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J. Cell Biol. 151 (3): 483-494

Copyright © 2000 by the Rockefeller University Press.

Original Article

Akt Regulates Cell Survival and Apoptosis at a Postmitochondrial Level

Honglin Zhoua, Xin-Ming Lia, Judy Meinkotha, , and Randall N. Pittmana

a Department of Pharmacology, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104-6084
Dept. Pharmacology, Room 154 John Morgan, Univ. of Pennsylvania School of Medicine, Philadelphia, PA 19104-6084.(215) 573-2236(215) 898-9736

Abstract: Phosphoinositide 3 kinase/Akt pathway plays an essential role in neuronal survival. However, the cellular mechanisms by which Akt suppresses cell death and protects neurons from apoptosis remain unclear. We previously showed that transient expression of constitutively active Akt inhibits ceramide-induced death of hybrid motor neuron 1 cells. Here we show that stable expression of either constitutively active Akt or Bcl-2 inhibits apoptosis, but only Bcl-2 prevents the release of cytochrome c from mitochondria, suggesting that Akt regulates apoptosis at a postmitochondrial level. Consistent with this, overexpressing active Akt rescues cells from apoptosis without altering expression levels of endogenous Bcl-2, Bcl-x, or Bax. Akt inhibits apoptosis induced by microinjection of cytochrome c and lysates from cells expressing active Akt inhibit cytochrome c induced caspase activation in a cell-free assay while lysates from Bcl-2–expressing cells have no effect. Addition of cytochrome c and dATP to lysates from cells expressing active Akt do not activate caspase-9 or -3 and immunoprecipitated Akt added to control lysates blocks cytochrome c–induced activation of the caspase cascade. Taken together, these data suggest that Akt inhibits activation of caspase-9 and -3 by posttranslational modification of a cytosolic factor downstream of cytochrome c and before activation of caspase-9.

Key Words: protein serine-threonine kinase • cytochrome c • apoptosis • neuron • mitochondria

Abbreviations used in this paper: CEB, cell extract buffer; HA, hemagglutinin; HMN1, hybrid motor neuron 1; MAP, mitogen-activated protein; PARP, poly (ADP-ribose) polymerase; PI 3-kinase, phosphoinositide 3 kinase.

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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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   Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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M. Gao, S. Fan, I. D. Goldberg, J. Laterra, R. N. Kitsis, and E. M. Rosen (2001)
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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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H. Liu, H. Perlman, L. J. Pagliari, and R. M. Pope (2001)
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   Abstract »    Full Text »    PDF »
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T. Niikura, Y. Hashimoto, T. Okamoto, Y. Abe, T. Yasukawa, M. Kawasumi, T. Hiraki, Y. Kita, K. Terashita, K. Kouyama, et al. (2001)
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   Abstract »    Full Text »    PDF »
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D. Tang, H. Okada, J. Ruland, L. Liu, V. Stambolic, T. W. Mak, and A. J. Ingram (2001)
J. Biol. Chem. 276, 30461-30466
   Abstract »    Full Text »    PDF »
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P. F. Dijkers, K. U. Birkenkamp, E. W.-F. Lam, N. S. B. Thomas, J.-W. J. Lammers, L. Koenderman, and P. J. Coffer (2002)
J. Cell Biol. 156, 531-542
   Abstract »    Full Text »    PDF »

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