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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

Suppression of the p300-dependent mdm2 negative-feedback loop induces the p53 apoptotic function

A Thomas1, E White

  • 1Center for Advanced Biotechnology and Medicine, Cancer Institute of New Jersey, Department of Molecular Biology and Biochemistry, Rutgers University, Piscataway, New Jersey 08854 USA.

Genes & Development
|July 3, 1998
PubMed

Insights

Adenovirus E1A protein inhibits p300, leading to p53 stabilization and apoptosis. Restoring p300 or Mdm2 function blocks this p53-induced cell death.

Area of Science:

  • Molecular Biology
  • Virology
  • Cancer Research

Background:

  • The p53 tumor suppressor regulates genes involved in cell cycle arrest and apoptosis.
  • p300 acts as a transcriptional coactivator for p53, enhancing the expression of p53-target genes.
  • Adenovirus E1A protein is known to interfere with cellular processes, including transcriptional regulation.

Purpose of the Study:

  • To investigate the mechanism by which adenovirus E1A protein affects p53 activity and apoptosis.
  • To elucidate the role of the p300 coactivator and Mdm2 in E1A-mediated modulation of p53 function.

Main Methods:

  • Studied the interaction between E1A, p300, p53, and Mdm2.
  • Analyzed the effects of E1A on the transactivation of p53-inducible genes, including Mdm2, p21(WAF1), and Bax.
  • Assessed p53 accumulation and apoptosis in cells expressing E1A, p300, or Mdm2.

Main Results:

  • E1A binds to p300, inhibiting its coactivation function and leading to p53 stabilization.
  • E1A specifically inhibits Mdm2 transactivation by p53, while not affecting p21(WAF1) or Bax.
  • Ectopic expression of p300 or Mdm2 restored Mdm2 levels and suppressed E1A-induced apoptosis.
  • E1B 19K or Bcl-2 expression rescued apoptosis by restoring Mdm2 transactivation.

Conclusions:

  • p300 is essential for p53-mediated induction of Mdm2, which normally inhibits p53 stabilization.
  • E1A's inhibition of p300 leads to p53 stabilization and subsequent apoptosis.
  • The p300-Mdm2 pathway is a critical regulator of p53 apoptotic activity, and viral proteins can disrupt this pathway.

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