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)

Following an earlier study linking monosomy 9 with recurrence of transitional cell carcinomas (TCCs) of the urinary bladder, 109 primary and recurrent TCCs (from 47 patients) were examined to explore genetic alterations at chromosome 9 associated with recurrence. Patient DNA was microdissected and extracted from archival tissue sections and analysed for loss of heterozygosity (LOH) at three regions on chromosome 9 where tumour suppressor genes (TSGs) are known to reside (INK 4A, DBC1, and TSC1). Patients were categorized into two groups, non-recurrent TCC (NR, n=18) and recurrent TCC (REC, n=29). It was noted that 12% of NR tumours, compared with 54% of REC primary tumours (p=0.01), had LOH at all informative markers spanning the TSC1 region. The risk of recurrence was significantly higher in patients with deleted TSC1 than in those who retained the TSC1 region (p=0.035). Levels of LOH at DBC1 or INK 4A were not significantly different in NR tumours than in REC primary tumours and recurrence-free survival was not affected by loss of either of these genes. Loss of all informative markers spanning chromosome 9 was observed in 0% of NR tumours compared with 25% of REC primary tumours (p=0.04). The probability of recurrence was also significantly increased in patients who had LOH at all informative markers spanning chromosome 9 (p=0.016), confirming earlier fluorescence in situ hybridization results. This study provides further evidence that recurrence in bladder cancer is a distinct event, with underlying molecular causes. It also identifies the TSC1 locus as a candidate for a TSG, which drives recurrence in a proportion of TCC patients. Loss of all informative markers, including those residing in the TSC1 region, spanning chromosome 9 was also linked to recurrence.
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PMID:Identification of loci associated with putative recurrence genes in transitional cell carcinoma of the urinary bladder. 1192 Jul 32

The DBC1 gene is a potential tumour suppressor gene that is commonly hypermethylated in epithelial cancers. We studied the role of promoter hypermethylation in the regulation of DBC1 in acute lymphoblastic leukaemia (ALL) cell lines and 170 ALL patients at diagnosis. Abnormal methylation of DBC1 was observed in all ALL cell lines and in 17% of ALL patients. Moreover, DBC1 methylation was associated with decreased DBC1 expression, while treatment of ALL cells with 5-Aza-2'-deoxycytidine resulted in demethylation of the promoter and upregulation of DBC1 expression. Fluorescence in situ hybridisation identified the deletion of one allele of DBC1 in some ALL cell lines, which indicated that the lack of DBC1 expression was due to deletion of one allele and methylation of the other. In conclusion, these results demonstrate, for the first time, that the expression of DBC1 is downregulated in a percentage of patients with ALL due to the hypermethylation of its promoter and/or gene deletion.
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PMID:Downregulation of DBC1 expression in acute lymphoblastic leukaemia is mediated by aberrant methylation of its promoter. 1684 74

SIRT1 is an NAD-dependent deacetylase critically involved in stress responses, cellular metabolism and, possibly, ageing. The tumour suppressor p53 represents the first non-histone substrate functionally regulated by acetylation and deacetylation; we and others previously found that SIRT1 promotes cell survival by deacetylating p53 (refs 4-6). These results were further supported by the fact that p53 hyperacetylation and increased radiation-induced apoptosis were observed in Sirt1-deficient mice. Nevertheless, SIRT1-mediated deacetylase function is also implicated in p53-independent pathways under different cellular contexts, and its effects on transcriptional factors such as members of the FOXO family and PGC-1alpha directly modulate metabolic responses. These studies validate the importance of the deacetylase activity of SIRT1, but how SIRT1 activity is regulated in vivo is not well understood. Here we show that DBC1 (deleted in breast cancer 1) acts as a native inhibitor of SIRT1 in human cells. DBC1-mediated repression of SIRT1 leads to increasing levels of p53 acetylation and upregulation of p53-mediated function. In contrast, depletion of endogenous DBC1 by RNA interference (RNAi) stimulates SIRT1-mediated deacetylation of p53 and inhibits p53-dependent apoptosis. Notably, these effects can be reversed in cells by concomitant knockdown of endogenous SIRT1. Our study demonstrates that DBC1 promotes p53-mediated apoptosis through specific inhibition of SIRT1.
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PMID:Negative regulation of the deacetylase SIRT1 by DBC1. 1823 2

Tumour recurrence has a major impact on patients with non-invasive papillary urothelial tumours of the bladder. To explore the role of DBC1 (deleted in bladder cancer 1 locus), a candidate tumour suppressor gene located at 9q32-33, as prognostic marker we have performed loss of heterozygosity (LOH) testing in 49 patients with primary papillary urothelial tumours and associated normal urothelium. Data from the 38 tumours and 11 specimens of normal urothelium that were informative in the LOH study (D9S195 marker) showed that LOH in urothelium (45.4%) but not in non-invasive tumours (60.5%) was associated with tumour recurrence (p = 0.026) but not to grade or progression. Also, tumours whose normal urothelium had LOH were larger (p = 0.020) and showed cyclin D1 over-expression (p = 0.032). Non-significant increased expression of p53, p21Waf1, apoptotic index and tumour proliferation, and decreased expression of p27Kip1 or cyclin D3 also characterized tumours whose normal urothelium had LOH. The expression of these G1-S modulators, apoptotic index and tumour proliferation was more heterogeneous in papillary urothelial tumours, irrespective of having retained heterozygosity or LOH. Also, Bax expression decreased in papillary urothelial tumours having LOH (p = 0.0473), but Bcl-2 was unrelated to LOH status. In addition, FGFR3 protein expression decreased in LOH tumours (p = 0.036) and in those having LOH in their normal urothelium (p = 0.022). FGFR3 immunohistochemical expression was validated by western blot in selected cases. The survival analysis selected LOH in normal urothelium as a marker of disease-free survival (log-rank 5.32, p = 0.021), progression-free survival (log-rank 3.97, p = 0.046) and overall survival (log-rank 4.26, p = 0.038); LOH in tumours was significant in progression-free survival (log-rank 3.83, p = 0.042). It is concluded that LOH at the DBC1 locus in normal urothelium seems to be relevant in the prognosis of non-invasive papillary tumours of the bladder via selecting cases with increased proliferation, frequent alterations of the G1-S phase modulators, and decreased FGFR3 protein expression.
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PMID:Loss of heterozygosity at 9q32-33 (DBC1 locus) in primary non-invasive papillary urothelial neoplasm of low malignant potential and low-grade urothelial carcinoma of the bladder and their associated normal urothelium. 1845 28

Urothelial carcinoma (UC) is the most common type of bladder cancer in Western nations. Most patients present with the non-muscle-invasive (NMIUC) form of the disease, while up to a third harbour the invasive form (MIUC). Specifically, the aetiology of NMIUC appears to be multifactorial and very different from that of MIUC. Loss of specific tumour suppressor genes as well as gain-of-function mutations in proteins within defined cellular signalling pathways have been implicated in NMIUC aetiology. The regions of chromosome 9 that harbour CDKN2A, CDKN2B, TSC1, PTCH1 and DBC1 are frequently mutated in NMIUC, resulting in functional loss; in addition, HRAS and FGFR3, which are both proto-oncogenes encoding components of the Ras-MAPK signalling pathway, have been found to harbour activating mutations in a large number of NMIUCs. Interestingly, some of these molecular events are mutually exclusive, suggesting functional equivalence. Since several of these driving changes are amenable to therapeutic targeting, understanding the signalling events in NMIUC may offer novel approaches to manage the recurrence and progression of this disease.
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PMID:Molecular genesis of non-muscle-invasive urothelial carcinoma (NMIUC). 2033 6