Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 99, Issue 12, Pages 7951-7955Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.122062299
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Funding
- NIMH NIH HHS [R01 MH038752, R56 MH038752, MH 38752] Funding Source: Medline
- NINDS NIH HHS [R01 NS037768, NS 37768] Funding Source: Medline
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Glycogen synthase kinase-3beta (GSK3beta) 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 GSK3beta. DNA damage induced by camptothecin, which activates the tumor suppressor p53, was found to activate GSK3beta. This activation occurred by a phosphorylation-independent mechanism involving direct binding of GSK3beta to p53, which was confined to the nucleus where p53 is localized, and mutated p53 (R175H) bound but did not activate GSK3beta. 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 GSK3beta, and these proteins act in concert to regulate cellular responses to DNA damage.
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