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J. Biol. Chem., Vol. 283, Issue 18, 12305-12313, May 2, 2008

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Hsp27 Inhibits Bax Activation and Apoptosis via a Phosphatidylinositol 3-Kinase-dependent Mechanism^*

Andrea Havasi, Zhijian Li, Zhiyong Wang, Jody L. Martin^¶, Venugopal Botla, Kathleen Ruchalski, John H. Schwartz, and Steven C. Borkan¹

From the Boston Medical Center, Boston, Massachusetts 02118, First Affiliated Hospital, Zhongshan University, Guang Zhou 510080, China, and ^¶Cardiovascular Institute, Loyola University, Maywood, Illinois 60153

Hsp27 inhibits mitochondrial injury and apoptosis in both normal and cancer cells by an unknown mechanism. To test the hypothesis that Hsp27 decreases apoptosis by inhibiting Bax, Hsp27 expression was manipulated in renal epithelial cells before transient metabolic stress, an insult that activates Bax, induces mitochondrial injury, and causes apoptosis. Compared with control, enhanced Hsp27 expression inhibited conformational Bax activation, oligomerization, and translocation to mitochondria, reduced the leakage of both cytochrome c and apoptosis-inducing factor, and significantly improved cell survival by >50% after stress. In contrast, Hsp27 down-regulation using RNA-mediated interference promoted Bax activation, increased Bax translocation, and reduced cell survival after stress. Immunoprecipitation did not detect Hsp27-Bax interaction before, during, or after stress, suggesting that Hsp27 indirectly inhibits Bax. During stress, Hsp27 expression prevented the inactivation of Akt, a pro-survival kinase, and increased the interaction between Akt and Bax, an Akt substrate. In contrast, Hsp27 RNA-mediated interference promoted Akt inactivation during stress. Hsp27 up- or down-regulation markedly altered the activity of phosphatidylinositol 3-kinase (PI3-kinase), a major regulator of Akt. Furthermore, distinct PI3-kinase inhibitors completely abrogated the protective effect of Hsp27 expression on Akt activation, Bax inactivation, and cell survival. These data show that Hsp27 antagonizes Bax-mediated mitochondrial injury and apoptosis by promoting Akt activation via a PI3-kinase-dependent mechanism.

Received for publication, February 19, 2008

^* This work was supported by a National Kidney Foundation Fellowship grant (to A. H.) and by National Institutes of Health Grants DK-53387 (to S. C. B.) and DK-52898 (to J. H. S.). 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.

¹ To whom correspondence should be addressed: Boston Medical Center, 650 Albany St., EBRC Rm. 546, Boston, MA 02118. Tel.: 617-638-7330; Fax: 617-638-7326; E-mail: sborkan{at}bu.edu.

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