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)

Induction of p53 in u.v.-irradiated primary human fibroblasts was monitored by immunostaining and Western blotting. Minimum u.v. doses required for induction of nuclear accumulation of p53 (minimum response dose: MRD) were estimated in various cells with different DNA repair capacities. The MRD in repair deficient xeroderma pigmentosum (XP) group A cells is eightfold lower than in normal cells, indicating that nuclear accumulation of p53 is related to DNA repair capacity. Cells from patients with another u.v.-sensitive disorder, Cockayne syndrome (CS), which have normal repair capacity for the overall genome but have a specific defect in preferential repair of lesions in active genes, have the same low MRD as of XP-A cells. Furthermore, the MRD in XP-C cells, which have normal preferential repair but have defects in overall genome repair, is as high as that of normal cells. DNA damage induced by X-ray is repaired at similar rates in normal, XP and CS cells. In contrast to u.v.-irradiation, the minimum dose of X-rays that induces nuclear accumulation of p53 is the same in these cells. Inhibition of transcription with alpha-amanitin evokes nuclear accumulation of p53 both in normal cells and in XP cells. These results strongly suggest that u.v.-induced nuclear accumulation of p53 is evoked through DNA damage of actively transcribed genes. Nuclear accumulation of p53 is observed in any phase of the cell cycle at both low and high u.v. doses.
 ...
PMID:U.v.-induced nuclear accumulation of p53 is evoked through DNA damage of actively transcribed genes independent of the cell cycle. 808 82

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

We have examined the capacity of UV-irradiated human diploid fibroblasts to support adenovirus (Ad) DNA synthesis in order to assess repair of UV-damaged DNA. The capacity of UV-irradiated xeroderma pigmentosum group C (XP-C) fibroblasts to support Ad DNA synthesis was similar to that of UV-irradiated normal diploid fibroblasts, following UV exposures of greater than 9 J/m2. In contrast, XP-A, Cockayne syndrome groups A and B (CS-A and CS-B) fibroblasts were reduced in their capacity to support Ad DNA synthesis compared to normal diploid fibroblasts following a similar UV treatment. These results demonstrate that the capacity of UV-irradiated fibroblasts to support Ad DNA synthesis correlates with their ability to remove UV-induced DNA damage from active genes by transcription-coupled repair (TCR). We also demonstrate that simian virus 40 (SV40)-transformed human fibroblasts, Li-Fraumeni syndrome (LFS) fibroblasts, heterozygous for mutations in one allele of the p53 gene and immortalized LFS cell lines expressing only mutant p53 are reduced in their capacity to support Ad DNA replication following similar UV treatments. These results suggest that the capacity of UV-irradiated cells to support viral DNA synthesis involves TCR of UV-damaged DNA and is disrupted by SV40 transformation and expression of mutant p53. We propose a model in which p53-dependent TCR regulates p53 stability in response to UV.
 ...
PMID:Capacity of UV-irradiated human fibroblasts to support adenovirus DNA synthesis correlates with transcription-coupled repair and is reduced in SV40-transformed cells and cells expressing mutant p53. 938 88

Trichothiodistrophy (TTD), xeroderma pigmentosum (XP), and Cockayne's syndrome (CS) are three distinct human diseases with sensitivity to ultraviolet (UV) radiation affected by mutations in genes involved in nucleotide excision repair (NER). Among the many responses of human cells to UV irradiation, both nuclear accumulation of p53, a tumor suppressor protein, and alterations in cell-cycle checkpoints play crucial roles. The purpose of this study was to define the signals transmitted after UV-C-induced DNA damage, which activates p53 accumulation in TTD/XP-D fibroblasts, and compare this with XP-D cell lines that carry different mutations in the same gene, XPD. Our results showed that p53 was rapidly induced in the nuclei of TTD/XP-D and XP-D fibroblasts in a dose-dependent manner after UV-C irradiation, as seen in XP-A and CS-A fibroblasts, much lower doses being required for the protein accumulation than in normal human fibroblasts, XP variant cells, and XP-C cells. The kinetics of accumulation of p53 and two effector proteins involved in cell-cycle arrest, WAF1 and GADD45, were also directly related to the repair potential of the cells, as in normal human fibroblasts their levels declined after 24 h, the time required for repair of UV-induced lesions, whereas NER-deficient TTD/XP-D cells showed p53, WAF1, and GADD45 accumulation for over 72 h after irradiation. Our results indicate that p53 accumulation followed by transcriptional activation of genes implicated in growth arrest is triggered in TTD/XP-D cells by the persistence of cyclobutane pyrimidine dimers, which are known to block transcription, on the transcribed strands of active genes.
 ...
PMID:Prolonged p53 protein accumulation in trichothiodystrophy fibroblasts dependent on unrepaired pyrimidine dimers on the transcribed strands of cellular genes. 943 78

Xeroderma pigmentosum group E (XP-E) fibroblasts (XP95TO) were transformed with pSV3neo. Selection in medium containing G418 yielded 14 clones with extended life span. Following crisis, one clone was recovered that behaved in culture as an immortal cell line and was named XPET6/1. Expression of the SV40 large T antigen gene (Tag) and increased level of p53 were demonstrated by western analyses. Fingerprinting with 14 polymorphic microsatellite genetic markers confirmed that XPET6/1 originated from the parental strain XP95TO. XPET6/1 retained the sensitivity to killing by UV observed with the parental strain. Cell-free extracts from the immortal or the parental XP-E cells were deficient in excision, compared to extracts from HeLa or extracts from Tag-transformed XP variant fibroblasts. Complementation of XP-E extracts with XP-A, XP-D or XP-G extracts restored nucleotide excision activity to normal levels. XPET6/1 could prove a useful cell line for cloning of the XPE gene by functional complementation.
 ...
PMID:Generation and characterization of an immortal cell line of xeroderma pigmentosum group E. 953 81

The mechanisms by which the p53 response is triggered following exposure to DNA-damaging agents have not yet been clearly elucidated. We and others have previously suggested that blockage of RNA polymerase II may be the trigger for induction of the p53 response following exposure to ultraviolet light. Here we report on the correlation between inhibition of mRNA synthesis and the induction of p53, p21WAF1 and apoptosis in diploid human fibroblasts treated with either UV light, cisplatin or the RNA synthesis inhibitors actinomycin D, DRB, H7 and alpha-amanitin. Exposure to ionizing radiation or the proteasome inhibitor LLnL, however, induced p53 and p21WAF1 without affecting mRNA synthesis. Importantly, induction of p53 by the RNA synthesis or proteasome inhibitors did not correlate with the induction of DNA strand breaks. Furthermore, cisplatin-induced accumulation of active p53 in repair-deficient XP-A cells occurred despite the lack of DNA strand break induction. Our results suggest that the induction of the p53 response by certain toxic agents is not triggered by DNA strand breaks but rather, may be linked to inhibition of mRNA synthesis either directly by the poisoning of RNA polymerase II or indirectly by the induction of elongation-blocking DNA lesions.
 ...
PMID:Inhibition of RNA polymerase II as a trigger for the p53 response. 998 8

The apoptotic response and the level of expression of p53 and of three genes transcriptionally activated by p53 (Mdm2, p21 and bax) were investigated in UV-sensitive cells from patients with xeroderma pigmentosum (XP) or Cockayne syndrome (CS). These disorders are due to different genetic defects affecting transcription-coupled repair (TCR) and/or global genome repair (GGR), the nucleotide excision repair subpathways which remove UV-induced lesions from the transcribed strand of active genes or from the rest of the genome, respectively. After 20 J/m2 UV light, normal and GGR-defective XP-C fibroblasts showed rapid increase in p53, late induction of Mdm2 and no evidence of apoptosis even 96 h after irradiation. In contrast, in XP-A (defective in GGR and TCR), CS-A and CS-B (defective only in TCR) fibroblasts, the p53 increase was not followed by Mdm2 induction and the persistence of high levels of p53, due to the lack of its degradation by Mdm2, was associated with the appearance of apoptosis. Besides indicating that the persistence of DNA damage in the transcribed strand of active genes leads to apoptosis, these findings provide the first evidence that the lack of activation of Mdm2 plays a key role in the cascade of events leading to apoptosis. Oncogene (2000).
 ...
PMID:Proneness to UV-induced apoptosis in human fibroblasts defective in transcription coupled repair is associated with the lack of Mdm2 transactivation. 1085 Oct 71

The increase in the p53 activity in response to DNA damage is thought to be one of the important mechanisms by which p53 contributes to transcriptional activation of p21(wafl), mdm2, and other downstream regulatory genes. To investigate the p53 response to ultraviolet (UV) type of DNA damage, p53 protein level, its transcriptional activity and in vivo ubiquitination were compared in repair-proficient normal human fibroblasts (NHFs) and repair-deficient xeroderma pigmentosum (XP) group A and group C (XP-C) fibroblasts subsequent to irradiation with UV light. Accumulation of p53 protein level was observed with increasing UV doses in all the cell lines; however, discordance between p53 and p21(waf1) and mdm2 levels was observed in NHF and XP-A cells. Induction of p21(waf1) and mdm2 was inhibited by UV irradiation, requiring higher doses in NHF and lower doses in XP-A cells. However, inhibition of p21(waf1) and mdm2 induction was not observed in XP-C cells. Ubiquitin-p53 conjugates could be detected in irradiated or unirradiated NHF and XP-A cells but not in XP-C cells irradiated with 30 and 50 J/m(2) UV light. Using a p53 reporter assay, p53 transcriptional activities were found to be induced by 10 J/m(2) UV exposure and dramatically inhibited with increasing UV doses in NHF cells. Compared with repair-proficient NHF cells, UV inhibition of p53 transcriptional activity was relatively more sensitive in XP-A cells but resistant in XP-C cells. These results indicate that DNA damage by UV, in addition to inducing p53, acts as a trigger for inhibition of p53 transcriptional activity. Overall, recognition of DNA damage links both p53 induction and p53 degradation to DNA repair mechanisms.
 ...
PMID:Modulation of transcriptional activity of p53 by ultraviolet radiation: linkage between p53 pathway and DNA repair through damage recognition. 1097 91

We previously reported that transcription-coupled repair (TCR)-deficient human fibroblasts are extremely sensitive to UV-induced apoptosis and this sensitivity correlated with the induction of the p53 tumour suppressor. However, we have also found that p53 can be protective against UV-induced apoptosis. Thus, prior to this study, it was not clear whether the induction of p53 in TCR-deficient fibroblasts contributed to their death. To address this issue, we have expressed human papillomavirus E6 (HPV-E6) in primary fibroblasts derived from patients affected with xeroderma pigmentosum (complementation groups A, B and C) and Cockayne syndrome (complementation group B). We found that TCR-deficient (XP-A, XP-B and CS-B) fibroblasts were more sensitive than TCR-proficient cells (XP-C and normal) to both UV light and cisplatin treatment and this increase in sensitivity was not p53 dependent. Importantly, HPV-E6 expression increased the sensitivity of TCR-proficient normal and XP-C fibroblasts to UV- and cisplatin-induced apoptosis. This increase in sensitivity correlated with a decrease in the capacity of HPV-E6 expressing cells to recover mRNA synthesis following UV-irradiation. Therefore, we propose that p53 protects against UV- and cisplatin-induced apoptosis in a TCR-dependent manner and that p53 does not contribute strongly to the induction of apoptosis in TCR-deficient fibroblasts.
 ...
PMID:P53 plays a protective role against UV- and cisplatin-induced apoptosis in transcription-coupled repair proficient fibroblasts. 1170 15

We examined ultraviolet (UV) irradiation and cisplatin treatment damage formation and repair efficiency in the p53 tumor suppressor gene of various cultured cell lines and lymphocytes using a nonradioactive multiplex long quantitative polymerase chain reaction (QPCR) assay, which amplified a 7-kb fragment of the target gene and a 500-bp fragment of the template control to successfully increase the sensitivity and reliability of the assay. The multiplex long QPCR detected a lesion frequency of 0.63 lesions/10kb/10J/m(2) in the p53 gene of fibroblast cells. In addition, the multiplex long QPCR assay detected pronounced differences in the repair of UV damage in the p53 gene among repair-proficient CRL-1475 cells and repair-deficient XP-A and XP-C cells. The multiplex long QPCR assay was also evaluated as a sensitive assay for the detection of DNA damage induced by cisplatin. The data indicated that the lesion frequency in the p53 gene was 1.27-1.75 times higher in the H23 cisplatin-sensitive cell than in the H1435 cisplatin-resistant cell at the IC(70) dose. After 8-h and 24-h repair periods, only 13 and 75% of cisplatin-induced damage had been removed in the H23 cells, whereas these values were 92 and 100% in the H1435 cells. In addition, our data indicate that multiplex long QPCR is a sensitive method for validly estimating repair in freshly isolated lymphocytes. The results suggest that the current protocol of the multiplex long QPCR method can be used to assess the damage formation and repair efficiency of various agents at biologically relevant doses and to allow a more precise determination of gene-specific repair in disease susceptibility and drug resistance in epidemiological studies.
 ...
PMID:Damage formation and repair efficiency in the p53 gene of cell lines and blood lymphocytes assayed by multiplex long quantitative polymerase chain reaction. 1287 14


1 2 Next >>