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

This paper examines the genetic defects associated with inherited cancer syndromes and their relevance to oral cancer. Tumour suppressor genes are now thought of as either gatekeepers or caretakers according to whether they control cell growth directly by inhibiting cell proliferation and/or promoting cell death (gatekeepers) or whether they maintain the integrity of the genome by DNA repair mechanisms (caretakers). In disorders such as xeroderma pigmentosum, ataxia telangiectasia, Bloom syndrome and Fanconi's anaemia, where there are defective caretaker genes, there is an increased incidence of second primary malignancies, including oral cancer. By contrast, with the exception of Li Fraumeni syndrome, abnormalities of gatekeeper genes do not predispose to oral cancer. Not only do Li Fraumeni patients develop second primary malignancies, but defects of the p53 pathway (p53 mutation, MDM2 over-expression, CDKN2A deletion) appear to be a ubiquitous feature of sporadic oral cancer as it occurs in the West. The findings suggest that genetic instability is of fundamental importance in the pathogenesis of oral cancer.
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PMID:A review of inherited cancer syndromes and their relevance to oral squamous cell carcinoma. 1185 72

In response to hormonal stimuli, a cascade of hierarchical post-translational modifications of nuclear receptors are required for the correct expression of target genes. Here, we show that the transcription factor TFIIH, via its cdk7 kinase, phosphorylates the androgen receptor (AR) at position AR/S515. Strikingly, this phosphorylation is a key step for an accurate transactivation that includes the cyclic recruitment of the transcription machinery, the MDM2 E3 ligase, the subsequent ubiquitination of AR at the promoter of target genes and its degradation by the proteasome machinery. Impaired phosphorylation disrupts the transactivation, as observed in cells either overexpressing the non-phosphorylated AR/S515A, isolated from xeroderma pigmentosum patient (bearing a mutation in XPD subunit of TFIIH), or in which cdk7 kinase was silenced. Indeed, besides affecting the cyclic recruitment of the transcription machinery, the AR phosphorylation defect favourizes to the recruitment of the E3 ligase CHIP instead of MDM2, at the PSA promoter, that will further attract the proteasome machinery. These observations illustrate how the TFIIH phosphorylation might participate to the transactivation by regulating the nuclear receptors turnover.
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PMID:The phosphorylation of the androgen receptor by TFIIH directs the ubiquitin/proteasome process. 2115 30