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

Published on: August 4, 2019

p53 can inhibit cell proliferation through caspase-mediated cleavage of ERK2/MAPK

A Marchetti1, B Cecchinelli, M D'Angelo

  • 1Molecular Oncogenesis Laboratory, Department of Experimental Oncology, Regina Elena Cancer Institute, 00158 Rome, Italy.

Cell Death and Differentiation
|May 20, 2004
PubMed

Insights

The tumor suppressor p53 directly inhibits Ras/MAPK signaling by inactivating ERK2, a process mediated by caspases. This mechanism contributes to p53-driven growth arrest and identifies ERK2 as a novel p53 target.

Area of Science:

  • Molecular Biology
  • Cellular Signaling
  • Cancer Research

Background:

  • The Ras/MAPK pathway plays a dual role in cell fate, influencing p53 activity, senescence, apoptosis, and survival.
  • Understanding how p53 interacts with and regulates key signaling pathways like Ras/MAPK is crucial for cancer therapy.

Purpose of the Study:

  • To investigate the direct mechanism by which p53 counteracts Ras/MAPK signaling.
  • To elucidate the role of ERK2 inactivation in p53-mediated growth suppression.

Main Methods:

  • Analysis of Ras-transformed cells and DNA damage-induced cell cycle arrest models.
  • Assays for ERK2 activity, phosphorylation, and protein half-life.
  • Utilized caspase inhibitors and caspase-resistant ERK2 mutants.

Main Results:

  • p53 directly inactivates ERK2/MAPK activity through caspase-mediated cleavage.
  • p53-induced growth arrest correlates with reduced ERK2 activity, phosphorylation, and half-life, alongside increased caspase activity.
  • Inhibition of caspase activity or expression of a resistant ERK2 mutant abrogates p53-mediated growth arrest.

Conclusions:

  • Caspase-mediated degradation of ERK2 is a key mechanism contributing to p53-induced growth arrest.
  • ERK2 represents a novel molecular target of p53 in the context of tumor suppressor functions.

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