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)

The tumor suppressor protein p53 functions in many cellular responses to UV-induced DNA damage, including activating the global nucleotide excision repair (NER) pathway. A potential mechanism for the effect on NER is through the ability of p53 to transcriptionally regulate genes that are directly involved in NER. DDB2 is one such gene that is regulated by p53 at both the basal and UV inducible levels. In order to further understand p53's role in NER, we transfected and selected clones that stably overexpress DDB2 in a human p53 deficient cell line. Global genomic repair (GGR) of cyclobutane pyrimidine dimers was significantly increased in the DDB2 expressing cells in comparison to controls, demonstrating that p53 wt protein itself is not directly required for efficient GGR. The protein product of DDB2, p48, is also post-translationally regulated by proteasomal degradation in response to UV irradiation. The regulation of p48 at both the transcriptional level by p53, and post-translationally by the proteasome suggests that p48 may be a rate limiting component of NER.
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PMID:The DDB2 nucleotide excision repair gene product p48 enhances global genomic repair in p53 deficient human fibroblasts. 1282 82

In response to a variety of types of DNA damage, the p53 tumor suppressor gene product is activated and regulates a number of downstream cellular processes such as cell cycle arrest, apoptosis and DNA repair. Recent discoveries concerning the regulation of DNA repair processes by p53, such as nucleotide excision repair (NER) and base excision repair (BER) have paved the way for studies to understand the mechanisms governing p53-dependent DNA repair. Although several theories have been proposed, accumulating evidence points to a transcriptional regulatory role for p53 in NER, mediating expression of the global genomic repair (GGR)-specific damage recognition genes, DDB2 and XPC. In BER, a more direct role for p53 has been proposed, potentially acting through protein-protein interactions with BER specific factors. These advances have greatly enhanced our understanding of the role of p53 in DNA repair and this review comprehensively summarizes current opinions on the mechanisms of p53-dependent DNA repair.
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PMID:p53 and regulation of DNA damage recognition during nucleotide excision repair. 1296 52

Tumor suppressor p53 controls cell cycle progression and apoptosis following DNA damage, thus minimizing carcinogenesis. Mutations in the human DDB2 gene generate the E subgroup of xeroderma pigmentosum (XP-E). We report here that XP-E strains are defective in UV irradiation-induced apoptosis due to severely reduced basal and UV-induced p53 levels. These defects are restored by infection with a p53 cDNA expression construct or with a DDB2 expression construct if and only if it contains intron 4, which includes a nonmutated p53 consensus-binding site. We propose that both before and after UV irradiation, DDB2 directly regulates p53 levels, while DDB2 expression is itself regulated by p53.
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PMID:Impaired regulation of tumor suppressor p53 caused by mutations in the xeroderma pigmentosum DDB2 gene: mutual regulatory interactions between p48(DDB2) and p53. 1456 2

The tumor suppressor p53 protein has been established as an important factor in modulating the efficiency of global genomic repair. Our recent repair studies in human cells reported that p53 regulates the recruitment of XPC and TFIIH proteins to specific DNA damage sites. Here, we have examined the influence of p53 and damaged-DNA binding complex (DDB2) proteins on the distribution of XPC within damaged chromatin in vivo and the recruitment of XPC to DNA damage sites in situ. The results show that UV irradiation causes the translocation of XPC from a loosely bound form into a tight association with chromatin in vivo. The UV radiation-induced redistribution of XPC was equally compromised in p53-deficient, as well as DDB2-deficient, human cells. Similarly, rapid recruitment of XPC to DNA damage in situ was also impaired in both cell lines. Ectopic expression of DDB2 in p53-deficient cells overcame the requirement of p53 function for UV-induced translocation of XPC in vivo. Restoration of DDB2 function also enhanced the recruitment of XPC to DNA damage sites in situ and increased the global repair of cyclobutane pyrimidine dimer from the genome. These results indicate that DDB2 is a key downstream factor of p53 for regulating the movement of XPC to DNA damage in irradiated cells.
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PMID:UV radiation-induced XPC translocation within chromatin is mediated by damaged-DNA binding protein, DDB2. 1474 21

Mutations in the human DDB2 gene give rise to xeroderma pigmentosum group E, a disease characterized by increased skin tumorigenesis in response to UV-irradiation. Cell strains derived from xeroderma pigmentosum group E individuals also have enhanced resistance to UV-irradiation due to decreased p53-mediated apoptosis. To further address the precise function(s) of DDB2 and the consequence of non-naturally occurring DDB2 mutations, we generated mice with a disruption of the gene. The mice exhibited significantly enhanced skin carcinogenesis in response to UV-irradiation, and cells from the DDB2(-/-) mice were abnormally resistant to killing by the radiation and had diminished UV-induced, p53-mediated apoptosis. Notably, the cancer-prone phenotype and the resistance to cellular killing were not observed after exposure to the chemical carcinogen, 7,12-dimethylbenz[a]anthracene (DMBA), to which mice carrying defective nucleotide excision repair genes respond with enhanced tumors and cell killing. Although cells from heterozygous DDB2(+/-) mice appeared normal, these mice had enhanced skin carcinogenesis after UV-irradiation, so that XP-E heterozygotes might be at risk for carcinogenesis. In sum, these results demonstrate that DDB2 is well conserved between humans and mice and functions as a tumor suppressor, at least in part, by controlling p53-mediated apoptosis after UV-irradiation.
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PMID:DDB2 gene disruption leads to skin tumors and resistance to apoptosis after exposure to ultraviolet light but not a chemical carcinogen. 1476 31

DDB2 is an essential subunit of the damaged-DNA recognition factor DDB, which is involved in global genomic repair in human cells. Moreover, DDB2 is mutated in the repair-deficiency disease xeroderma pigmentosum (Group E). Expression of DDB2 in human cells is induced by P53, BRCA1 and by ionizing radiation. The DDB2 protein associates with transcriptional activator and coactivator proteins. In addition, DDB2 in conjunction with DDB1 associates with cullin 4A and the Cop9/signalosome. We generated a mouse strain deficient for DDB2 (DDB2-/-). Consistent with the human disease (XP-E), the DDB2-/- mice were susceptible to UV-induced skin carcinogenesis. We observed a significant difference in the initial rate of cyclobutane pyrimidine dimer (CPD)-removal from the skin following UV irradiation. Also, the DDB2-deficient mice exhibited a significantly reduced life span compared to their wild-type littermates. Moreover, unlike other XP-deficient mice, the DDB2-deficient mice developed spontaneous malignant tumors at a high rate between the ages of 20 and 25 months. The observations suggest that, in addition to DNA repair, the other interactions of DDB2 are significant in its tumor suppression function.
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PMID:Tumor-prone phenotype of the DDB2-deficient mice. 1555 25

We have previously demonstrated that c-Myc impairs p53-mediated apoptosis in K562 human leukemia cells, which lack ARF. To investigate the mechanisms by which c-Myc protects from p53-mediated apoptosis, we used K562 cells that conditionally express c-Myc and harbor a temperature-sensitive allele of p53. Gene expression profiles of cells expressing wild-type conformation p53 in the presence of either uninduced or induced c-Myc were analysed by cDNA microarrays. The results show that multiple p53 target genes are downregulated when c-Myc is present, including p21WAF1, MDM2, PERP, NOXA, GADD45, DDB2, PIR121 and p53R2. Also, a number of genes that are upregulated by c-Myc in cells expressing wild-type conformation p53 encode chaperones related to cell death protection as HSP105, HSP90 and HSP27. Both downregulation of p53 target genes and upregulation of chaperones could explain the inhibition of apoptosis observed in K562 cells with ectopic c-Myc. Myc-mediated impairment of p53 transactivation was not restricted to K562 cells, but it was reproduced in a panel of human cancer cell lines derived from different tissues. Our data suggest that elevated levels of Myc counteract p53 activity in human tumor cells that lack ARF. This mechanism could contribute to explain the c-Myc deregulation frequently found in cancer.
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PMID:Inhibitory effect of c-Myc on p53-induced apoptosis in leukemia cells. Microarray analysis reveals defective induction of p53 target genes and upregulation of chaperone genes. 1585 24

In response to DNA damage, the p53 tumor suppressor gene product is activated leading to the induction of several downstream cellular processes including cell cycle checkpoints, DNA repair or apoptosis. Experiments first performed in the Hanawalt laboratory identified a p53-dependent pathway affecting global genomic nucleotide excision repair. The mechanisms involved in this process include both transcriptional and post-translational regulation by p53 of the DDB2 and XPC gene products, two critical DNA damage recognition proteins required for GGR. A historical review of this work is presented.
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PMID:Regulation of DNA damage recognition and nucleotide excision repair: another role for p53. 1592 9

Human lymphocyte subpopulations differ in their cellular responses to ionizing radiation. To shed light on the molecular basis of this effect, we characterized the transcriptional response to 1 Gy X-rays of CD4+ T lymphocytes. Of 18,433 genes tested, 102 were modulated more than 1.5-fold. The majority of the strongly activated genes were p53 targets involved in DNA repair and apoptosis. The expression of three of these genes was further tested by quantitative RT-PCR in lymphocyte subpopulations [CD4+ and CD8+ T, CD19+ B, CD56+ natural killer cells and peripheral blood lymphocytes (PBLs)] from ten adult donors. In contrast to DDB2, TNFRSF10B and BAX were differentially modulated among the subpopulations and the PBLs, being more activated in irradiated CD19+ B and CD8+ T lymphocytes. The level of BAX activation in the various subpopulations correlated with the sensitivity of the cells to radiation, suggesting its possible role in the differential radiosensitivity of hematopoietic cell subsets.
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PMID:Transcriptional response to ionizing radiation in lymphocyte subsets. 1597 Oct 1

Terminally differentiating keratinocytes constitute the predominant cell type within the skin epidermis and play an important role in the overall photobiology of human skin following ultraviolet radiation. However, the DNA repair capacity of differentiating keratinocytes is unclear, and little is known regarding how such repair activity is regulated in these cells. We systematically compared the global genomic nucleotide excision repair response of cultured undifferentiated human keratinocytes to those that were allowed to differentiate in 1.2 mM Ca(2+), in some cases supplemented with phorbol ester or Vitamin C. Differentiated cells ceased replication and expressed typical markers of differentiation. Following ultraviolet radiation, keratinocytes that were differentiated up to 12 days removed cyclobutane pyrimidine dimers and pyrimidine(6,4)pyrimidone photoproducts from the global genome as efficiently as undifferentiated cells. However, following the onset of calcium-induced differentiation, basal levels of p53 were nearly undetectable by 12 days of differentiation when global repair activity was unaffected. Following ultraviolet radiation, induction of p53 following ultraviolet radiation was abrogated by 6 days of calcium-induced differentiation. Basal levels of mRNA encoding the DNA damage recognition proteins, XPC and DDB2, were relatively insensitive to differentiation and p53 levels. However, following ultraviolet radiation, inductions of mRNA encoding the DNA damage recognition proteins, DDB2 and XPC, were differentially affected by differentiation. Rapid loss of DDB2 mRNA induction was associated with differentiation, while XPC mRNA induction diminished more slowly with differentiation. These results indicate that human keratinocytes preserve global nucleotide excision repair as well as expression of genes encoding key DNA damage recognition proteins well into the terminal differentiation process, perhaps using mechanisms other than p53.
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PMID:Differentiating human keratinocytes are deficient in p53 but retain global nucleotide excision repair following ultraviolet radiation. 1604 23


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