Akt Regulates Cell Survival and Apoptosis at a Postmitochondrial Level

doi:10.1083/jcb.151.3.483

Published online 30 October 2000. doi:10.1083/jcb.151.3.483

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© The Rockefeller University Press, 0021-9525/2000//483 $5.00
The Journal of Cell Biology, Volume 151, Number 3, , 2000 483-494

Original Article

Akt Regulates Cell Survival and Apoptosis at a Postmitochondrial Level

Honglin Zhou^a, Xin-Ming Li^a, Judy Meinkoth^a, and Randall N. Pittman^a

^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

Phosphoinositide 3 kinase/Akt pathway plays an essential rolein neuronal survival. However, the cellular mechanisms by whichAkt suppresses cell death and protects neurons from apoptosisremain unclear. We previously showed that transient expressionof constitutively active Akt inhibits ceramide-induced deathof hybrid motor neuron 1 cells. Here we show that stable expressionof 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 postmitochondriallevel. Consistent with this, overexpressing active Akt rescuescells from apoptosis without altering expression levels of endogenousBcl-2, Bcl-x, or Bax. Akt inhibits apoptosis induced by microinjectionof cytochrome c and lysates from cells expressing active Aktinhibit cytochrome c induced caspase activation in a cell-freeassay while lysates from Bcl-2–expressing cells have noeffect. Addition of cytochrome c and dATP to lysates from cellsexpressing active Akt do not activate caspase-9 or -3 and immunoprecipitatedAkt added to control lysates blocks cytochrome c–inducedactivation of the caspase cascade. Taken together, these datasuggest that Akt inhibits activation of caspase-9 and -3 byposttranslational modification of a cytosolic factor downstreamof 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-activatedprotein; PARP, poly (ADP-ribose) polymerase; PI 3-kinase, phosphoinositide3 kinase.

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