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

To identify the sites in the p53 tumor suppressor gene most susceptible to carcinogenic mutation by sunlight, the entire coding region of 27 basal cell carcinomas (BCCs) of the skin was sequenced. Fifty-six percent of tumors contained mutations, and these were UV-like: primarily CC-->TT or C-->T changes at dipyrimidine sites. Such mutations can alter more than half of the 393 amino acids in p53, but two-thirds occurred at nine sites at which mutations were seen more than once in BCC or in 27 previously studied squamous cell carcinomas of the skin. Seven of these mutation hotspots were specific to skin cancers. Internal-cancer hotspots not located at dipyrimidine sites were not mutated in skin cancers; moreover, UV photoproducts were absent at these nucleotides. The existence of hotspots altered the process of inactivating p53 in BCC compared to other cancers: allelic loss was rare, but 45% of the point mutations were accompanied by a second point mutation on the other allele. At least one of each pair was located at a hotspot. Sunlight, acting at mutation hotspots, appears to cause mutations so frequently that it is often responsible for two genetic events in BCC development.
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PMID:Mutation hotspots due to sunlight in the p53 gene of nonmelanoma skin cancers. 848 37

Carcinogenesis is a multigenic phenomenon where 3 prevailing types of genes are involved: oncogenes which stimulate the cell proliferation, tumor suppressor genes which act as inhibitors and metastagenes which contribute to the tumor progress. In animal models it has been shown that epithelial skin carcinogenesis proceeds stepwise: initiation, promotion, premalignant progression and finally malignant conversion. The oncogene c-H-ras and the tumor suppressor gene P53 are the genes whose involvement in these steps of epithelial skin cancers are duly established. Less experimental data are available concerning melanoma. the role of the oncogene N-ras, the tumor suppressor gene MTS-1 (encoding for protein p16) ans the metastagene nm 23 has recently be emphasized. Some cytogenetic abnormalities on chromosomes 1, 6, 9, 10, 11 and 17 have also been observed and incite to look for other genes potentially involved in the development of this tumor.
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PMID:[Genetic bases of cutaneous tumors]. 852 16

To investigate the role of nucleotide excision repair (NER) in the cellular processing of carcinogenic DNA photoproducts induced by defined, environmentally relevant portions of the solar wavelength spectrum, we have determined the mutagenic specificity of simulated sunlight (310-1100 nm), UVA (350-400 nm), and UVB (290-320 nm), as well as of the "nonsolar" model mutagen 254-nm UVC, at the adenine phosphoribosyltransferase (aprt) locus in NER-deficient (ERCC1) Chinese hamster ovary (CHO) cells. The frequency distributions of mutational classes induced by UVB and by simulated sunlight in repair-deficient CHO cells were virtually identical, each showing a marked increase in tandem CC-->TT transitions relative to NER-proficient cells. A striking increase in CC-->TT events was also previously documented for mutated p53 tumor-suppressor genes from nonmelanoma tumors of NER-deficient, skin cancer-prone xeroderma pigmentosum patients, compared to normal individuals. The data therefore indicate that the aprt gene in NER-deficient cultured rodent cells irradiated with artificial solar light generates the same distinctive "fingerprint" for sunlight mutagenesis as the p53 locus in NER-deficient humans exposed to natural sunlight in vivo. Moreover, in strong contrast to the situation for repair-component CHO cells, where a significant role for UVA was previously noted, the mutagenic specificity of simulated sunlight in NER-deficient CHO cells and of natural sunlight in humans afflicted with xeroderma pigmentosum can be entirely accounted for by the UVB portion of the solar wavelength spectrum.
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PMID:Mutagenic specificity of solar UV light in nucleotide excision repair-deficient rodent cells. 855 99

High levels of the p53 protein are immunohistochemically detectable in a majority of human nonmelanoma skin cancers and UVB-induced murine skin tumors. These increased protein levels are often associated with mutations in the conserved domains of the p53 gene. To investigate the timing of the p53 alterations in the process of UVB carcinogenesis, we used a well defined murine model (SKH:HR1 hairless mice) in which the time that tumors appear is predictable from the UVB exposures. The mice were subjected to a series of daily UVB exposures, either for 17 days or for 30 days, which would cause skin tumors to appear around 80 or 30 weeks, respectively. In the epidermis of these mice, we detected clusters of cells showing a strong immunostaining of the p53 protein, as measured with the CM-5 polyclonal antiserum. This cannot be explained by transient accumulation of the normal p53 protein as a physiological response to UVB-induced DNA damage. In single exposure experiments the observed transient CM-5 immunoreactivity lasted for only 3 days and was not clustered, whereas these clusters were still detectable as long as 56 days after 17 days of UVB exposure. In addition, approximately 70% of these patches reacted with the mutant-specific monoclonal antibody PAb240, whereas transiently induced p53-positive cells did not. In line with indicative human data, these experimental results in the hairless mouse model unambiguously demonstrate that constitutive p53 alterations are causally related to chronic UVB exposure and that they are a very early event in the induction of skin cancer by UVB radiation.
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PMID:Early p53 alterations in mouse skin carcinogenesis by UVB radiation: immunohistochemical detection of mutant p53 protein in clusters of preneoplastic epidermal cells. 855 21

Radiation carcinogenesis almost certainly involves multiple genetic alterations. Identification of such genetic alterations would provide information to help understand better the molecular mechanism of radiation carcinogenesis. The energy released by ionizing radiation has the potential to produce DNA strand breaks, major gene deletions or rearrangements, and other base damages. Alterations of the p53 gene, a common tumour suppressor gene altered in human cancers, were examined in radiation-induced rat skin cancers. Genomic DNA from a total of 33 rat skin cancers induced by ionizing radiation was examined by Southern blot hybridization for abnormal restriction fragment patterns in the p53 gene. An abnormal p53 restriction pattern was found in one of 16 cancers induced by electron radiation and in one of nine cancers induced by neon ions. The genomic DNA from representative cancers, including the two with an abnormal restriction pattern, was further examined by polymerase chain reaction amplification and direct sequencing in exons 5-8 of the p53 gene. The results showed that one restriction fragment length polymorphism (RFLP)-positive cancer induced by electron radiation had a partial gene deletion which was defined approximately between exons 2-8, while none of the other cancers showed sequence changes. Our results indicate that the alterations in the critical binding region of the p53 gene are infrequent in rat skin cancers induced by either electron or neon ion radiation.
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PMID:Infrequent alterations of the p53 gene in rat skin cancers induced by ionizing radiation. 862 3

Microdissection of biopsies with sequencing of exons 4-8 of the p53 gene permitted precise morphological identification of correlation between mutations and/or loss of heterozygosity, immunoreactivty of p53 and type of squamous neoplasia. Seventy-two specimens from ten lesions of sun-exposed sites including normal epidermis were analysed. Irrespective of p53 immunoreactivity and morphological grade dysplasia, in situ or invasive cancer, in each case, carried the identical mutation indicating that invasive skin cancer and its precursors derive from the same original neoplastic clone. Additionally, morphologically normal epidermis showed some sharply demarcated immunoreactive areas. These never had the same p53 mutation as that of the adjacent tumor, indicating that their mutations were separate events and ruling them out as common precursors of cancer. Non-immunoreactive normal epidermis did not show p53 mutations. Our findings indicate that a large fraction of keratinocytes in sun-exposed human skin carry mutations of p53 and suggest that at least two options exist for such cells (i) innocuous clonal expansion with preserved morphology and normal differentiation or (ii) malignant transformation with the p53 mutation as an early event. Suggestive evidence existed that the p53 mutations were qualitatively different in the two respective groups of lesions.
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PMID:Human epidermal cancer and accompanying precursors have identical p53 mutations different from p53 mutations in adjacent areas of clonally expanded non-neoplastic keratinocytes. 863 98

p53 tumor suppressor plays a vital role in the cellular responses to genotoxic stress. It is believed that p53 regulates the cell cycle by activating the G1 checkpoint after exposure to agents like ionizing radiation, ultraviolet (UV) radiation, or genotoxic chemicals. Recently, it is conjectured that p53 may have additional functions in DNA repair and apoptosis. Previously, we demonstrated that p53-transgenic mice that carry mutant alleles of a p53 gene developed twice as many skin tumors as control mice after UV exposure. To elucidate the molecular mechanisms of mutant p53 in skin cancers, we studied DNA repair efficiency and the rate of apoptosis in murine keratinocytes after UV irradiation. In this report, we show that mutant p53-transgenic mouse skin has reduced repair of UV-induced DNA damage in both in vivo and in vitro radioimmunoassays. In control mice, DNA repair is associated with increased amounts of wild-type P53 protein. Unexpectedly, mutant p53-transgenic mice had slightly increased apoptosis after UV irradiation, suggesting that the wild-type p53 protein in the cells still functions in inducing apoptosis, or that this cell death results from p53-independent mechanisms. These results suggest that mutant p53 interferes with wild-type p53 in the repair of UV-induced DNA damage but not in apoptosis.
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PMID:Decreased DNA repair but normal apoptosis in ultraviolet-irradiated skin of p53-transgenic mice. 864 54

Mutations in p53, a tumor suppressor gene, are one of the most common genetic lesions of human cancers. The relationship between p53 gene mutation and ultraviolet (UV) light has been demonstrated in skin cancers of sun-exposed sites. In this study, genomic DNA from 12 skin cancers was screened for mutations in exons 5 to 9 of this gene using the polymerase chain reaction--single strange configuration polymorphism (PCR-SSCP) analysis followed by DNA sequencing. DNA samples were obtained from 8 basal cell carcinomas (BCCs): 1 from an organoid nevus, 1 from a patient with basal cell nevus syndrome, 1 from a patient with xeroderma pigmentosum, and 1 from a recurrent and 4 from primary sporadic lesions on actinic damaged skin, and from 4 squamous cell carcinomas (SCCs): 1 from a burn scar, 1 from a patient with epidermodysplasia verruciformis, and 2 from actinic keratosis. Mutation of the p53 gene was detected in only 1 case of SCC which had arisen from actinic keratosis. The mutation occurred at codon 159 in exon 5 with a GCC to CCC base-pair substitution resulting in an amino acid change of alanine to proline. This mutation does not correspond to results of UV mutagenesis studies reported in the literature. Our findings imply that, although p53 gene mutation and UV exposure play an important role in the carcinogenesis of some skin cancers, they are not crucial, especially in skin cancers that develop from underlying skin disorders.
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PMID:p53 gene mutations in skin cancers with underlying disorders. 866 19

Specimens of squamous-cell neoplasms (81 invasive cancers, 36 in situ cancers, 70 dysplasias, 5 keratoacanthomas, 19 papillomas) and normal skin were immunostained with p53 antibody. Nuclear accumulation of p53 was visualized as following 2 distinct patterns: dispersed or compact. The former is interpreted as a reversible reaction to sunlight, whereas the latter, after microdissection and sequencing of DNA, has been shown to reflect clonal multiplication of keratinocytes with mutated p53. The dispersed pattern was diffusely distributed and usually only involved a small proportion of epidermal cells. The compact pattern was characterized as a contiguous area of homogeneously stained cells sharply demarcated from its surroundings. It involved patches of normal epidermis or large areas of dysplastic or malignant squamous epithelium. Immature cells were always stained, whereas immunoreactivity was variably present in differentiating keratinocytes. Dispersed patterns occurred in 94.7% of strongly UV-exposed skin (mainly face) and to a lesser extent in less exposed parts of the body. It showed no correlation to the age of the individual. About two-thirds of biopsies from individuals over age 50 displayed compact patterns in sun-exposed, otherwise normal, epidermis. About 65% of pre-malignant and malignant squamous-cell neoplasms had a compact pattern. The presence of p53 immunoreactivity as a compact pattern supports the idea that mutations of the p53 gene are early events in the sequence from dysplasia to invasive squamous-cell cancer of the skin. Also, even in the absence of cellular atypia, patches of epidermal cells can accumulate p53 in a way that is indistinguishable from that of cancer and pre-cancer.
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PMID:Two distinct p53 immunohistochemical patterns in human squamous-cell skin cancer, precursors and normal epidermis. 868 83

Actinic keratoses (AKs) are small scaly red areas of skin characterised histologically by dysplasia, a minority of which are thought to be precursors of squamous cell carcinoma (SCC), and which show a high frequency of regression. Surprisingly, in view of their benign clinical course, they show a high frequency of loss of heterozygosity (LOH) with a median loss of four loci with almost 20% of lesions showing loss of eight or more alleles, as well as frequent p53 mutation. Loss was common on 3p (31%), 9p (39%), 9q (22%), 13q (52%), 17p (64%) and 17q (46%), and allele loss correlated with dysplasia. Topological disturbance of p21WAF1/CIP1 expression correlated with allele loss but was also seen together with increased wild-type p53 expression and an increase in the fraction of cycling cells in the absence of allele loss or p53 mutation, and is likely to represent an early change. P21WAF1/CIP1 expression appeared independent of p53 status. The frequency of LOH in AKs exceeded that of (invasive) SCCs suggesting that the relation between the accumulation of genetic change and behaviour for non-melanoma skin cancer is not straightforward.
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PMID:Genetic change in actinic keratoses. 870 May 6


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