Wajapeyee, Narendra and Britto, Ramona and Ravishankar, Halasahalli M and Somasundar, Kumaravel (2006) Apoptosis induction by activator Protein 2\alpha involves transcriptional repression of Bcl-2. In: Journal Of Biological Chemistry, 281 (24). 16207 -16219.
05__01.pdf - Published Version
Activator protein 2 alpha ( AP-2 alpha) induces cytotoxicity by inducing cell cycle arrest and apoptosis. In this study we investigated the mechanism of apoptosis induction by AP-2 alpha. We found that AP-2 alpha induced apoptosis efficiently in cells treated with benzyloxycarbonyl-IETD-fluoromethyl ketone or FADD silenced cells but failed to do so in benzyloxycarbonyl- EHD-fluoromethyl ketone-treated or apoptosis protease activation factor-1 ( Apaf1)-silenced cells, suggesting the central role of mitochondria in AP-2 alpha-induced apoptosis. In good correlation, cells overexpressing AP-2 alpha showed a reduction in mitochondrial membrane potential ( Delta Psi(m)), cytochrome c and Smac/DIABLOm release into cytosol, and Bax translocation into mitochondria. We found that the pro-apoptotic protein Bax is important for AP-2 alpha-induced apoptosis as adenovirus AP2 failed to induce apoptosis in HCT116 Bax(-/-) cells. However, we found the IAP ( inhibitor of apoptosis) inhibitor Smac/DIABLO may have a limited role in AP-2 alpha-induced apoptosis as we found the IAP member Survivin down-regulated by AP-2 alpha. Although the total Bax level remains unaltered, we found a time-dependent increase in the activated form of Bax in adenovirus AP2-infected cells. In addition, we show that AP-2 alpha transcriptionally represses Bcl-2 by binding to its promoter both in vitro and in vivo and that this is essential for AP-2 alpha- nduced apoptosis as ectopic expression of Bcl-2 efficiently inhibited apoptosis induced by AP-2 alpha. Furthermore, we show that chemotherapy-induced endogenous AP-2 alpha down-regulates Bcl-2 and induces apoptosis in an AP-2 alpha-dependent manner. Moreover, we demonstrate that inhibition of okadaic acid or staurosporine-sensitive pathways in AP-2 alpha overexpressing breast cancer cells resulted in AP-2 alpha-dependent apoptosis induction. These results suggest that AP-2 alpha induces apoptosis by down-regulating Bcl-2 and utilizing a bax/cytochrome c/Apaf1/caspase 9-dependent mitochondrial pathway.
|Item Type:||Journal Article|
|Additional Information:||Copyright of this article belongs to American Society for Biochemistry and Molecular Biology|
|Keywords:||Biochemistry & Molecular Biology; reast-Cancer Cells; actor Ap-2;Dna-Binding;Signal-Transduction;Phosphatase 2a;Human-Melanoma;Up-Regulation;Cycle Arrest;Tumor-Growth;Kinase-C|
|Department/Centre:||Division of Biological Sciences > Microbiology & Cell Biology|
|Date Deposited:||04 Dec 2008 07:37|
|Last Modified:||19 Sep 2010 04:53|
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