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Yeast As a Chassis for Developing Functional Assays to Study Human P53
14:57

Yeast As a Chassis for Developing Functional Assays to Study Human P53

Published on: August 4, 2019

Mycophenolic acid activation of p53 requires ribosomal proteins L5 and L11

Xiao-Xin Sun1, Mu-Shui Dai, Hua Lu

  • 1Department of Biochemistry and Molecular Biology, Indiana University School of Medicine and Simon Cancer Center, Indianapolis, Indiana 46202, USA.

The Journal of Biological Chemistry
|February 29, 2008
PubMed

Insights

Mycophenolate mofetil (MMF) activates the p53 pathway by inhibiting pre-ribosomal RNA synthesis, causing nucleolar stress. This stress leads to p53 activation through ribosomal proteins L5/L11 and MDM2 interaction.

Area of Science:

  • Molecular Biology
  • Immunology
  • Cancer Biology

Background:

  • Mycophenolate mofetil (MMF) is an immunosuppressant prodrug of mycophenolic acid (MPA).
  • MPA inhibits inosine monophosphate dehydrogenase (IMPDH), depleting guanine nucleotides and causing cell cycle arrest and apoptosis.
  • MPA induces p53, but the activation mechanism remains unclear.

Purpose of the Study:

  • To elucidate the mechanism of p53 activation by MPA.
  • To investigate the role of nucleolar stress and ribosomal proteins in MPA-induced p53 activation.

Main Methods:

  • Assessing pre-rRNA synthesis and nucleolar integrity following MPA treatment.
  • Analyzing the interaction between MDM2, L5, and L11 proteins.
  • Evaluating p53 induction and cell cycle arrest in cells with L5/L11 knockdown.

Main Results:

  • MPA treatment inhibited pre-rRNA synthesis and disrupted the nucleolus.
  • MPA enhanced the interaction between MDM2 and ribosomal proteins L5/L11.
  • Knockdown of L5 or L11 impaired MPA-induced p53 activation and G1 cell cycle arrest.

Conclusions:

  • MPA induces p53 activation via nucleolar stress.
  • Ribosomal proteins L5 and L11 mediate p53 induction by inhibiting MDM2 in response to nucleolar stress.

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