Glycogen Synthase Kinase-3β (GSK3β) Binds to and Promotes the Actions of p53*

By Piyajit Watcharasit, G. N. Bijur, Ling Song, Jian‐hui Zhu, Xinbin Chen, R. Jope. Journal of Biological Chemistry, 2003

266 citations recorded by the source corpus.

The recent discovery of direct interactions between two important regulators of cell fate, the tumor suppressor p53 and glycogen synthase kinase-3β (GSK3β), led us to examine the mechanism and outcomes of this interaction. Two regions of p53 were identified that regulate its binding to GSK3β. Deletion of the p53 activation domain-1 (AD1), but not mutations that prevent MDM2 binding through the AD1 domain, enhanced GSK3β binding to p53, indicating that the AD1 domain interferes with p53 binding to GSK3β. Deletion of the p53 basic domain (BD) abrogated GSK3β binding, and a ten amino acid region within the C-terminal BD domain was identified as necessary for binding to GSK3β. GSK3β activity was not required for p53 binding, but inhibition of GSK3β stabilized the association, suggesting a transient interaction during which active GSK3β promotes actions of p53. This regulatory role of GSK3β was demonstrated by large reductions of p53-induced increases in the levels of MDM2, p21, and Bax when GSK3β was inhibited. Besides promoting p53-mediated transcription, GSK3β also contributed to mitochondrial p53 apoptotic signaling. After DNA damage, mitochondrial GSK3β co-immunoprecipitated with p53 and was activated, and inhibition of GSK3β blocked cytochrome c release and caspase-3 activation. Thus, GSK3β interacts with p53 in both the nucleus and mitochondria and promotes its actions at both sites.

Subfields: Molecular Biology, Oncology

View Paper: https://www.semanticscholar.org/paper/f69274cb3f10466a56564f3f5983e0282e36ae2c

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Citations in the corpus

Glycogen synthase kinase-3 (GSK3): regulation, actions, and diseases (2014, background): “by phosphorylating guanyl nucleotide dissociation factor (GID), a regulator of Rab5 that mediates endocytosis of AMPA receptors (Wei et al., 2010; Wang et al., 2013).”
Glycogen Synthase Kinase-3 (GSK3): Inflammation, Diseases, and Therapeutics (2007, background): “actions of major tumor suppressor proteins such as p53 [177, 179].”