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)

The p53 gene is known to play a central role in cancer. In fact, no human tumor type is devoid of p53 mutations, although differences can be seen in the relative frequencies and patterns of nucleotide substitutions. Our work illustrates these differences, since frequencies of mutations ranged from 15 to 80% and the patterns of mutations were distinctly different in skin cancers compared to breast tumors. Furthermore, it is well established that whenever p53 mutations occur during tumor progression, their appearance greatly affects the natural evolution of cancer. This is confirmed by the correlations found between p53 mutations and the negative outcome of the disease in a number of tumor types.
 ...
PMID:[P53 genes and solid tumors]. 820 50

We have measured the gene-specific and strand-specific DNA repair of UV-induced cyclobutane pyrimidine dimers in the p53 tumor suppressor gene in a normal, repair-proficient human fibroblast strain and in fibroblasts from a patient with the repair deficient disorder xeroderma pigmentosum, complementation xeroderma pigmentosum group C (XP-C). In both cell strains, repair was measured in the p53 gene and in its individual DNA strands. For comparison, the repair also was measured in other genomic regions in these human fibroblast strains, including the housekeeping gene dihydrofolate reductase, and two inactive genomic regions, the delta globin gene, and the 754 locus of the X chromosome. In both cell strains, we find that the p53 gene is repaired faster than the dihydrofolate reductase gene and much more efficiently than the inactive genomic regions. Selective repair of the transcribed DNA strand of p53 is observed in both human cell strains; the strand bias of repair is particularly distinct in XP-C. Mutations specific to the nontranscribed strand may occur due to replication errors at the sites of unrepaired DNA damage. Therefore, our results predict that the majority of mutations in skin cancers, especially those from patients with XP-C, would occur on the nontranscribed strand of the p53 gene. Indeed, Dumasz et al. (Proc. Natl. Acad. Sci. USA, in press, 1993) report such a strand bias of p53 mutation in skin cancers from XP-C patients.
 ...
PMID:DNA strand bias in the repair of the p53 gene in normal human and xeroderma pigmentosum group C fibroblasts. 822 75

The UV component of sunlight is the major carcinogen involved in the etiology of skin cancers. We have studied the rare, hereditary syndrome xeroderma pigmentosum (XP), which is characterized by a very high incidence of cutaneous tumors on exposed skin at an early age, probably due to a deficiency in excision repair of UV-induced lesions. It is interesting to determine the UV mutation spectrum in XP skin tumors in order to correlate the absence of repair of specific DNA lesions and the initiation of skin tumors. The p53 gene is frequently mutated in human cancers and represents a good target for studying mutation spectra since there are > 100 potential sites for phenotypic mutations. Using reverse transcription-PCR and single-strand conformation polymorphism to analyze > 40 XP skin tumors (mainly basal and squamous cell carcinomas), we have found that 40% (17 out of 43) contained at least one point mutation on the p53 gene. All the mutations were located at dipyrimidine sites, essentially at CC sequences, which are hot spots for UV-induced DNA lesions. Sixty-one percent of these mutations were tandem CC-->TT mutations considered to be unique to UV-induced lesions; these mutations are not observed in internal human tumors. All the mutations, except two, must be due to translesion synthesis of unrepaired dipyrimidine lesions left on the nontranscribed strand. These results show the existence of preferential repair of UV lesions [either pyrimidine dimers or pyrimidine-pyrimidone (6-4) photoproducts] on the transcribed strand in human tissues.
 ...
PMID:Specific UV-induced mutation spectrum in the p53 gene of skin tumors from DNA-repair-deficient xeroderma pigmentosum patients. 824 41

Transplant recipients successively develop benign, premalignant and malignant skin lesions on sun-exposed areas. It has been suggested that UV radiations might induce mutations in ras oncogenes and p53 tumour-suppressor gene, responsible for skin cancers. With PCR and oligoprobe hybridization, we investigated c-Ha-ras gene mutations at codons 12 and 61 in 120 cutaneous lesions from grafted patients, since they could represent a marker of the evolution of benign skin lesions towards malignancy in this population; 29 similar skin biopsies from non-immunosuppressed patients were also analyzed. In transplant recipients, we detected mutations at codon 12 only in 1/42 non-melanoma skin cancers and 2/29 pre-cancerous keratoses. No mutation was detected in 11 cases of cutaneous Bowen's disease from grafted patients and in pre-malignant and malignant skin samples from control patients. Benign warts exhibited an overall incidence of 18% and 15% of mutations at codon 12 of c-Ha-ras gene in grafted and control patients respectively. We detected only one mutation at codon 61 in a plantar wart. Human papillomaviruses (HPV) are thought to be involved in the malignant evolution of cutaneous disorders in transplant recipients and cooperate with a ras oncogene to induce malignancy in vitro. The presence of HPV DNA in our series of skin samples from grafted patients showed no correlation with the occurrence of c-Ha-ras mutations. Our findings indicate that c-Ha-ras-gene activation by mutations is rare in cutaneous lesions from transplant recipients, and is unlikely to play a crucial role in transformation towards malignancy in skin carcinogenesis among grafted patients.
 ...
PMID:Low incidence of c-Ha-ras gene mutations in benign and malignant cutaneous lesions from transplant recipients. 825 28

Defects in nucleotide excision repair are associated with the human condition xeroderma pigmentosum which predisposes to skin cancer. Mice with defective DNA repair were generated by targeting the excision repair cross complementing gene (ERCC-1) in the embryonic stem cell line, HM-1. Homozygous ERCC-1 mutants were runted at birth and died before weaning with liver failure. Examination of organs revealed polyploidy in perinatal liver, progressing to severe aneuploidy by 3 weeks of age. Elevated p53 levels were detected in liver, brain and kidney, supporting the hypothesised role for p53 as a monitor of DNA damage.
 ...
PMID:Mice with DNA repair gene (ERCC-1) deficiency have elevated levels of p53, liver nuclear abnormalities and die before weaning. 827 78

Many human skin tumors contain mutated p53 genes that probably result from UV exposure. To investigate the link between UV exposure and p53 gene mutation, we developed two methods to detect presumptive UV-specific p53 gene mutations in UV-exposed normal skin. The methods are based on mutant allele-specific PCRs and ligase chain reactions and designed to detect CC to TT mutations at codons 245 and 247/248, using 10 micrograms of DNA samples. These specific mutations in the p53 gene have been reported in skin tumors. CC to TT mutations in the p53 gene were detected in cultured human skin cells only after UV irradiation, and the mutation frequency increased with increasing UV dose. Seventeen of 23 samples of normal skin from sun-exposed sites (74%) on Australian skin cancer patients contained CC to TT mutations in one or both of codons 245 and 247/248 of the p53 gene, and only 1 of 20 samples from non-sun-exposed sites (5%) harbored the mutation. None of 15 biopsies of normal skin from non-sun-exposed or intermittently exposed sites on volunteers living in France carried such mutations. Our results suggest that specific p53 gene mutations associated with human skin cancer are induced in normal skin by solar UV radiation. Measurement of these mutations may be useful as a biologically relevant measure of UV exposure in humans and as a possible predictor of risk for skin cancer.
 ...
PMID:UV and skin cancer: specific p53 gene mutation in normal skin as a biologically relevant exposure measurement. 827 94

Expression of the p53 tumor suppressor gene product was determined in keratoses and skin cancers associated with psoralen photochemotherapy (PUVA). An immunocytochemical study was employed using CM-1 (polyclonal) and Do-1 (monoclonal) antibodies to human wild-type p53. Thirty-two cutaneous lesions and 20 perilesional PUVA-irradiated skin biopsies were examined from 7 patients, all of whom had received more than 200 PUVA treatments and/or a cumulative UVA dose of greater than 1000J/cm2 as treatment for widespread plaque psoriasis. p53 immunoreactivity was seen in 7 of 15 squamous cell carcinomas (46.7%), 5 of 8 dysplastic keratoses (62.5%) and in no basal cell carcinomas or benign keratoses. The overall prevalence of p53 immunoreactivity in 46.2% of malignant or dysplastic PUVA-associated skin tumors is similar to that previously found by our group in comparable skin tumors from the general population. Most patients with lesions showing positive p53 immunoreactivity had, however, been exposed to additional risk factors before receiving PUVA therapy. p53 gene sequencing of PUVA-associated non-melanoma skin cancer (NMSC) may clarify whether p53 mutation contributes to the development of these tumors and whether this relates to PUVA therapy or prior carcinogen exposure.
 ...
PMID:p53 immunoreactivity in cutaneous PUVA tumors is similar to that in other non-melanoma skin neoplasms. 830 Sep 28

Exposure to UV radiation has long been associated with the development of skin cancers. To identify the molecular targets in UV carcinogenesis, we analyzed 11 UV-induced murine skin cancers for mutations in the p53 tumor suppressor gene and found a 100% incidence rate. Such a high frequency of p53 mutations is unprecedented and suggests that this gene plays an important role in the development of UV-induced skin cancers. The mutations were predominantly "UV-signature" transitions (C-->T and CC-->TT) at pyrimidine-rich sequences located on the nontranscribed strand of the gene. In addition, seven tumors harbored multiple mutant alleles of p53, providing strong evidence for tumor heterogeneity at the molecular level.
 ...
PMID:High frequency of p53 mutations in ultraviolet radiation-induced murine skin tumors: evidence for strand bias and tumor heterogeneity. 831 2

Mutations in the p53 gene have been found in a large proportion of human skin cancers. These mutations show the same characteristics as mutations induced by UV light in experimental systems. To establish correlations between formation of DNA adducts by a known carcinogen and incidence of mutations within a specific human gene, we have investigated the formation of UV-induced photoproducts along exons 5-9 of the p53 gene after UV irradiation of human cells. The two major types of DNA photoproducts, cyclobutane pyrimidine dimers and pyrimidine (6-4) pyrimidone photoproducts [(6-4) photoproducts], were mapped at the DNA sequence level by strand cleavage at the sites of photoproducts. This was followed by ligation-mediated polymerase chain reaction (LMPCR) to amplify gene-specific fragments. In human skin cancers, mutations were most frequently found at codons 151/152, 245, 248, 278 and 286 of the p53 gene. The frequency of UV photoproducts is particularly high at codon 286, which is within a run of 12 adjacent pyrimidines. High levels of both photoproducts were also seen at codons 151 and 278. However, UV-induced DNA adducts are barely detectable at codons 245 and 248, which are mutation hotspots also for internal malignancies. At these positions, the frequency of photoproducts is much lower than at surrounding dipyrimidine sequences. These findings have some implications on molecular mechanisms of mutagenesis in the human genome.
 ...
PMID:The distribution of UV photoproducts along the human p53 gene and its relation to mutations in skin cancer. 833 34

In the present study we analysed 38 epithelial skin cancers, 19 basal cell carcinomas (BCCs), 13 squamous cell carcinomas (SCCs) and six Bowen diseases (BwDs), using a combination of polymerase chain reaction (PCR) and single-stranded conformation polymorphism (SSCP) techniques for the presence of p53 and RAS gene mutations. Whereas 48% (9/19) of the BCCs tested presented a mutated p53 gene, the frequency was lower (15%, 2/13) in our series of SCCs and negative in the BwDs. Nine of the 11 characterized mutations were single-nucleotide substitutions and, interestingly, seven of these involved CC dimers, where a C was changed into a T or a G (three C-->T transitions and four C-->G transversions). This mutational pattern, added to the fact that all the mutated tumors occurred at sun-exposed body sites, implicates UV light in their genesis. Furthermore, we observed two internal deletions of 6 and 24 bp whose flanking sequences contained two or three Cs on either strand. In addition to molecular detection, we searched for p53 protein accumulation, by immunocytochemical staining, in a subset of 23 epithelial skin tumors (nine bearing a mutation, 14 which scored negative in our assay). Three commercially available anti-p53 antibodies (PAb CM1, mAbs DO7 and 1801) were used, and 3/23 (all showing a mutated p53 gene) presented specific nuclear staining. In contrast to other reported data we could not detect any activating RAS gene mutation in our series of human skin cancers.
 ...
PMID:p53 gene mutations in human epithelial skin cancers. 843 42


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