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J. Biol. Chem., Vol. 282, Issue 31, 22856-22864, August 3, 2007

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Neural Precursor Cells Are Protected from Apoptosis Induced by Trophic Factor Withdrawal or Genotoxic Stress by Inhibitors of Glycogen Synthase Kinase 3^*

Tae-Yeon Eom, Kevin A. Roth, and Richard S. Jope¹

From the Department of Psychiatry and Behavioral Neurobiology and Department of Pathology, University of Alabama at Birmingham, Birmingham, Alabama 35294-0017

Mechanisms controlling the survival of neural precursor cells (NPCs) are critical during brain development, in adults for neuron replenishment, and after transplantation for neuron replacement. This investigation found that glycogen synthase kinase 3 (GSK3) promotes apoptotic signaling in cultured NPCs derived from embryonic mouse brain subjected to two common apoptotic conditions, trophic factor withdrawal and genotoxic stress. Trophic factor withdrawal activated GSK3 and the key apoptosis mediators Bax and caspase-3. Pharmacological inhibition of GSK3 activity produced dramatic reductions in the activation of Bax and caspase-3 and NPC death after trophic factor withdrawal. Trophic factor withdrawal-induced apoptosis was delayed in Bax knock-out NPCs, but GSK3 inhibitors provided additional protection. Genotoxic stress induced by camptothecin treatment of NPCs stabilized p53, which formed a complex with GSK3 and activated Bax and caspase-3. Camptothecin-induced activation of caspase-3 was reduced by GSK3 inhibitors in both bax^+/+ and bax^-/- NPCs. Thus, NPCs are sensitive to loss of trophic factors and genotoxic stress, and inhibitors of GSK3 are capable of enhancing NPC survival.

Received for publication, April 9, 2007 , and in revised form, May 21, 2007.

^* This research was supported by National Institutes of Health Grants MH38752, AG021045, and NS41962. 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.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Figs. 1-3.

¹ To whom correspondence should be addressed: Dept. of Psychiatry and Behavioral Neurobiology, 1720 Seventh Ave. South, Sparks Center 1057, University of Alabama at Birmingham, Birmingham, AL 35294-0017. Tel.: 205-934-7023; Fax: 205-934-3709; E-mail: jope{at}uab.edu.

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