Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P04637 (p53)
 77,613 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We report here a family with some of the characteristics of Li-Fraumeni syndrome (Li-Fraumeni-like) in which there is a 2 base pair deletion within exon 6 of TP53 in two affected individuals. Of particular interest in this family is a study of loss of heterozygosity (LOH) of the TP53 gene, and the finding that there is LOH in all cancers available for study from mutation carriers, and additionally from a benign endometrial polyp from one of those patients. Two other family members, one with a rectal carcinoma aged 55, the other with two separate benign lesions under the age of 45, were both wild-type for the TP53 mutation.
 ...
PMID:A novel deletion within exon 6 of TP53 in a family with Li-Fraumeni-like syndrome, and LOH in a benign lesion from a mutation carrier. 878 Jul 40

Susceptibility to environmental carcinogenesis is the consequence of a complex interplay between intrinsic hereditary factors and actual exposures to potential carcinogenic agents. We must learn the nature of these interactions as well as the genetic defects that confer enhanced risk. In some genetic diseases an increased cancer risk correlates with a defect in the repair or replications of damaged DNA. Examples include xeroderma pigmentosum (XP), ataxia telangiectasia, Fanconi's anemia, and Bloom's syndrome. In Cockayne's syndrome the Specific defect in transcription-coupled repair (TCR) does not predispose the patients to the sunlight-induced skin cancer characteristic of XP. The demonstration of TCR in the XP129 partial revertant of XP-A cells indicates that ultraviolet (UV) resistance correlates with repair of cyclobutane pyrimidine dimers in active genes. Repair measured as an average over the genome can be misleading, and it is necessary to consider genomic locations of DNA damage and repair for a meaningful assessment of the biological importance of particular DNA lesions. Mutations in the p53 tumor suppressor gene are found in many human tumors. TCR accounts for the resulting mutational spectra in the p53 gene in certain tumors. Li-Fraumeni syndrome fibroblasts expressing only mutant p53 are more UV-resistant and exhibit less UV-induced apoptosis than normal human cells or heterozygotes for mutations in only one allele of p53. The p53-defective cells are deficient in global excision repair capacity but have retained TCR. The loss of p53 function may lead to greater genomic instability by reducing the efficiency of global DNA repair while cellular resistance may be assured through the operation of TCR and the elimination of apoptosis.
 ...
PMID:Role of transcription-coupled DNA repair in susceptibility to environmental carcinogenesis. 878 81

The radiation response of Epstein-Barr virus (EBV)-immortalised lymphoblastoid cell lines derive from Li-Fraumeni syndrome (LFS) and LFS-like individuals was investigated. Cells from all LFS and LFS-like cases showed an accumulation of p53 protein following 137Cs gamma-irradiation, which was associated with cell cycle arrest at the G1/S border. This response was indistinguishable from that seen in cells derived from normal individuals, and occurred in cases with missense mutations in the TP53 gene at codons 175, 180, 220 and 248 and also in two LFS-like individuals with no TP53 mutation. Previous studies using lymphocytes and fibroblasts from LFS individuals have demonstrated abnormal radiation responses in these cells. This suggest cell type specificity in the contribution of a mutant p53 protein to phenotype.
 ...
PMID:No defect in G1/S cell cycle arrest in irradiated Li-Fraumeni lymphoblastoid cell lines. 879 70

This study addresses the question of whether loss of p16INK4 expression contributes to the immortalization of human cells. In vitro immortalization usually proceeds through two phases. In the first phase (lifespan extension), cells continue proliferating and their telomeres continue shortening beyond the point at which normal cells become senescent. In the second phase (immortalization), the cells activate a telomere maintenance mechanism and acquire an unlimited proliferative potential. It has previously been shown that immortalized cells containing viral oncoproteins that bind and inactivate p110RB contain wild-type p16INK4; we therefore examined the p16INK4 status of cell lines that became immortalized in vitro in the absence of these oncoproteins. Three such lines were identified: III-CF/.2A1 and III-CF/E6A2 (both derived from Li-Fraumeni syndrome fibroblasts, probably by spontaneous immortalization) and MePV-231 (normal mesothelial cells transfected with HPV-16 E6/E7 genes that underwent deletion of these genes before immortalization). In each case p16INK4 expression was lost at or before immortalization. Further, a cell strain was identified that had an extended but finite lifespan associated with loss of p16INK4 (and p53) expression. Thus loss of p16INK4 expression was associated with extended in vitro lifespan but was not sufficient for immortalization, even in the absence of wild-type p53.
 ...
PMID:Association of extended in vitro proliferative potential with loss of p16INK4 expression. 880

We present an extended family with Li-Fraumeni syndrome characterised by gastric and breast carcinoma, glioma, sarcoma, and leukaemia. This family showed strong evidence of linkage to TP53, and three of four tumours analysed showed loss of the wild type allele. A codon 175 missense mutation was identified in exon 5 in all available affected subjects. Counselling, screening, and issues surrounding presymptomatic testing are discussed.
 ...
PMID:An extended Li-Fraumeni kindred with gastric carcinoma and a codon 175 mutation in TP53. 882 20

Although acquired mutations in the human p53 gene occur in many tumor types, germline mutations are rare. An exception is the occurrence of germline p53 mutations in a fraction of families afflicted with the Li-Fraumeni syndrome (LFS). Previous studies from our laboratory demonstrated increased levels of wild type p53 protein in skin fibroblasts (SF) of patients from heritable cancer syndrome, including familial adenomatous polyposis (FAP), neurofibromatosis type 1 (NF1), and bilateral retinoblastoma (bRB) (Kopelovich and DeLeo, 1984,1986). Here, we further address the association between germline p53 alterations and genetic predisposition to cancer in the SBLA syndrome and in FAP. DNA sequencing and single-stranded conformational polymorphism analysis (SSCP) were utilized to screen for the presence of mutations within exons 5-9 of the p53 gene in SF and in benign tumors. Thus we observed no germline mutations in exons 5-9 of the p53 gene in SF from SBLA or FAP patients, including the Gardner variant. In addition, we observed no acquired mutations in exons 5-9 of the p53 gene in benign tumors from FAP patients. In conclusion, we found no association between germline p53 mutations and SBLA or FAP. How mechanisms that involve nonmutational activation of the p53 protein might affect genetic predisposition to cancer remains to be established.
 ...
PMID:Absence of germline mutations in exons 5-9 of the p53 gene in patients with Li-Fraumeni-like (SBLA) and familial adenomatous polyposis heritable cancer syndromes. 883 Jul 20

Senescence and immortalization have been studied in skin fibroblasts derived from two individuals with the Li-Fraumeni syndrome. These cells inherit one wild-type and one mutant p53 allele and lose the former during culture. Despite this loss, cultures of Li-Fraumeni syndrome cells progressed normally from early passage to replicative senescence. Senescent cells also expressed barely detectable levels of p21 mRNA, and, in marked contrast to normal cultured cells, levels of p21 expression decreased during in vitro aging. Further maintenance for up to 10 months of post-mitotic cultures has led to the isolation of cells with an extended lifespan. Four potentially immortal cultures have continued to proliferate, and two have completed more than 110 population doublings. These results indicate that p53 and p21 are not required for replicative senescence in human fibroblasts. However, their inactivation may enhance the probability of spontaneous immortalization.
 ...
PMID:Expression of p21 is not required for senescence of human fibroblasts. 884 Sep 65

Recently, genetic analyses in high risk families with several members suffering of breast and/or ovarian carcinoma led to the discovery of two genes, called BRCA1 and BRCA2, clearly responsible for hereditary predisposition of breast carcinoma. Another gene, p53, was also shown to be involved in hereditary predisposition of breast and other tumors in the setting of Li-Fraumeni syndrome. It is very important that women at risk could be seen by a specialized team for genetic counselling and explanation of advances and limits of molecular genetics. Such a team should be multidisciplinary in order to cover genetic, oncological, social, psychological and economical aspects of hereditary cancer predisposition. Prevention interventions and early detection methods are still investigational and definitely need to be performed in the setting of protocols in order to better evaluate their long term efficacy.
 ...
PMID:[Hereditary breast cancers]. 884 74

This report describes an unusual clinical presentation of Li-Fraumeni syndrome. Family history revealed a mild aggregation of adult cancers in one generation, and an unusual clustering of brain tumours of early childhood in the following generation. In order to evaluate the genetic basis for cancer predisposition in this family, molecular genetic analysis for the occurrence of germline TP53 tumour suppressor gene mutations was performed on 12 siblings of two generations. Indirect mutation analysis was performed by the single-strand conformation polymorphism (SSCP) technique. Alterations were characterised by automated direct fluorescence sequencing analysis. Tumour material was also examined for p53 protein accumulation by immunohistochemistry. Initially, a TP53 gene germline missense mutation was detected in an 11-year-old kindred with acute myeloid leukaemia (AML) following intensive treatment of a brain tumour. In peripheral blood and bone marrow samples of this proband, a reduction to hemizygosity occurred. During AML treatment, detection of LOH of 17p was used as a marker for clonality and treatment control. The mutation was found to be inherited from the proband's mother, who was diagnosed with breast cancer at the age of 48 years. Further, three siblings were carriers, and two are apparently healthy at the age of 21 and 23 years. Knowledge of germline mutations may allow accurate DNA-based carrier diagnosis which is of important clinical significance for treatment strategy and control. Furthermore, the occurrence of unaffected carriers in this family raises questions about appropriate methods of cancer surveillance and counselling for these people.
 ...
PMID:A new germline TP53 gene mutation in a family with Li-Fraumeni syndrome. 886

Numerous factors have been noted to be associated with risk of breast cancer. Indicators of endogenous hormonal alterations are among them: early age at menarche and late age at menopause, nulliparity, late age at first full term pregnancy and obesity in postmenopausal women. Other established risk factors are family history of breast cancer, histologic characteristics of benign tissue, mammographic patterns, exogenous hormones and alcohol consumption. Endogenous indicators may be a reflection of enhanced susceptibility, whereas exogenous exposures can have both independent effects on risk and the ability to interact with markers of inherited susceptibility. In case control studies of breast cancer, family history confers a risk elevation of two to three fold. The higher risk estimate occurs when first degree rather than second degree relatives are affected, or if more than one relative is affected. A relative diagnosed before age 45 increases risk for early-onset breast cancer. These findings have been obtained using either traditional analytic methods for case control data or an alternative strategy, which uses case control status as the predictor variable and models the risk to relatives in a time-dependent fashion. Risk of breast cancer is greater for the mother and sisters of cases than controls. The magnitude of risk increases with 1) decreasing age of diagnosis of the index case 2) additional family members with diagnosed breast cancer and 3) bilateral breast cancer in the index case. Although these two analytic approaches have somewhat different data requirements and may be subject to different biases, the results produced are quite consistent. Mutated p53 in female family members of patients with Li-Fraumeni syndrome was one of the first identified genetic susceptibility markers for breast cancer. Application of segregation and linkage analyses to pedigrees with multiple affected family members successfully focused the search for BRCA1. Recent cloning and sequencing of BRCA1 will allow for its use in risk assessment, diagnostic evaluation and screening of high risk women. BRCA1 appears to be primarily responsible for early-onset breast cancer in high risk families. Rare alleles of H-ras could account for some of the late-onset cases in unselected populations since at least 85% of breast cancer appears to be sporadic, other genetic markers yet to be identified undoubtedly exist.
 ...
PMID:Epidemiology of susceptibility to breast cancer. 889 88


<< Previous 1 2 3 4 5 6 7 8 9 10