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Molecular and Cellular Biology, August 1999, p. 5800-5810, Vol. 19, No. 8
0270-7306/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.

Akt/Protein Kinase B Inhibits Cell Death by Preventing the Release of Cytochrome c from Mitochondria

Scott G. Kennedy,dagger Eugene S. Kandel, Torry K. Cross, and Nissim Hay*

Department of Molecular Genetics, University of Illinois at Chicago, Chicago, Illinois 60607

Received 9 March 1999/Returned for modification 26 April 1999/Accepted 13 May 1999

Growth factors signaling through the phosphoinositide 3-kinase/Akt pathway promote cell survival. The mechanism by which the serine/threonine kinase Akt prevents cell death remains unclear. We have previously shown that Akt inhibits the activity of DEVD-targeted caspases without changing the steady-state levels of Bcl-2 and Bcl-xL. Here we show that Akt inhibits apoptosis and the processing of procaspases to their active forms by delaying mitochondrial changes in a caspase-independent manner. Akt activation is sufficient to inhibit the release of cytochrome c from mitochondria and the alterations in the inner mitochondrial membrane potential. However, Akt cannot inhibit apoptosis induced by microinjection of cytochrome c. We also demonstrated that Akt inhibits apoptosis and cytochrome c release induced by several proapoptotic Bcl-2 family members. Taken together, our results show that Akt promotes cell survival by intervening in the apoptosis cascade before cytochrome c release and caspase activation via a mechanism that is distinct from Bad phosphorylation.

* Corresponding author. Mailing address: Department of Molecular Genetics (M/C 669), University of Illinois in Chicago, 900 South Ashland Ave., Chicago, IL 60607. Phone: (312) 355-1684. Fax: (312) 355-2032. E-mail: nhay{at}uic.edu.

dagger Present address: Dept. of Molecular Biology, MGH and Harvard Medical School, Boston, Mass.

Molecular and Cellular Biology, August 1999, p. 5800-5810, Vol. 19, No. 8
0270-7306/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.


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