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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.
Abstract:
Activation of the p53 tumour suppressor protein can lead to cell-cycle arrest or apoptosis. p53 function is controlled by the mdm2 oncogene product, which targets p53 for proteasomal degradation. In this report we demonstrate that Mdm2 induces translation of the p53 mRNA from two alternative initiation sites, giving full-length p53 and another protein with a relative molecular mass (M(r)) of approximately 47K; we designate this protein as p53/47. This translation induction requires Mdm2 to interact directly with the nascent p53 polypeptide. The alternatively translated p53/47 does not contain the Mdm2-binding site and it lacks the most amino-terminal transcriptional-activation domain of p53. Increased expression of p53/47 stabilizes p53 in the presence of Mdm2, and alters the expression levels of p53-induced gene products. These results show how the interaction of Mdm2 with p53 leads to a change in the ratio of full-length p53 to p53/47 by inducing translation of both p53 proteins and the subsequent selective degradation of full-length p53. Thus, Mdm2 controls the expression levels of p53 through a dual mechanism that involves induction of synthesis and targeting for degradation.
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.