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

Published on: August 4, 2019

Selenomethionine regulation of p53 by a ref1-dependent redox mechanism

Young R Seo1, Mark R Kelley, Martin L Smith

  • 1Department of Microbiology, Walther Oncology Center, and Walther Cancer Institute, Indiana University School of Medicine, Indianapolis, IN 46208, USA.

Proceedings of the National Academy of Sciences of the United States of America
|October 3, 2002
PubMed

Insights

Selenium (SeMet) activates the p53 tumor suppressor protein through a redox mechanism involving Ref1, enhancing DNA repair and cancer prevention. This study elucidates a key molecular pathway for selenium

Area of Science:

  • Biochemistry
  • Molecular Biology
  • Cancer Research

Background:

  • The cancer chemopreventive effects of selenium compounds are recognized, but the underlying mechanisms remain largely unknown.
  • Understanding how selenium inhibits carcinogenesis is crucial for developing effective cancer prevention strategies.

Purpose of the Study:

  • To elucidate the mechanism by which selenomethionine (SeMet) activates the p53 tumor suppressor protein.
  • To investigate the role of the redox factor Ref1 and specific p53 cysteine residues in SeMet-mediated p53 activation.
  • To determine the cellular responses to SeMet, focusing on the DNA repair pathway.

Main Methods:

  • Direct reduction/oxidation assays of p53.
  • Use of dominant-negative Ref1 to block SeMet-induced responses.
  • Peptide assays focusing on p53 cysteine residues 275 and 277.
  • Measurement of SeMet-induced p53 DNA binding and transactivation.
  • Analysis of cellular responses in p53 wild-type and null mouse embryo fibroblasts.

Main Results:

  • Selenomethionine (SeMet) activates p53 via a redox mechanism dependent on the redox factor Ref1.
  • Specific p53 cysteine residues (275 and 277) are critical for the SeMet-induced response.
  • SeMet treatment leads to sequence-specific DNA binding and transactivation by p53.
  • The DNA repair pathway of the p53 pathway was activated by SeMet in cellular assays.

Conclusions:

  • Selenomethionine activates the p53 tumor suppressor protein through a redox mechanism involving Ref1 and specific cysteine residues.
  • SeMet-induced p53 activation enhances DNA repair, suggesting a key role in cancer chemoprevention.
  • These findings provide mechanistic insights into selenium's cancer-preventive properties.

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