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J. Biol. Chem., Vol. 282, Issue 23, 16989-17001, June 8, 2007

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Resolution of the Nuclear Localization Mechanism of Glycogen Synthase Kinase-3

FUNCTIONAL EFFECTS IN APOPTOSIS^*

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

Mechanisms regulating the nuclear localization of glycogen synthase kinase-3 (GSK3) remained enigmatic despite the crucial regulation by nuclear GSK3 of important cellular functions. These include regulation of gene expression, cell cycle progression, and apoptosis, achieved by the phosphorylation by GSK3 of nuclear substrates (e.g. numerous transcription factors). We resolved this mechanism by identifying a bipartite nuclear localization sequence (NLS) that is necessary for the nuclear accumulation of GSK3 and is sufficient to drive yellow fluorescent protein into the nucleus. Despite the NLS, most GSK3 is cytosolic, sequestered in protein complexes that, although still mobile in the cytosol, block the NLS. Conditions promoting nuclear translocation of GSK3 release it from cytosolic complexes, allowing the NLS to direct nuclear import. Using this information to prepare a nucleus-excluded active GSK3 construct, we found that the antiapoptotic effect of GSK3 in tumor necrosis factor-induced apoptosis is mediated by cytosolic, not nuclear, GSK3. Identification of a GSK3 NLS allows new strategies to decipher and manipulate its subcellular actions regulating gene expression and apoptosis and its involvement in diseases.

Received for publication, January 22, 2007 , and in revised form, April 16, 2007.

^* This research was supported by National Institutes of Health Grants AG021045 and NS37768. 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.

¹ To whom correspondence should be addressed: Dept. of Psychiatry, 1720 Seventh Ave. S., SC1057, 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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