Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0043346 (xeroderma pigmentosum)
 2,924 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The INK4a-ARF locus, localized on 9p21, encodes two tumor suppressor proteins, p16INK4a and p14ARF, acting respectively through the CDK4-pRb and the p53 pathways. Familial melanoma (comprising between 8 and 12% of all melanoma cases) is a genodermatosis transmitted as an autosomal dominant trait, often associated with clinically atypical moles (AN). Germline mutations of p16INK4a are found in up to 20-30% of melanoma prone families. Mutated families often contain more than three family members affected and/or comprise at least one relative with multiple melanomas. Most of these mutations have been shown to affect p16INK4a protein function (i.e. CDK4 binding or pRB phosphorylation). Germline mutations of p16INK4a are also found in a lesser extend in sporadic multiple melanoma and in familial pancreatic cancer. The INK4a-ARF locus plays also an important role in skin carcinogenesis. P16INK4a UV induced mutations (CC:GG > TT:AA tandem transition or C:G > T:A transition at dipyrimidic site) are found in 12% of sporadic skin carcinomas, mainly in epidermoid tumors, and seem to occur independently of p53 mutations. Xeroderma pigmentosum (XP) is characterized by an inheritable DNA repair defect (involving the nucleotid excision repair (NER) system) predisposing to skin carcinomas. In skin tumors from (XP) patients, p16INK4a UV induced mutations occur more frequently, are often multiple, and significantly associated with the presence of p53 mutations. Such data, which could be related to the XP genetic instability and indicates a possible cooperative effect of inactivation of these pathways in the tumoral process of XP skin tumors.
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PMID:[The INK4a-ARF locus: role in the genetic predisposition to familial melanoma and in skin carcinogenesis]. 1174 99

The expression from a reporter construct driven by a cytomegalovirus (CMV) immediate early (IE) promoter is strongly inducible by UV in human fibroblasts. This response is induced at lower UV fluences in transcription-coupled repair (TCR)-deficient fibroblasts compared with normal fibroblasts and is absent in their simian virus 40-transformed counterparts. In this study we demonstrate that expression of human papilloma virus (HPV) E7 (but not of HPV E6) can attenuate UV-induced expression from the human CMV-IE-driven reporter construct in human fibroblasts. Furthermore, UV-induced expression from the reporter construct appears impaired in murine fibroblasts harboring inactivating mutations in the retinoblastoma (Rb) gene family members p107 and pRb but not in fibroblasts harboring such mutations in the p53 gene. Taken together, these data suggest that one or more members of the pRb family (but not p53) play an essential role in mediating UV-induced expression from the CMV-IE promoter. In this study we report normal UV-upregulation of reporter expression in xeroderma pigmentosum (XP) group E fibroblasts, consistent with normal TCR. Because XP-E cells deficient in the p48 subunit of the damaged DNA-binding protein are impaired in E2F-1-activated transcription, these results also suggest that the (pRb-regulated) transcription factor E2F-1 does not play an essential role in UV-enhanced expression from the CMV-IE promoter.
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PMID:Role for retinoblastoma protein family members in UV-enhanced expression from the human cytomegalovirus immediate early promoters. 1287 Aug 48

The retinoblastoma Rb/E2F tumor suppressor pathway plays a major role in the regulation of mammalian cell cycle progression. The pRb protein, along with closely related proteins p107 and p130, exerts its anti-proliferative effects by binding to the E2F family of transcription factors known to regulate essential genes throughout the cell cycle. We sought to investigate the role of the Rb/E2F1 pathway in the lesion recognition step of nucleotide excision repair (NER) in mouse embryonic fibroblasts (MEFs). Rb-/-, p107-/-, p130-/- MEFs repaired both cyclobutane pyrimidine dimers (CPDs) and 6-4 photoproducts (6-4PPs) at higher efficiency than did wildtype cells following UV-C irradiation. The expression of damaged DNA binding gene DDB2 involved in the DNA lesion recognition step was elevated in the Rb family-deficient MEFs. To determine if the enhanced DNA repair in the absence of the Rb gene family is due to the derepression of E2F1, we assayed the ability of E2F1-deficient cells to repair damaged DNA and demonstrated that E2F1-/- MEFs are impaired for the removal of both CPDs and 6-4PPs. Furthermore, wildtype cells induced a higher expression of DDB2 and xeroderma pigmentosum gene XPC transcript levels than did E2F1-/- cells following UV-C irradiation. Using an E2F SiteScan algorithm, we uncovered a putative E2F-responsive element in the XPC promoter upstream of the transcription start site. We showed with chromatin immunoprecipitation assays the binding of E2F1 to the XPC promoter in a UV-dependent manner, suggesting that E2F1 is a transcriptional regulator of XPC. Our study identifies a novel E2F1 gene target and further supports the growing body of evidence that the Rb/E2F1 tumor suppressor pathway is involved in the regulation of the DNA lesion recognition step of nucleotide excision repair.
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PMID:The role of the retinoblastoma/E2F1 tumor suppressor pathway in the lesion recognition step of nucleotide excision repair. 1937 52