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)

A large number of studies have demonstrated that various kinds of DNA damage accumulate during aging and one of the causes for this could be a decrease in DNA repair capacity. However, the level of total genomic repair has not been strongly correlated with aging. DNA repair of certain kinds of damage is known to be closely connected to the transcription process; thus, we chose to investigate the level of gene-specific repair of UV-induced damage using in vitro aging of human diploid skin fibroblasts and trabecular osteoblasts as model systems for aging. We find that the total genomic repair is not significantly affected during cellular aging of cultures of both human skin fibroblasts and trabecular osteoblasts. Gene-specific repair was analyzed during cellular aging in the dihydrofolate reductase housekeeping gene, the p53 tumor suppressor gene, and the inactive region X(754). There was no clear difference in the capacity of young and old cells to repair UV-induced pyrimidine dimers in any of the analyzed genes. Thus, in vitro senescent cells can sustain the ability to repair externally induced damage.
 ...
PMID:Gene-specific DNA repair of pyrimidine dimers does not decline during cellular aging in vitro. 1073 78

We have examined the mutational spectrum in the Trp53 gene from UVB radiation-induced skin cancers in Trp53+/+ and Trp53+/- mutant mice of all three possible Xpc genotypes. Mutations were detected in exons 2-10 of the Trp53 coding region in approximately 90% of >80 different skin cancers examined. In contrast to Trp53+/+ mice in which most mutations in the Trp53 gene were located in exons 5-8, the majority of the mutations in Trp53+/- mice were at other exons. We observed a high predilection for C-->T transition mutations at a unique CpG site in codon 122 (exon 4) of the Trp53 gene in Xpc-/- Trp53+/- mice. This site is not part of a pyrimidine dinucleotide. Mutations at this codon, as well as in codons 124 and 210, were observed exclusively in Xpc-/- or Xpc+/- mice. Mutations at the corresponding codons (127 and 213) in the human p53 gene have been reported in skin tumors from human patients with xeroderma pigmentosum. Hence, mutations at codons 122 (125), 124 (127), and 210 (213) may constitute signatures for defective or deficient nucleotide excision repair in mice (humans). In Xpc-/- mice, the majority of mutations were located at C residues in CpG sites, in which the C is presumably methylated. A similar bias can be deduced from studies in human XP individuals.
 ...
PMID:Genotype-specific Trp53 mutational analysis in ultraviolet B radiation-induced skin cancers in Xpc and Xpc Trp53 mutant mice. 1074 25

The tumor suppressor protein p53 plays a central role in modulating the cellular responses to DNA damage. Several recent studies, undertaken with the whole genomic DNA or full-length gene segments, have shown that p53 is involved in nucleotide excision repair and it selectively influences the adduct removal from the non-transcribed strand in the genome. In this study, we have analyzed the damage induction at nucleotide resolution by ligase-mediated polymerase chain reaction and compared the repair of ultraviolet radiation-induced cyclobutane pyrimidine dimers within exon 8 of p53 gene in normal and Li-Fraumeni syndrome fibroblasts as well as in normal and human papillomavirus 16 E6 and E7 protein-expressing human mammary epithelial cells. The results demonstrate that (i) loss or disruption of p53 function decreases efficiency of DNA repair, by preferentially affecting the repair of non-transcribed strand and of intrinsically slow repair sites in transcribed strand; (ii) mutant p53 protein affects DNA repair, at least of non-transcribed strand, in a dominant negative manner; and (iii) pRb does not have an effect on the repair of DNA damage within transcribed or non-transcribed strand. The overall data suggest that p53 could regulate excision repair or related events through direct protein-protein interaction.
 ...
PMID:Decreased DNA repair efficiency by loss or disruption of p53 function preferentially affects removal of cyclobutane pyrimidine dimers from non-transcribed strand and slow repair sites in transcribed strand. 1075 68

Mechanisms of carcinogenesis through abnormalities of DNA repair genes are overviewed. Inactivation of DNA mismatch repair(MMR) gene(s) observed in tumors of hereditary non-polyposis colorectal cancer induces frameshift mutator mutation in MMR genes themselves, growth inhibitory genes and apoptosis inhibitory genes providing favorable genetic background for a malignant clone to be expanded. Deficiency of nucleotide excision repair that is usually employed for the removal of pyrimidine dimer formed by ultraviolet-irradiation in xeroderma pigmentosum (XP) causes hypersensitivity of the skin to sunlight as well as increased risk of skin cancer. Strand specificity and absence of hot spots for p53 tumor suppressor gene mutations was reported in ultraviolet induced skin cancers of XP model mice.
 ...
PMID:[Carcinogenesis through abnormalities of DNA repair genes]. 1087 47

The p53 tumor-suppressor gene has been implicated in the inducible activation of excision repair of ultraviolet (UV)-induced cyclobutane pyrimidine dimers (CPDs) in human cells. Because the large T antigen (LTAg) of the simian virus 40 (SV40) binds p53 protein and can interfere with its function, it was of interest to study DNA repair in normal human fibroblasts that had been transformed by SV40 compared with that in their nontransformed parental counterparts and to determine whether such transformation attenuated global genomic repair (GGR) of CPDs. Three methods were used to measure GGR in UV-irradiated cells: (i) an immunoassay using monoclonal antibodies specific for CPDs or 6-4 photoproducts (6-4PPs), (ii) zone sedimentation in alkaline sucrose gradients to measure the average DNA strand size after specific nicking at CPD sites in duplex DNA with T4 endonuclease V (TEV), and (iii) Southern hybridization of TEV-treated DNA with strand-specific mRNA probes to assess removal of CPDs from either strand of a defined genetic sequence in an expressed gene. Whereas repair of 6-4PPs was very similar in paired SV40-transformed and primary fibroblasts, GGR of CPDs was significantly reduced in the SV40-transformed cells. In contrast, SV40 transformation did not appreciably affect the efficiency of transcription-coupled repair. These data support the hypothesis that SV40 transformation can result in reduced levels of GGR, most likely because of the inhibition of normal p53 function by LTAg.
 ...
PMID:Reduced global genomic repair of ultraviolet light-induced cyclobutane pyrimidine dimers in simian virus 40-transformed human cells. 1102 Feb 43

The most prevalent DNA lesion induced by UV irradiation is the cyclobutane pyrimidine dimer (CPD) which forms at positions of neighboring pyrimidines. In mouse skin tumors induced by irradiation with UVB (280-320 nm) lamps or solar UV simulators, a major mutational hotspot occurs at codon 270 (Arg-->Cys) involving a sequence change from 5'-TCGT to 5'-TTGT. We have shown previously that CPD formation by UVB or sunlight is enhanced up to 10-fold at 5'-CCG and 5'-TCG sequences due to the presence of 5-methylcytosine bases. Sequence analysis showed that the CpG at codon 270 is methylated in mouse epidermis at a level of approximately 85%. Irradiation of mouse skin or mouse cells in culture produced the strongest CPD signal within exon 8 at the 5'-TCG sequence which is part of codon 270. Time course experiments showed that CPDs at this particular sequence persist longer than at several neighboring positions. The data suggest that formation of CPDs is responsible for induction of the major p53 mutational hotspot in UV-induced mouse skin tumors.
 ...
PMID:Cyclobutane pyrimidine dimers form preferentially at the major p53 mutational hotspot in UVB-induced mouse skin tumors. 1106 76

In mammalian cells, the rate of nucleotide excision repair of UV dimers is heterogeneous throughout the genome, with repair occurring more rapidly in the transcribed strand of active genes than in the genome overall. This repair pathway is termed transcription-coupled repair (TCR) and is thought to permit the rapid resumption of RNA synthesis following UV irradiation. To evaluate the inducibility of the TCR process, we examined the repair of UV-induced cyclobutane pyrimidine dimers (CPDs) at the level of the gene following exposure of hamster cells to a sub-lethal UV fluence, 3 h prior to a higher dose. Repair was detected by a well-established technique allowing quantification of CPDs at the level of a specific strand by Southern blot hybridization. Here, we show that prior low-dose irradiation clearly enhanced the early rate of CPD removal in the transcribed strand of the active DHFR gene. Furthermore, the RNA synthesis recovery following UV exposure was stimulated by the priming UV dose. Thus, we provide evidence for an inducible TCR response to CPDs in hamster cells. This pathway is independent of the p53 activation, since the hamster cell line that we used expresses high levels of mutant p53 protein.
 ...
PMID:Transcription-coupled repair is inducible in hamster cells. 1109 77

Decreases in stratospheric ozone levels from anthropogenic inputs of chlorinated fluorocarbons have resulted in an increased amount of harmful ultraviolet-B (UVB, 290-320 nm) radiation reaching the sea surface in temperate latitudes (30-50 degrees N). In the Gulf of Maine, present-day irradiances of ultraviolet-A (UVA, 320-400 nm) radiation can penetrate to depths of 23 m and UVB radiation can penetrate to depths of 7-12 m, where the rapidly developing embryos and larvae of the Atlantic cod (Gadus morhua) are known to occur. Laboratory exposures of embryos and larvae of Atlantic cod to ultraviolet radiation (UVR) equivalent to a depth of approximately 10 m in the Gulf of Maine resulted in significant mortality of developing embryos and a decrease in standard length at hatching for yolk-sac larvae. Larvae at the end of the experimental period also had lower concentrations of UVR-absorbing compounds and exhibited significantly greater damage to their DNA, measured as cyclobutane pyrimidine dimer formation, after exposure to UVB radiation. Larvae exposed to UVB radiation also exhibited significantly higher activities and protein concentrations of the antioxidant enzyme superoxide dismutase and significantly higher concentrations of the transcriptional activator p53. p53 is expressed in response to DNA damage and can result in cellular growth arrest in the G1- to S-phase of the cell cycle or to programmed cell death (apoptosis). Cellular death caused by apoptosis is the most likely cause of mortality in embryos and larvae in these laboratory experiments, while the smaller size at hatching in those larvae that survived is caused by permanent cellular growth arrest in response to DNA damage. In addition, the sub-lethal energetic costs of repairing DNA damage or responding to oxidative stress may also contribute to poor individual performance in surviving larvae that could also lead to increases in mortality. The irradiances of UVB radiation that elicit these responses in cod larvae can occur in many temperate latitudes, where these ecologically and commercially important fish are known to spawn, and may contribute to the high mortality of cod embryos and larvae in their natural environment.
 ...
PMID:Oxidative stress, DNA damage and p53 expression in the larvae of atlantic cod (Gadus morhua) exposed to ultraviolet (290-400 nm) radiation. 1110 19

In the p53 gene of human sunlight-associated skin cancers, 35 % of the mutations involve trinucleotide sequences with the rare base 5-methylcytosine (5'PymCG). In order to determine the involvement of 5-methylcytosine in sunlight-induced mutations, we have analyzed the cII transgene in mouse cells, a mutational target gene that we found is methylated at most CpG sequences. We report that the mutational spectra produced by irradiation with 254 nm UVC radiation and simulated sunlight, respectively, differ most dramatically by the much higher involvement of dipyrimidine structures containing 5-methylcytosine in the solar UV mutation spectrum (32 % versus 9 % of all mutations). A distinct mutational hotspot induced by simulated sunlight occurs at a sequence 5'TmCG and is associated with high levels of cis-syn cyclobutane pyrimidine dimer formation. A comparison of sunlight-induced mutational spectra of the cII and lacI transgenes, as well as the p53 gene in skin tumors, shows that 5-methylcytosine is involved in 25 to 40 % of all mutations in all three systems. The combined data make a strong case that cyclobutane pyrimidine dimers forming preferentially at dipyrimidine sequences with 5-methylcytosine are responsible for a considerable fraction of the mutations induced by sunlight in mammalian cells.
 ...
PMID:Similarities in sunlight-induced mutational spectra of CpG-methylated transgenes and the p53 gene in skin cancer point to an important role of 5-methylcytosine residues in solar UV mutagenesis. 1115 98

The fluoroquinolone antibiotic, lomefloxacin, is phototoxic in human skin exposed to UVA radiation, photosensitises DNA strand breaks and pyrimidine dimers in human keratinocytes in vitro, and is phototumorigenic in mouse skin. The p53 tumour suppressor protein is activated by a variety of cellular insults including UV radiation, to become a transcription factor for downstream markers such as the cyclin-kinase inhibitor p21CIP1/WAF1 or cause caspase transactivation which cleaves poly ADP ribose polymerase (PARP) as an early step in apoptosis. We have investigated these molecular defence responses in human skin cells treated with lomefloxacin and UVA radiation in vitro. Western blots revealed that lomefloxacin photosensitised the stabilisation of p53 protein in human fibroblasts. Lomefloxacin also photosensitised p53 transcriptional activity in amelanotic melanoma cells expressing wild-type p53 and stably transfected with a construct containing a beta-galactosidase reporter gene downstream from a p53 consensus binding sequence. Neither photosensitised production of H2O2 nor the resultant DNA strand breaks, appeared to be involved in this effect. Interestingly, p21CIP1/WAFI protein was upregulated by lomefloxacin in the dark by a p53-independent mechanism. Lomefloxacin also photosensitised the degradation of nuclear PARP, suggestive of caspase mediated, early apoptotic events.
 ...
PMID:The phototumorigenic fluoroquinolone, lomefloxacin, photosensitises p53 accumulation and transcriptional activity in human skin cells. 1119 49


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