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Mol Cell Biol, April 1998, p. 2143-2152, Vol. 18, No. 4
0270-7306/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.

Akt, a Target of Phosphatidylinositol 3-Kinase, Inhibits Apoptosis in a Differentiating Neuronal Cell Line

Eva M. Eves,1,2,* Wen Xiong,1,2 Alfonso Bellacosa,3 Scott G. Kennedy,1,dagger Philip N. Tsichlis,3 Marsha Rich Rosner,1,2 and Nissim Hay1,dagger

Ben May Institute for Cancer Research and Department of Pharmacological and Physiological Sciences1 and Laboratory for Eczema Research,2 University of Chicago, Chicago, Illinois 60637, and Fox Chase Cancer Research Center, Philadelphia, Pennsylvania 191113

Received 28 August 1997/Returned for modification 22 October 1997/Accepted 27 December 1997

Phosphatidylinositol (PI) 3-kinase has been suggested to mediate cell survival. Consistent with this possibility, apoptosis of conditionally (simian virus 40 Tts) immortalized rat hippocampal H19-7 neuronal cells was increased in response to wortmannin, an inhibitor of PI 3-kinase. Downstream effectors of PI 3-kinase include Rac1, protein kinase C, and the serine-threonine kinase Akt (protein kinase B). Here, we show that activation of Akt is one mechanism by which PI 3-kinase can mediate survival of H19-7 cells during serum deprivation or differentiation. While ectopic expression of wild-type Akt (c-Akt) does not significantly enhance survival in H19-7 cells, expression of activated forms of Akt (v-Akt or myristoylated Akt) results in enhanced survival which can be comparable to that conferred by Bcl-2. Conversely, expression of a dominant-negative mutant of Akt accelerates cell death upon serum deprivation or differentiation. Finally, the results indicate that Akt can transduce a survival signal for differentiating neuronal cells through a mechanism that is independent of induction of Bcl-2 or Bcl-xL or inhibition of Jun kinase activity.

* Corresponding author. Mailing address: Ben May Institute for Cancer Research, University of Chicago, 5841 S. Maryland Ave. MC 6027, Chicago, IL 60637. Phone: (773) 702-6989. Fax: (773) 702-4634. E-mail: eeves{at}ben-may.bsd.uchicago.edu.

dagger Present address: Department of Molecular Genetics, College of Medicine, University of Illinois at Chicago, Chicago, IL 60607.




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