF1. The ATM protein is therefore critical both for cellular responses to ionizing radiation and for normal cell-cycle progression. ATM+/- fibroblasts and thymocytes showed intermediately defective responses to irradiation but no growth defect, suggesting that the increased cancer risk of AT heterozygotes could be attributable to poor checkpoint function.
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PMID:Dual roles of ATM in the cellular response to radiation and in cell growth control. 884 91

The radiation hypersensitivity disorder ataxia-telangiectasia (A-T) is uniquely characterized by a failure to immediately inhibit DNA synthesis in response to low dose ionizing radiation which is referred to as radioresistant DNA synthesis (RDS). As it remains controversial as to whether p53 abnormalities are central to RDS and the A-T radiation hypersensitivity disorder, post-irradiation p53 responses and cell cycle alterations were investigated in EBV immortalized B cells (LCL's) from normal individuals (N LCL's) and A-T patients (A-T LCL's). Here it is shown that mutations in p53 are insufficient to give cells such as HL-60 cells RDS potential. Furthermore, RDS which is demonstrable at 2 Gy, does not correlate with radiation induced alterations in p53 or with alterations in the Gt/S block. However, at 10 Gy, abnormalities in p53 and cell cycle changes were noted for A-T LCL's. Although the results suggest that p53 abnormalities are not central to RDS or the A-T ionizing radiation hypersensitivity disorder, the demonstration of a threshold effect for secondary abnormalities in p53 and cell cycle changes post-irradiation, may help resolve conflicting reports on the involvement of p53 downstream of the central defect in A-T.
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PMID:Alterations in p53 do not correlate with radioresistant DNA synthesis. 891 92

Familial breast cancer is characterized by young age at diagnosis, an increased risk of bilateral breast cancer, an increasing risk in conjunction with increasing numbers of affected family members, and a strong association with ovarian cancer. At least eight candidate breast cancer susceptibility genes have been identified. Mutations in BRCA1, BRCA2, p53, and the Cowden disease gene are relatively uncommon, are highly penetrant, and produce striking familial clusters of breast cancer. BRCA1 and BRCA2 are the most important of these, accounting for an estimated 80% of hereditary breast cancer and 5 to 6% of all breast cancers. Specific BRCA1 and BRCA2 mutations are of particular importance in population subgroups, such as those identified among Jewish women of central European (Ashkenazi) origin. Mutations in the ataxia-telangiectasia gene and the rare HRAS1 variable number of tandem repeats polymorphisms are much more common but also much less penetrant. They do not produce dramatic familial aggregations of breast cancer but may prove to be responsible for a substantial proportion of all breast cancers if their epidemiologic association with breast cancer is confirmed. Predictive genetic testing for breast cancer risk is under way. Oncologists and primary-care physicians must become familiar with these genetic disorders and the issues surrounding predictive testing in order to make appropriate management decisions about women thought to have a high genetic risk of breast cancer.
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PMID:Genetics of breast cancer. 900 88


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