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Updated: Jun 15, 2026

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

Mutant p53-induced up-regulation of mitogen-activated protein kinase kinase 3 contributes to gain of function

Aymone Gurtner1, Giuseppe Starace, Giuseppe Norelli

  • 1Molecular Oncogenesis Laboratory, Department of Experimental Oncology, Regina Elena Cancer Institute, Via delle Messi D'Oro 156, 00158 Rome, Italy.

The Journal of Biological Chemistry
|March 13, 2010
PubMed

Insights

Gain-of-function p53 mutants regulate MAP2K3 expression, promoting cancer cell proliferation and survival. Targeting MAP2K3 offers a novel strategy against mutant p53-driven cancers.

Area of Science:

  • Molecular Biology
  • Cancer Research
  • Signal Transduction

Background:

  • Mitogen-activated protein kinase kinase 3 (MAP2K3) is implicated in cancer invasion and progression.
  • Gain-of-function (GOF) p53 mutants are frequently observed in human cancers and contribute to tumor development.
  • Understanding the regulatory mechanisms of MAP2K3 in cancer is crucial for therapeutic development.

Purpose of the Study:

  • To investigate MAP2K3 as a transcriptional target of endogenous GOF p53 mutants.
  • To elucidate the molecular mechanisms by which GOF p53 mutants regulate MAP2K3.
  • To determine the functional role of MAP2K3 in cancer cell proliferation and survival under GOF p53 conditions.

Main Methods:

  • Identification of MAP2K3 as a transcriptional target using p53 mutant expression models.
  • Analysis of MAP2K3 mRNA and protein levels.
  • Chromatin immunoprecipitation assays to assess p53 binding to the MAP2K3 promoter.
  • Reporter assays to evaluate promoter activity.
  • Knockdown and ectopic expression studies of MAP2K3 in human tumor cells.

Main Results:

  • Endogenous GOF p53 mutants (R273H, R175H, R280K) directly activate the MAP2K3 promoter.
  • MAP2K3 expression is modulated at both mRNA and protein levels by these p53 mutants.
  • Transcriptional cofactors NF-Y and NF-kappaB are involved in p53-mediated MAP2K3 regulation.
  • MAP2K3 knockdown inhibits proliferation and survival of human tumor cells.
  • Ectopic MAP2K3 expression rescues the proliferative defect caused by mutant p53 knockdown.

Conclusions:

  • MAP2K3 is a novel transcriptional target of GOF p53 mutants.
  • Mutant p53 promotes cancer cell proliferation and survival through the upregulation of MAP2K3.
  • MAP2K3 represents a potential therapeutic target for cancers harboring GOF p53 mutations.

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