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

Mutations of the human BRCA1 and BRCA2 genes encoding tumor suppressors have been implicated in inherited predisposition to breast and other cancers. Disruption of the homologous mouse genes Brca1 and Brca2 by targeting showed that they both have indispensable roles during embryogenesis, because nullizygous embryos become developmentally retarded and disorganized, and die early in development. In Brca1 mutants, the onset of abnormalities is earlier by one day and their phenotypic features and time of death are highly variable, whereas the phenotype of Brca2 null embryos is more uniform, and they all survive for at least 8.5 embryonic days. Observations with Brca1/Brca2 double nullizygotes raise the possibility that the two developmental pathways could be linked. Interestingly, the impact of the Brca1 or Brca2 null mutation is less severe in a p53 null background.
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PMID:Targeted mutations of breast cancer susceptibility gene homologs in mice: lethal phenotypes of Brca1, Brca2, Brca1/Brca2, Brca1/p53, and Brca2/p53 nullizygous embryos. 917 68

Breast cancer is the most common malignancy among women. Genetic predisposition is considered to account for 5-10% of all cases while the majority of these cancers are sporadic and caused by complex interactions of exogenous and endogenous factors. The inherited predisposition can be due to germline mutations in one of several cancer susceptibility genes. For high risk families the two most important genes are BRCA1 on chromosome 17q, which confers a high risk of both, breast and ovarian cancer and BRCA2 on chromosome 13 associated with high penetrance of breast cancer but lower risk of ovarian cancer. A high risk of breast cancer is conferred by mutations in the p53 tumor suppressor gene as part of the rare Li-Fraumeni-syndrome, and possibly also by the estrogen receptor gene. Other cancer genes associated with a less increased risk of breast cancer are the autosomal recessive ataxia telangiectasia (AT) gene and the HRAS1 gene. Germline mutations in BRCA1 and BRCA2 account for the majority of families with multiple cases of breast and/or ovarian cancer and also at least 10% of cases below the age of 40 years. Genetic testing for BRCA1 mutations is not generally recommended except for women with a strong family history. The aim for the management of familial breast cancer should be the establishment of interdisciplinary teams to cover genetic counseling, molecular analysis, onco-surgical therapy, psychosocial support and clinical follow-up.
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PMID:[Molecular genetics of hereditary breast carcinoma]. 917 60

Chromosome 17 is one of the most frequently altered chromosomes in malignant breast cancer. At least four genes implicated in breast cancer reside on chromosome 17 (p53, 17p13; Her-2/neu/ERBB2, 17q12; BRCA1, 17q21; and nm23, 17q22). In addition, allelic imbalance has been described for at least five regions of chromosome 17. We have previously shown that the introduction of a normal human chromosome 17 into the breast cancer cell line MCF7 by microcell mediated chromosome transfer (MMCT) results in the in vitro growth arrest of these cells within 8 weeks, suggesting the presence of a growth suppressor on chromosome 17. Additionally, we have shown that the tumor suppressor gene p53 is not responsible for this phenotype, as it is wild type in MCF7 cells, and overexpression has no effect on either the in vitro or in vivo growth of these cells. We have further localized this growth suppressor gene to 17q24-q25 by transfer of chromosome 17 hybrids containing defined deletions. Whereas transfer of hybrids that contained an intact 17q (delta43/A9 and delta26/A9) resulted in growth arrest, two hybrids with overlapping deletions at 17q24-q25, had no effect on growth of MCF7 cells. Molecular analyses revealed that 50/70 (71%) of the resulting delta2/MCF7 or delta624/MCF7 MMCT clones retained an intact introduced chromosome 17. In contrast, only 8/34 (24%) of delta43/MCF7 revertants (deleted for 17p13.1-pter) which escaped growth arrest showed no breakage of the introduced chromosome 17. We did not observe a preferential loss of an intragenic BRCA1 marker in the MMCT hybrids, excluding BRCA1 as the gene responsible for this growth arrest phenotype. These data therefore implicate a new growth suppressor gene involved in breast cancer that is localized to chromosome 17q24-q25.
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PMID:Localization of a growth suppressor activity in MCF7 breast cancer cells to chromosome 17q24-q25. 917 10

Sporadic breast carcinoma is associated with multiple genetic alterations. The clinical relevance of these alterations, however, needs further clarification. In the present study we analyzed 266 spontaneously arising breast carcinomas for allelic losses in the BRCA1 and TP53 regions on chromosome 17, the BRCA2 region on chromosome 13, the ATM (mutated in ataxia-telangiectasia) region on chromosome 11 and on the chromosomal arms 7q and 16q. In addition the following clinical and pathological parameters were evaluated: age at diagnosis, tumor size, presence or absence of regional and distant metastases, hormone-receptor status, histopathological classification and tumor grading. The analysis of genetic and clinical observations revealed significant associations: absence of expression of the estrogen receptor was linked to a high rate of allelic losses of markers in the BRCA1, TP53 and BRCA2 regions. Expression of the progesterone receptor coincided with allelic loss on the long arm of chromosome 16. High-grade malignant lesions and ductal differentiation were frequently associated with allelic losses in the proximal portion of chromosome 17q. The accumulation of multiple allelic deletions was linked to high-grade malignant tumors, to tumor size, and to loss of expression of the estrogen receptor. Our data point to a relationship between clinically relevant prognostic factors and specific genomic deletions in the BRCA1, BRCA2 and TP53 region.
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PMID:Genomic deletions in the BRCA1, BRCA2 and TP53 regions associate with low expression of the estrogen receptor in sporadic breast carcinoma. 922 12

Cancer incidence varies markedly by ethnicity and geographic location. Ethnic variation in cancer occurrence has traditionally been ascribed to differences in social, cultural, economic, and physical environments. However, this interpretation of the epidemiologic evidence may need to be revised as a result of new biological evidence and theories of carcinogenesis. Carcinogenesis is now recognized to be a multistep process during which mutations or heritable changes in expression occur in genes involved in cellular growth control and genome stability. Inherited cancer susceptibility may be a stronger determinant of ethnic differences in cancer incidence than is currently appreciated. To examine the potential role of inherited susceptibility, the theoretical contribution of inherited susceptibility to ethnic differences in rates in considered using a simple probability model. Germline mutations in tumor suppressor genes BRCA1 and p53 are used to illustrate the magnitude of the ethnic differences for breast cancer that might arise from differences in inherited susceptibility. Our simple model suggests that ethnic differences in cancer occurrence can result from differences in genetic susceptibility. However, the magnitude of ethnic relative risk is likely to more strongly reflect differences in the distribution of susceptibility genotypes between groups than the magnitude of the disease risk associated with the genotypes. For many scenarios, the ethnic relative risk arising from differences in susceptibility may be bounded by the ratio of the proportion of susceptible individuals in each group.
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PMID:Ethnic differences in cancer incidence: a marker for inherited susceptibility? 925 77

Much of the predisposition to hereditary breast and ovarian cancer has been attributed to inherited defects in the BRCA1 tumour-suppressor gene. The nuclear protein BRCA1 has the properties of a transcription factor, and can interact with the recombination and repair protein RAD51. Young women with germline alterations in BRCA1 develop breast cancer at rates 100-fold higher than the general population, and BRCA1-null mice die before day 8 of development. However, the mechanisms of BRCA1-mediated growth regulation and tumour suppression remain unknown. Here we show that BRCA1 transactivates expression of the cyclin-dependent kinase inhibitor p21WAF1/CIP1 in a p53-independent manner, and that BRCA1 inhibits cell-cycle progression into the S-phase following its transfection into human cancer cells. BRCA1 does not inhibit S-phase progression in p21-/- cells, unlike p21+/+ cells, and tumour-associated, transactivation-deficient mutants of BRCA1 are defective in both transactivation of p21 and cell-cycle inhibition. These data suggest that one mechanism by which BRCA1 contributes to cell-cycle arrest and growth suppression is through the induction of p21.
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PMID:Arrest of the cell cycle by the tumour-suppressor BRCA1 requires the CDK-inhibitor p21WAF1/CiP1. 929 97

Five human ovarian carcinoma cell lines cultured from primary and metastatic tumors of Korean patients were characterized. These lines were isolated from two papillary serous cystadenocarcinomas, two endometrioid carcinomas, and one malignant Brenner tumor. It was shown that the growth of these cell lines was stable when cultured after at least 20 passages. Population doubling times varied from 40 to 67 hr. All lines showed high viability and were proven by DNA fingerprinting analysis to be unique. Contamination by mycoplasma or bacteria was excluded. In two lines, SNU-8 and SNU-840, an elevated level of CA125 antigen secretion could be detected, whereas CEA was undetectable in all five lines. Four different mutations in functional and highly conserved regions of the p53 gene were identified in three of our five lines (60%), namely in SNU-119, SNU-251, and SNU-563. Included were two missense mutations, one in-frame 3-base-pair deletion, and one out-of-frame 1-base-pair deletion. It is interesting to note that one of these three lines, SNU-251, presented an additional simultaneous nonsense mutation of the BRCA1 gene and missense mutation of the hMLH1 gene. In its lacking both wild-type alleles of the BRCA1 gene, SNU-251 might serve as an unusual and important in vitro model for studies related to ovarian carcinoma and the BRCA1 gene. It is thus likely that the establishment and characterization of these permanent human ovarian carcinoma cell lines in continuous cultures can provide useful tools for in vitro studies related to human ovarian carcinomas.
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PMID:Establishment and characterization of human ovarian carcinoma cell lines. 929 49

We performed a detailed and comprehensive study of the involvement of tumor suppressor genes in human prostate cancer. We utilized primers flanking either the restriction fragment length polymorphism (RFLP) or variable number of tandem repeat [VNTR; microsatellite or simple repeat site (SRS)] polymorphic sites to polymerase chain reaction (PCR) amplify the genomic DNA and detect loss of heterozygosity of the target genes. Quantitative reverse transcription (RT)-PCR was performed to measure the mRNA expression levels and PCR/single strand conformational polymorphism (SSCP) and DNA sequencing carried out to detect mutation of the tumor suppressor genes. We found that multiple tumor suppressor genes (e.g., p53, DCC, APC, MCC, BRCA1, and WAF1/CIP1) were inactivated at different frequencies via various mechanisms [e.g., loss of heterozygosity (LOH), loss of expression (LOE), mutation, and inactivation by cellular binding protein]. Several important and novel findings are as following: LOH and LOE of the DCC gene, LOH, LOE, and possible mutation of the APC/MCC genes, LOH of the BRCA1 locus, and mutation of the WAF1/CIP1 gene. For p53 tumor suppressor gene alone, multiple inactivation mechanisms (i.e., LOH, LOE, mutation, and amplification of the cellular inactivating protein MDM2) were identified. A possible involvement of genomic instability or mutator phenotype in human prostate cancer was investigated by microsatellite typing using PCR. A high frequency of microsatellite instability was detected and the microsatellite instability found to correlate with advanced stage and poor differentiation of prostate cancer, suggesting that genes functioning in DNA mismatch repair or general stabilization of the genome may be involved in prostate cancer. The results obtained in this study suggested that multiple tumor suppressor genes (both known and unknown genes) may share the role in prostate cancer; a pattern which has been found in a number of human malignancies such as cancers of the esophagus, colon and breast. In fact, we performed deletion studies aimed at localizing potential tumor suppressor loci on various chromosomal regions. A number of chromosomal regions (i.e., 6p12-24 and 17q21) were found to potentially harbor unidentified tumor suppressor genes. Detailed deletion mapping has localized the potential tumor suppressor loci to a < 2 Mb region centromeric to the BRCA1 gene on chromosome 17q. In addition, we identified a number of novel mechanisms of tumor suppressor gene inactivation, in prostate cancer such as loss of mRNA expression of the DCC, APC, MCC and p53 gene, and mutator phenotype. And for the very first time, we identified somatic mutations of the WAF1/CIP1 gene in primary human malignancy-human prostate cancer. This finding provides the first evidence in primary tumor that the WAF1/CIP1 gene may be a tumor suppressor gene and may be involved in prostate cancer. We identified 12-lipoxygenase (12-LOX) as a potential prognostic marker for human prostate cancer. mRNA expression levels of the 12-LOX gene was measured by quantitative reverse transcription-polymerase chain reaction (RT-PCR) and semi-quantitative in situ hybridization (ISH) in 122 pairs of matched normal and tumor tissues from prostate cancer patients. We found that 12-LOX expression levels were elevated in approximately half of the patients analyzed and the 12-LOX elevation correlates with advanced stage, poor differentiation, and surgical margin positivity. Our data suggest that 12-LOX may serve as a correlative marker for a more aggressive phenotype of prostate cancer and therefore for poor prognosis. We are currently refining our assays for possible clinical applicability. Since not all patients with loss of expression of the DCC gene showed LOH of the DCC locus, there must be other mechanism(s) responsible for loss of expression of the DCC gene. When we analyzed the relationship between DCC loss of expression and 12-LOX elevation in prostate cancer pati
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PMID:Involvement of the multiple tumor suppressor genes and 12-lipoxygenase in human prostate cancer. Therapeutic implications. 932 30

Epidemiologic studies have shown that the risk of cancer in the ovarian surface epithelium is decreased by factors that suppress ovulation, whereas uninterrupted ovulation has been associated with increased risk. This suggests that ovulation may play a critical role in ovarian carcinogenesis. More recently, molecular studies have demonstrated alterations in specific oncogenes and tumor suppressor genes in ovarian cancers. Overexpression of the HER-2/neu oncogene occurs in approximately 30% of ovarian cancers and correlates with poor survival. Although mutation of the K-ras oncogene has been found in some mucinous ovarian cancers, mutations in this gene appear to be more common in borderline ovarian tumors. Amplification of c-myc occurs in approximately 30% of ovarian cancers and is more frequently seen in serous cancers. Mutation of the p53 tumor suppressor gene, with resultant overexpression of mutant p53 protein, occurs in 50% of stage III/IV and 15% of stage I/II ovarian cancers. Most p53 mutations in ovarian cancers are transitions, which suggests that they arise spontaneously rather than due to exogenous carcinogens. In contrast to the acquired genetic alterations described above that are a feature of sporadic ovarian cancers, 5-10% of ovarian cancers probably arise due to inherited genetic defects. Recently, the BRCA1 tumor suppressor gene has heen identified and shown to be responsible for most cases of hereditary ovarian cancer. Further studies are needed to augment our understanding of the molecular pathogenesis of ovarian cancer.
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PMID:Human ovarian cancer of the surface epithelium. 933 69

Fanconi anemia (FA) is a genetically heterogeneous autosomal recessive syndrome associated with chromosomal instability, hypersensitivity to DNA crosslinking agents, and predisposition to malignancy. The gene for FA complementation group A (FAA) recently has been cloned. The cDNA is predicted to encode a polypeptide of 1,455 amino acids, with no homologies to any known protein that might suggest a function for FAA. We have used single-strand conformational polymorphism analysis to screen genomic DNA from a panel of 97 racially and ethnically diverse FA patients from the International Fanconi Anemia Registry for mutations in the FAA gene. A total of 85 variant bands were detected. Forty-five of the variants are probably benign polymorphisms, of which nine are common and can be used for various applications, including mapping studies for other genes in this region of chromosome 16q. Amplification refractory mutation system assays were developed to simplify their detection. Forty variants are likely to be pathogenic mutations. Seventeen of these are microdeletions/microinsertions associated with short direct repeats or homonucleotide tracts, a type of mutation thought to be generated by a mechanism of slipped-strand mispairing during DNA replication. A screening of 350 FA probands from the International Fanconi Anemia Registry for two of these deletions (1115-1118del and 3788-3790del) revealed that they are carried on about 2% and 5% of the FA alleles, respectively. 3788-3790del appears in a variety of ethnic groups and is found on at least two different haplotypes. We suggest that FAA is hypermutable, and that slipped-strand mispairing, a mutational mechanism recognized as important for the generation of germ-line and somatic mutations in a variety of cancer-related genes, including p53, APC, RB1, WT1, and BRCA1, may be a major mechanism for FAA mutagenesis.
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PMID:Sequence variation in the Fanconi anemia gene FAA. 937 98


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