Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P43146 (tumour suppressor)
 5,935 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The p53 tumour suppressor is mutated in the majority of human tumours. p53's proposed role as the guardian of the genome is reflected in its multiple effects on transcription genome stability, cell growth and survival. We show that p53 interacts both physically and functionally with the TFIIH complex. There are multiple protein-protein contacts, involving two regions of p53 and three subunits of TFIIH, ERCC2 (XPD), ERCC3 (XPB) and p62. p53 and its C-terminus (amino acids 320-393) inhibit both of the TFIIH helicases and in vitro transcription in the absence of TFIIH. Transcription inhibition is overcome by TFIIH. The N-terminal region of p53 (1-320), lacking the C-terminus, is inactive on its own, yet apparently affects the activity of the C-terminus in the native protein. Interestingly, mutant p53s that are frequently found in tumours are less efficient inhibitors of the helicases and transcription. We hypothesize that the interactions provide an immediate and direct link for p53 to the multiple functions of TFIIH in transcription, DNA repair and possibly the cell cycle.
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PMID:Functional interactions between p53 and the TFIIH complex are affected by tumour-associated mutations. 861 85

WWOX is a bona fide tumour suppressor, with hypomorphic and knockout mouse models exhibiting increased tumour susceptibility. In ovarian cancer cells WWOX transfection abolishes tumourigenicity, suppresses tumour cell adhesion to extracellular matrix and induces apoptosis in non-adherent cells. One-third of ovarian tumours show loss of WWOX expression, and this loss significantly associates with clear cell and mucinous histology, advanced stage, low progesterone receptor expression and poor survival, suggesting that WWOX status affects ovarian cancer progression and prognosis. Genetic variation in other tumour suppressors (e.g. p53 and XPD) is reported to modify cancer progression/outcome, and single nucleotide polymorphisms (SNPs) within the WWOX gene are reported to associate with prostate cancer risk. We previously identified polymorphic variants within WWOX, some of which have potential to affect its expression. We therefore examined a cancer modifier role for these WWOX variants. Eight SNPs, based upon location, frequency and potential to affect WWOX expression, were genotyped in 554 ovarian cancer patients (CGP samples), and associations with pathological and survival data were examined. The CGP samples demonstrated significant associations after Bonferroni correction between Isnp1 and both tumour grade (p(corr)=0.033) and histology (p(corr)=0.046), Isnp8 and tumour grade (p(corr)=0.032) and T1497G and progression-free survival (p(corr)=0.037). None of these positive associations were confirmed in an independent ovarian cancer population (Scotroc1 samples, n=863). While these results may suggest that the associations are false positives, differences between the two populations cannot be excluded, and thus highlight the challenges in validation studies.
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PMID:WWOX tumour suppressor gene polymorphisms and ovarian cancer pathology and prognosis. 2007 32