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

Germline p53 mutations are frequently observed in the normal DNA of cancer-prone patients with Li-Fraumeni syndrome (LFS). Fibroblasts from LFS patients develop chromosomal aberrations, loss of cell cycle control, and spontaneous immortalization. We transfected four different mutant p53 genes into human skin fibroblasts from normal donors with two copies of wild-type p53 (p53(wt/wt)). Each mutant p53 expression-plasmid induced genomic instability equivalent to that seen in LFS cells. To test the role of wild-type and mutant p53 alleles in DNA replication and fidelity in LFS cells, we analysed the replication of the SV40-based shuttle vector pZ189 in four types of cells. We used p53(wt/mut) and p53(mut/-) LFS fibroblasts, and p53(-/-) non-LFS cells. Replication of pZ189 in vivo was significantly reduced by the presence of a p53(wt) allele. To show that this was not just due to inhibition of the function of T-antigen in SV40-based replication, we constructed a shuttle vector, pZ402, that contains a mutation in SV40 T-antigen which blocks its ability to interact with p53. Replication of pZ402 in LFS cells was also reduced by the presence of p53(wt), indicating that p53 can inhibit replication by interacting with proteins within the cellular replication machinery. Replicative errors in this shuttle vector are detected as mutations in a marker gene, supF. In addition to supF mutations, we observed deletion of a portion of the SV40 T-antigen gene in 100% of replicated plasmid pZ189 mutants (supF-) from the p53(wt/mut) fibroblasts and in 88% of the supF mutants from the p53(mut/-) (amino acid 175 arg to his) LFS cells. In one cell strain of immortal LFS cells, P53(mut/-) , containing a p53 frameshift mutation at amino acid 184, pZ189 replication yielded very few of these deleted shuttle vector plasmids (15%). These large deletions were not detected in plasmids replicated in p53(-/-) non-LFS cells, Saos-2 cells. Replicated plasmids with a normal supF gene were never found to have this large deletion regardless of the cell from which they were derived. Because the supF gene is not in the same region of the shuttle vector as the T-antigen gene it appears that second, independent gene deletions are frequent when replicative errors in supF occur in cells with a mutant p53. We conclude, therefore, that p53(wt/mut) LFS cells contain an activity that promotes mutations. Such an activity, which is likely to be due to the p53(mut), could result in the high rate of chromosomal instability and allelic loss of the wild-type p53 observed as these cells spontaneously immortalize.
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PMID:Analysis of genomic instability in Li-Fraumeni fibroblasts with germline p53 mutations. 864 66

We report details of a family with classic Li-Fraumeni syndrome in which there is a mutation in codon 344 of the tumour suppressor gene TP53. Codon 344 is a key residue within the tetramerisation domain, and the amino acid substitution of a proline for a leucine is predicted to have profound implications for tetramerisation and potentially DNA binding. This is the first report of a mutation at this residue in either sporadic tumours or in the germline and the first report of a germline mutation within the tetramerisation domain. The family does not appear to be remarkable in the spectrum of tumours, and there is loss of the wild-type allele in a leiomyosarcoma from the proband. A cell line has been established from the tumour of the proband and cytogenetic and molecular studies carried out, providing an extensive analysis in this family.
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PMID:A previously undescribed mutation within the tetramerisation domain of TP53 in a family with Li-Fraumeni syndrome. 864 85

The time course of induction of SOS-like stress responses such as enhanced reactivation (ER) and enhanced mutagenesis (EM) has been investigated in UV-C-irradiated skin fibroblasts from a xeroderma pigmentosum (XP) family, using herpes simplex virus type 1 as a probe. Similar ER studies were performed in a Li-Fraumeni syndrome (LFS) family and in a family with a high incidence of breast, ovarian, and colon cancer. In two XP (complementation group B) patients, with a striking absence of skin tumors even at an age of >40 years, only induction of EM was observed, whereas ER was absent (XPER-). The ER- phenotype was inherited from the father, whereas cells from the mother exhibited normal expression of ER and EM. This suggests that the absence of ER is a hereditary trait that is not correlated with a repair-deficient phenotype. Abnormally high levels of ER were observed in UV-C-exposed skin fibroblasts from rive LFS patients. The inheritance of the ER response was studied in one LFS family. High levels of ER were observed only in cells derived from affected individuals carrying one mutated p53 allele, whereas cells from unaffected family members, carrying two wild-type p53 alleles, exhibited normal ER levels. This result shows that abnormally high levels of ER positively correlate with the occurrence of cancer in affected individuals from a LFS family. Interestingly, abnormally high levels of ER were observed in cells from afflicted as well as from unafflicted members of a family with a high incidence of breast, ovarian, colon, and stomach cancer. This suggests that these latter individuals have inherited a mutated, putative predisposing gene, resulting in abnormal expression of ER, but that cancer had not yet developed. The results indicate that the ER response can possibly be used as a prognostic marker to identify carriers in various hereditary cancer-prone syndromes at an early age.
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PMID:Inheritance of abnormal expression of SOS-like response in xeroderma pigmentosum and hereditary cancer-prone syndromes. 865 7

The p53 tumor suppressor gene controls cellular growth after DNA damage through mechanisms involving growth arrest and apoptosis. Mutations that inactivate p53 occur commonly in virtually all human malignancies and can be detected by sequencing of the p53 gene, immunohistochemical staining of tumor tissue with anti-p53 antibodies, single-strand conformation polymorphisms, or other biological assays. Identification of p53 mutation in the germ line is diagnostic of the cancer-prone Li-Fraumeni syndrome. Alterations of the p53 gene result in defective cellular responses after DNA damage and predispose cells to dysregulated growth, tumor formation and progression, and potential resistance (of tumor cells) to certain chemotherapeutic agents or ionizing radiation. A variety of tumors involving mutant p53 have a worse prognosis than tumors of the same type containing no p53 mutations. New diagnostic and therapeutic strategies are evolving as the p53 pathways of cell-cycle arrest and apoptosis become elucidated.
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PMID:Biological and clinical importance of the p53 tumor suppressor gene. 866 76

Oncogene is not categorized as a tumor marker in a strict sense, however, cancer related oncogens play an important role as a biomarker in hereditary malignant tumors in a wide sense. Various suppressor oncogenes have been identified in the autosomal dominant hereditary diseases such as APC, in familial adenomatous polyposis, p53 in Li-Fraumeni syndrome and BRACA 1 and 2 in breast cancer. By identifying the mutation site or deletions of germ line, it is possible to make a presymptomatic diagnosis of those hereditary malignant tumors. There is splendid progress in understanding of DNA repair mechanism. Recently, the mismatch repair genes were cloned as a causing gene of HNPCC. There are another group of genes called nucleotide excision repair genes which are causative genes of various autosomal recessive hereditary diseases such as xeroderama pigmentation. Pro and cons of presymptomatic diagnosis of familial adenomatous polyposis were discussed in a series of 72 patients among 42 family trees.
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PMID:[Role of tumor marker in the presymptomatic diagnosis of hereditary malignant tumors]. 869 15

Approximately 20% of breast cancer patients have a family history of the disease, and in one-fourth of these cases breast cancer appears to be inherited as an autosomally dominant trait. Five genes and gene regions involved in breast cancer susceptibility have been uncovered. Germ-line mutations in the recently cloned BRCA1 gene at 17q21 is considered to be responsible for the disease in a majority of the breast-ovarian cancer families and in 40-45% of the site-specific breast cancer families, but appears not to be involved in families with both male and female breast cancer cases. The BRCA2 locus at 13q12-q13 appears to be involved in 40-45% of the site-specific breast cancer families, and in most of the families with affected males. The gene located in this region, however, does not seem to confer susceptibility to ovarian cancer. The TP53 gene is involved in breast cancer development in the Li-Fraumeni syndrome and Li-Fraumeni syndrom-like families, whereas germ-line mutations in the androgen receptor (AR) gene is present in a subset of male breast cancers. Furthermore, females who are obligate carriers of ataxia telangiectasia (AT) have a 4-12 times relative risk of developing breast cancer as compared with the general female population, indicating that germ-line mutations in AT also confer susceptibility to breast cancer.
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PMID:Genetic heterogeneity in breast cancer susceptibility. 869 52

Germline mutations in the p53 tumor suppressor gene are associated with the Li-Fraumeni syndrome, characterized by childhood sarcoma, leukemia and early onset breast cancer and has occasionally been found also in familial breast-ovarian cancer. Most mutations found are of missense type and located in the central region of the gene (exons 5 to 8). In the present study, a germline p53 alteration was identified in a late onset breast cancer family (kindred Lund 5; mean age 58 years) using single stranded conformation polymorphism and sequence analysis. The mutation (a CCG to CTG transition) at codon 82 in exon 4, resulting in a proline to leucine substitution, has not previously been reported and was not present in a control set of 60 healthy individuals. Three of five woman with breast cancer (45, 57 and 65 years) were carriers of the alteration. Loss of heterozygosity at the p53 locus was not seen in the primary tumors of these women, but appeared as a partial loss of the wildtype allele in subsequent recurrent lesions of two gene carriers. The family manifested no linkage to the p53 gene (a two-point LOD-score of -0.41), and has previously also been excluded for linkage to the BRCA1 and BRCA2 loci, as well as being carrier of a BRCA1 germline mutation. Although it seems unlikely that the p53 germline mutation is the major cause of disease predisposition in Lund 5, the data suggest that some p53 alteration may confer a subtle influence on breast cancer development and progression.
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PMID:A novel p53 germline alteration identified in a late onset breast cancer kindred. 871 Mar 80

Since the majority of germline mutations in the TP53 gene seem to occur in LFS or LFL families, and these are rare, research is best conducted in a collaborative setting (Li and Fraumeni, in press). In a report from a meeting at Bethesda in 1993, the following areas were outlined for collaborative study: the correlation (if any) of phenotypes with specific mutation; age specific penetrance; cumulative cancer incidence; gender differences in tumour development in carriers; the effects of DNA damaging agents on individuals with a TP53 mutation; the frequency of TP53 germline mutations in cohorts of patients with rare childhood tumours (eg adrenocortical carcinoma); and the psychosocial aspects of predictive TP53 testing. In addition, if, as seems likely from recent data, X irradiation in these individuals induces DNA damage that is tolerated, urgent collaborative studies are needed to investigate new methods of screening, such as magnetic resonance imaging. Treatment modalities should be carefully chosen, and for this reason alone, predictive testing may be desirable in all LFS and LFL families. Individuals carrying TP53 mutations could be offered chemoprevention within trials in an effort to reduce their mortality from cancer.
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PMID:Germline mutations in the TP53 gene. 871 14

Molecular cancer epidemiology is a relatively new strategy for malignancies. This strategy has made it possible to diagnose the predisposition to cancer. An individual is said to have a predisposition to cancer when a tumor-suppressor gene is inactivated in germ-line cells. Mainly the inactivation of the tumor-suppressor gene is caused by mutations at the coding region of the gene. However, we clarified that point mutations or hypermethylations of the retinoblastoma tumor-suppressor gene (RB) also cause inactivation of the gene, resulting in retinoblastoma. On the other hand, studies to improve the diagnosed predisposition to cancer have not been performed. We therefore started a basic study for this purpose. As the first example of limiting the predisposition to cancer, the cases with a point mutation at the RB promoter region might be good candidates. In these carriers, only the RB promoter region is inactivated in spite of a lack of abnormalities in the coding region. Therefore, if the RB promoter activity is recovered by drugs, predisposition to retinoblastoma should be limited. As the second example, Li-Fraumeni syndrome in which the p53 gene is hereditarily mutated might be a good candidate. Recently p53 has been reported to stimulate the WAF1 gene, and the WAF1 protein to inhibit cdk activity, which inactivates the RB gene product by phosphorylation. In addition, we found that p53 up-regulates the promoter activity of the RB gene. These findings suggest that p53 directly or indirectly activates RB at the transcriptional or post-transcriptional level. Therefore, reactivation of the WAF1 or RB gene by certain drugs might compensate for the loss of function of p53 in Li-Fraumeni syndrome. We then suggest that it might be possible to prevent cancer by enhancing some intact target genes of the genetically inactivated tumor-suppressor gene. We term this new strategy "gene-regulating chemoprevention." To test this hypothesis it is important to clarify the structure of the RB promoter. In summary we found that RBF-1 and ATF sites are the core promoter regions, that the neighboring E2F site is a silencer site, and that E4TF1 preferentially binds to the RBF-1 site. We then speculate that drugs interfering with the binding of the E2F complex might become good candidates enhancing RB promoter activity. To find drugs regulating the promoters of these genes, it is reasonable to try G1 arresting drugs, because WAF1 and RB are thought to arrest cells at the G1 phase. Actually we found several drugs causing G1 arrest. They are several flavonoids which we ingest daily from vegetables and fruits, or prostaglandin D2 and its metabolite. In summary, we propose that "gene-regulating chemoprevention" will be a useful method for molecular cancer epidemiology.
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PMID:[Molecular cancer epidemiology--the present status and future possibilities]. 872 Sep 30

Identification of inherited cancer-predisposing genes offers opportunities for cancer prevention. Inherited susceptibility genes have been identified, primarily through studies of unusual cancer cases and families but also through general population studies. Examples include the RB1 gene for retinoblastoma; the WT1 gene for Wilms' tumor; germline p53 mutations in families with the Li-Fraumeni syndrome; the NF1 and NF2 genes for neuroblastomatosis, types 1 and 2; the VHL gene for renal cancer and other tumors associated with Von Hippel-Lindau disease; the APC gene for adenomatous polyposis coli; the BRCA1 gene for hereditary breast and ovarian cancer; and the mismatch repair genes for colon and other common cancers. For some cancers, identification of gene carriers might be beneficial for targeting screening and chemopreventive interventions. On the other hand, predisposition testing for cancer has the potential for harm from loss of insurability and employability, psychological distress, social stigmatization and other adverse effects. Research is needed to identify predisposition testing procedures that maximize benefits while minimizing harm to subjects. Chemoprevention trials in genetically susceptible populations offer the prospect of finding effective methods of reducing future cancer risk.
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PMID:Identification and management of inherited cancer susceptibility. 874 2


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