Glycogen synthase kinase-3beta (GSK3beta) binds to and promotes the actions of p53.
The recent discovery of direct interactions between two important regulators of cell fate, the tumor suppressor p53 and glycogen synthase kinase-3beta (GSK3beta), led us to examine the mechanism and outcomes of this interaction. Two regions of p53 were identified that regulate its binding to GSK3beta. Deletion of the p53 activation domain-1 (AD1), but not mutations that prevent MDM2 binding through the AD1 domain, enhanced GSK3beta binding to p53, indicating that the AD1 domain interferes with p53 binding to GSK3beta. Deletion of the p53 basic domain (BD) abrogated GSK3beta binding, and a ten amino acid region within the C-terminal BD domain was identified as necessary for binding to GSK3beta. GSK3beta activity was not required for p53 binding, but inhibition of GSK3beta stabilized the association, suggesting a transient interaction during which active GSK3beta promotes actions of p53. This regulatory role of GSK3beta was demonstrated by large reductions of p53-induced increases in the levels of MDM2, p21, and Bax when GSK3beta was inhibited. Besides promoting p53-mediated transcription, GSK3beta also contributed to mitochondrial p53 apoptotic signaling. After DNA damage, mitochondrial GSK3beta co-immunoprecipitated with p53 and was activated, and inhibition of GSK3beta blocked cytochrome c release and caspase-3 activation. Thus, GSK3beta interacts with p53 in both the nucleus and mitochondria and promotes its actions at both sites.
Watcharasit
Piyajit
P
Department of Psychiatry, University of Alabama at Birmingham, Birmingham, Alabama 35294-0017, USA.
Bijur
Gautam N
GN
Song
Ling
L
Zhu
Jianhui
J
Chen
Xinbin
X
Jope
Richard S
RS
D017209:Apoptosis / Q000502:physiology; D045744:Cell Line, Tumor; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism*; D000071679:Glycogen Synthase Kinase 3 beta; D006801:Humans; D011485:Protein Binding; D014158:Transcription, Genetic / Q000502:physiology; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism* / Q000502:physiology
D016159:Tumor Suppressor Protein p53; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; D038362:Glycogen Synthase Kinase 3