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Purification of Ubiquitinated p53 Proteins from Mammalian Cells
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p53 Stability and activity is regulated by Mdm2-mediated induction of alternative p53 translation products

Yili Yin1, C W Stephen, M Gloria Luciani

  • 1Department of Surgery and Molecular Oncology, Ninewells Hospital and Medical School, University of Dundee, Dundee, DD1 9SY, UK.

Nature Cell Biology
|May 29, 2002
PubMed

Insights

The Mdm2 oncogene product controls p53 tumor suppressor levels by inducing translation of both full-length p53 and a shorter variant, p53/47. Mdm2 then selectively degrades full-length p53, regulating cell cycle arrest and apoptosis.

Area of Science:

  • Molecular Biology
  • Oncology
  • Cell Biology

Background:

  • The p53 tumor suppressor protein regulates cell-cycle arrest and apoptosis.
  • The mdm2 oncogene product inhibits p53 function by targeting it for proteasomal degradation.

Purpose of the Study:

  • To investigate the mechanism by which Mdm2 controls p53 expression.
  • To elucidate the role of alternative translation initiation in p53 regulation by Mdm2.

Main Methods:

  • Analysis of p53 mRNA translation initiation sites.
  • Investigation of Mdm2 interaction with nascent p53 polypeptide.
  • Assessment of p53/47 protein expression and its effect on p53 stability and target gene expression.

Main Results:

  • Mdm2 induces translation of p53 mRNA from two initiation sites, producing full-length p53 and a 47 kDa variant (p53/47).
  • Mdm2 interaction with nascent p53 is required for this translation induction.
  • p53/47 lacks the Mdm2-binding site and the N-terminal transcriptional-activation domain, stabilizes p53 against Mdm2-mediated degradation, and alters p53-induced gene expression.

Conclusions:

  • Mdm2 employs a dual mechanism to control p53 levels: inducing synthesis of both p53 and p53/47, and selectively degrading full-length p53.
  • This regulation impacts the balance between cell-cycle arrest and apoptosis by modulating p53 activity.

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