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J. Biol. Chem., Vol. 281, Issue 42, 31380-31388, October 20, 2006

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Quantitative Analysis of Anti-apoptotic Function of Akt in Akt1 and Akt2 Double Knock-out Mouse Embryonic Fibroblast Cells under Normal and Stressed Conditions^*

Xuesong Liu¹, Yan Shi, Morris J. Birnbaum, Keqiang Ye^¶, Ron De Jong^||, Tillman Oltersdorf^||, Vincent L. Giranda, and Yan Luo²

From the Department of Cancer Research (R47S), Abbott L, Abbott Park, Illinois 60064, the Department of Medicine, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104, the ^¶Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, Georgia 30322, and ^||Idun Pharmaceuticals, San Diego, California 92121

The serine/threonine kinases Akt1/PKB, Akt2/PKB, and Akt3/PKB have been implicated in preventing cells from undergoing apoptosis. Although several small molecule inhibitors of Akt have been reported to induce apoptosis in cancer cells, these inhibitors may have additional targets. In the current study, we used an Akt3 small interfering RNA (Akt3 siRNA) to analyze apoptosis induction in Akt1 and Akt2 double knock-out mouse embryonic fibroblast cells (MEF-Akt1,2-DKO). Our data indicated that Akt3 siRNA inhibited Akt3 protein expression in a dose-dependent manner. As a result, phosphorylation of Akt and its downstream targets, including FKHRL1 and GSK3/, were reduced accordingly. The treatment also induced apoptosis in MEF-Akt1,2-DKO cells. However, apoptosis induction is significant only when more than 80% of Akt3 protein was depleted. Reintroducing Akt3 totally rescued Akt3-siRNA-induced apoptosis in MEF-Akt1,2-DKO cells. In addition, reintroducing Akt1 also inhibited apoptosis induced by Akt3 siRNA. Moreover, Akt3 siRNA potentiated different stress-induced apoptosis in MEF-Akt1,2-DKO cells at a lower dose when compared with what is required for apoptosis induction by itself. Our study suggests that only a small portion of Akt is active in wild-type MEF cells and a threshold of Akt inhibition is required to induce apoptosis by pure Akt inhibitors. In addition, our data indicate that cells under stress require more Akt for its survival.

Received for publication, July 11, 2006 , and in revised form, August 14, 2006.

^* 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 may be addressed: Dept. R47S, Cancer Research, Abbott Laboratories, 100 Abbott Park Rd., Abbott Park, IL 60064. Tel.: 847-938-4409; Fax: 847-938-2365; E-mail: xuesong.liu{at}abbott.com. ² To whom correspondence may be addressed: Dept. R47S, Cancer Research, Abbott Laboratories, 100 Abbott Park Rd., Abbott Park, IL 60064. Tel.: 847-835-6811; E-mail: Yan.luo{at}abbott.com.

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