Carcinogenesis Advance Access originally published online on August 25, 2005
Carcinogenesis 2006 27(2):205-215; doi:10.1093/carcin/bgi217
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Carcinogenesis vol.27 no.2 © Oxford University Press 2005; all rights reserved.
Proteasome mediated degradation of Id-1 is associated with TNF
-induced apoptosis in prostate cancer cells
Cancer Biology Group, Department of Anatomy, Faculty of Medicine, The University of Hong Kong, 21 Sassoon Road, Hong Kong, SAR, China
* To whom correspondence should be addressed. Tel: +852 2819 9226; Fax: +852 2817 0857; Email: ycwong{at}hkucc.hku.hk; xhwang{at}hkucc.hku.hk
Overexpression of the helix–loop–helix protein Id-1 has been reported in over 20 types of cancer. While a number of factors have been demonstrated to regulate Id-1 gene transcription, little is known about the mechanisms responsible for its degradation. In this study, we have demonstrated that Id-1 protein stability was regulated by TNF
in prostate cancer cells. We found that exposure of prostate cancer cell lines, DU145 and PC-3, to TNF resulted in a rapid and significant downregulation of the Id-1 protein level. The fact that neither the Id-1 promoter activity nor the Id-1 mRNA level was affected by the TNF treatment suggested that the decrease in Id-1 protein was not due to the suppression of gene transcription. In addition, the half-life of the Id-1 protein was decreased in both cell lines in the presence of TNF, and the addition of an ubiquitin/proteasome inhibitor (MG-132) prior to the TNF treatment completely blocked the effect of the TNF-induced Id-1 protein degradation. Furthermore, introduction of a Flag-tag sequence into the N-terminus region of the Id-1 protein, which has been shown to stabilize the protein, was able to protect the Id-1 protein from TNF-induced degradation. These results suggest that TNF downregulated Id-1 through activation of the ubiquitin/proteasome degradation pathway in prostate cancer cells. Interestingly, in both DU145 and PC-3 cells, the decrease of Id-1 protein was associated with the activation of apoptotic pathway, as evidenced by the increased expression of cleaved PARP and caspase 3. In addition, TNF failed to downregulate Id-1 in a sub-line of LNCaP cells that was resistant to TNF-induced apoptosis. These results further suggest that the downregulation of Id-1 may facilitate TNF-induced apoptosis in prostate cancer cells. In conclusion, our findings indicate that Id-1 protein may be regulated by TNF through the ubiquitin/proteasome degradation pathway and the stability of the Id-1 protein appears to correlate with the sensitivity of TNF-induced apoptosis.
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