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J. Biol. Chem., Vol. 281, Issue 24, 16207-16219, June 16, 2006

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Apoptosis Induction by Activator Protein 2 Involves Transcriptional Repression of Bcl-2^*

From the Department of Microbiology and Cell Biology, Indian Institute of Science, Bangalore 560 012, India

Activator protein 2 (AP-2) induces cytotoxicity by inducing cell cycle arrest and apoptosis. In this study we investigated the mechanism of apoptosis induction by AP-2. We found that AP-2 induced apoptosis efficiently in cells treated with benzyloxycar-bonyl-IETD-fluoromethyl ketone or FADD-silenced cells but failed to do so in benzyloxycarbonyl-LEHD-fluoromethyl ketone-treated or apoptosis protease activation factor-1 (Apaf1)-silenced cells, suggesting the central role of mitochondria in AP-2-induced apoptosis. In good correlation, cells overexpressing AP-2 showed a reduction in mitochondrial membrane potential (_m), cytochrome c and Smac/DIABLO release into cytosol, and Bax translocation into mitochondria. We found that the pro-apoptotic protein Bax is important for AP-2-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-induced apoptosis as we found the IAP member Survivin down-regulated by AP-2. 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 transcriptionally represses Bcl-2 by binding to its promoter both in vitro and in vivo and that this is essential for AP-2-induced apoptosis as ectopic expression of Bcl-2 efficiently inhibited apoptosis induced by AP-2. Furthermore, we show that chemotherapy-induced endogenous AP-2 down-regulates Bcl-2 and induces apoptosis in an AP-2-dependent manner. Moreover, we demonstrate that inhibition of okadaic acid or staurosporine-sensitive pathways in AP-2 overexpressing breast cancer cells resulted in AP-2-dependent apoptosis induction. These results suggest that AP-2 induces apoptosis by down-regulating Bcl-2 and utilizing a bax/cytochrome c/Apaf1/caspase 9-dependent mitochondrial pathway.

Received for publication, January 18, 2006 , and in revised form, March 8, 2006.

^* This work was supported by ICMR (Center for Advanced studies in Molecular Medicine), DBT (Program support and Expression Profiling), DST (FIST), and University Grants Commission (Special assistance). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Figs. S1 and S2.

¹ Supported by a fellowship from University Grants Commission, Government of India.

² A Wellcome Trust International Senior Research Fellow. To whom correspondence should be addressed. Tel.: 91-80-22932973; Fax: 91-80-23602697; E-mail: skumar{at}mcbl.iisc.ernet.in.

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