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PNAS 99 (12): 7951-7955

Copyright © 2002 by the National Academy of Sciences.

BIOLOGICAL SCIENCES / BIOCHEMISTRY

Direct, activating interaction between glycogen synthase kinase-3β and p53 after DNA damage

Piyajit Watcharasit*, Gautam N. Bijur*, Jaroslaw W. Zmijewski*, Ling Song*, Anna Zmijewska*, Xinbin Chen{dagger}, Gail V. W. Johnson*,{dagger}, and Richard S. Jope*,{dagger},{ddagger}

Departments of *Psychiatry and Behavioral Neurobiology and {dagger}Cell Biology, University of Alabama, Birmingham, AL 35294-0017

Received for publication February 2, 2002.

Abstract: Glycogen synthase kinase-3β (GSK3β) is a central figure in Wnt signaling, in which its activity is controlled by regulatory binding proteins. Here we show that binding proteins outside the Wnt pathway also control the activity of GSK3β. DNA damage induced by camptothecin, which activates the tumor suppressor p53, was found to activate GSK3β. This activation occurred by a phosphorylation-independent mechanism involving direct binding of GSK3β to p53, which was confined to the nucleus where p53 is localized, and mutated p53 (R175H) bound but did not activate GSK3β. Activation of GSK3 promoted responses to p53 including increases in p21 levels and caspase-3 activity. Thus, after DNA damage there is a direct interaction between p53 and GSK3β, and these proteins act in concert to regulate cellular responses to DNA damage.

{ddagger} To whom reprint requests should be addressed at: Department of Psychiatry, Sparks Center 1057, University of Alabama, Birmingham, AL 35294-0017. E-mail: jope{at}uab.edu.

Edited by Joseph A. Beavo, University of Washington School of Medicine, Seattle, WA, and approved April 19, 2002

This paper was submitted directly (Track II) to the PNAS office.

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