Bax, a proapoptotic member of the Bcl-2 family, localizes largely in the cytoplasm but redistributes to mitochondria in response to apoptotic stimuli, where it induces cytochrome c release. In this study, we show that the phosphatidylinositol 3-OH kinase (PI3K)-Akt pathway plays an important role in the regulation of Bax subcellular localization. We found that LY294002, a PI3K inhibitor, blocked the effects of serum to prevent Bax translocation to mitochondria and that expression of an active

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... rm of PI3K suppressed staurosporine-induced Bax translocation, suggesting that PI3K activity is essential for retaining Bax in the cytoplasm. In contrast, both U0126, a MEK inhibitor, and active MEK had little effect on Bax localization. In respect to downstream effectors of PI3K, we found that expression of active Akt, but not serum and glucocorticoid-induced protein kinase (SGK), suppressed staurosporine-induced translocation of Bax, whereas dominant negative Akt moderately promoted Bax translocation. Expression of Akt did not alter the levels of Bax, Bcl-2, Bcl-X L , or phosphorylated JNK under the conditions used, suggesting that there were alternative mechanisms for Akt in the suppression of Bax translocation. Collectively, these results suggest that the PI3K-Akt pathway inhibits Bax translocation from cytoplasm to mitochondria and have revealed a novel mechanism by which the PI3K-Akt pathway promotes survival. Apoptosis plays a critical role in the normal development and maintenance of tissue homeostasis (1, 2). The regulation of mitochondrial membrane integrity and the release of cytochrome c from mitochondria are important processes during apoptosis (3, 4) and are controlled by the Bcl-2 family (5, 6). The Bcl-2 family includes both pro-and antiapoptotic members that possess up to four conserved Bcl-2 homology domains designated BH1, BH2, BH3, and BH4 (5, 6). Many of the antiapoptotic members, including Bcl-2 and Bcl-X L , contain all four domains, whereas the proapoptotic members, including Bax and Bak, lack the BH4 domain, and the other proapoptotic members, so-called "BH3 domain only proteins," including Bid, Bim and Bad, contain only the BH3 domain. One of the intriguing aspects of the Bcl-2 family is their subcellular localization and translocation. For example, antiapoptotic members such as