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Identification of Intracellular Signaling Events Induced in Viable Cells by Interaction with Neighboring Cells Undergoing Apoptotic Cell Death
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Glycogen synthase kinase-3beta (GSK3beta) binds to and promotes the actions of p53

Piyajit Watcharasit1, Gautam N Bijur, Ling Song

  • 1Department of Psychiatry, University of Alabama at Birmingham, Birmingham, Alabama 35294-0017, USA.

The Journal of Biological Chemistry
|October 3, 2003
PubMed

Insights

Glycogen synthase kinase-3beta (GSK3beta) interacts with the tumor suppressor p53, promoting its nuclear and mitochondrial functions. GSK3beta inhibition reduces p53-mediated transcription and apoptosis signaling.

Area of Science:

  • Cell Biology
  • Molecular Biology
  • Biochemistry

Background:

  • p53 and GSK3beta are key regulators of cell fate.
  • Direct interactions between p53 and GSK3beta have been recently discovered.
  • Understanding this interaction's mechanism and outcomes is crucial.

Purpose of the Study:

  • To investigate the mechanism of p53-GSK3beta interaction.
  • To identify the regions of p53 involved in binding GSK3beta.
  • To elucidate the functional outcomes of this interaction on p53 activity.

Main Methods:

  • Deletion analysis of p53 domains (AD1, BD) to map GSK3beta binding sites.
  • Mutation analysis of p53 AD1 domain to assess MDM2 binding influence.
  • GSK3beta inhibition studies to evaluate its effect on p53 binding and activity.
  • Co-immunoprecipitation assays to detect p53-GSK3beta interaction in mitochondria.
  • Assessment of downstream targets: MDM2, p21, Bax, cytochrome c release, and caspase-3 activation.

Main Results:

  • The p53 AD1 domain interferes with GSK3beta binding; its deletion enhances binding.
  • A specific 10-amino acid region in the p53 basic domain is essential for GSK3beta binding.
  • GSK3beta activity is not required for binding, but inhibition stabilizes the interaction.
  • GSK3beta inhibition significantly reduces p53-induced MDM2, p21, and Bax levels.
  • GSK3beta is present and activated in mitochondria with p53 after DNA damage.
  • Inhibition of GSK3beta blocks mitochondrial p53 apoptotic signaling, including cytochrome c release and caspase-3 activation.

Conclusions:

  • GSK3beta binds to p53 via its basic domain and modulates p53 transcriptional activity.
  • GSK3beta also plays a critical role in mitochondrial p53-mediated apoptosis.
  • The interaction between p53 and GSK3beta occurs in both the nucleus and mitochondria, promoting p53 functions at both sites.

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