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Glycogen synthase kinase 3 promotes p53 mRNA translation via phosphorylation of RNPC1

Min Zhang1, Jin Zhang, Xiangling Chen

  • 1Comparative Oncology Laboratory, University of California at Davis, Davis, California 95616, USA.

Genes & Development
|October 22, 2013
PubMed

Insights

Glycogen synthase kinase 3 (GSK3) phosphorylates RNPC1, a protein that regulates p53. This phosphorylation enhances p53 mRNA translation, offering new cancer therapy strategies by modulating p53 tumor suppression activity.

Area of Science:

  • Molecular Biology
  • Cancer Biology
  • Biochemistry

Background:

  • The p53 tumor suppressor pathway is crucial for cancer prevention.
  • RNPC1 (Rbm38) is an RNA-binding protein that represses p53 mRNA translation.
  • Regulation of the p53-RNPC1 feedback loop is essential for understanding p53 modulation.

Purpose of the Study:

  • To elucidate the regulatory mechanism of the p53-RNPC1 feedback loop.
  • To investigate the role of glycogen synthase kinase 3 (GSK3) in regulating RNPC1 and p53.
  • To explore the potential of targeting this loop for cancer therapy.

Main Methods:

  • Phosphorylation site mapping of RNPC1 by GSK3.
  • Analysis of RNPC1 interaction with eukaryotic translation factors (eIF4E, eIF4G).
  • Assessment of p53 mRNA translation and p53 expression under various pathway inhibitions (PI3K-Akt).

Main Results:

  • GSK3 phosphorylates RNPC1 at Serine 195.
  • Phosphorylated RNPC1 loses its ability to repress p53 mRNA translation by disrupting interaction with eIF4E.
  • Phosphorylated RNPC1 promotes p53 mRNA translation via interaction with eIF4G, facilitating eIF4F complex assembly.
  • Inhibition of the PI3K-Akt pathway activates GSK3, leading to increased RNPC1 phosphorylation and p53 expression.

Conclusions:

  • GSK3-mediated phosphorylation of RNPC1 is a key regulatory mechanism in the p53-RNPC1 loop.
  • This phosphorylation switches RNPC1 from a repressor to a promoter of p53 mRNA translation.
  • Targeting the GSK3-RNPC1-p53 axis presents a potential therapeutic strategy for cancer treatment by modulating p53 activity.
Keywords:
GSK3RNPC1Rbm38eIF4EeIF4Gp53

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