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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

A direct intersection between p53 and transforming growth factor beta pathways targets chromatin modification and

Deepti S Wilkinson1, Stacey K Ogden, Sabrina A Stratton

  • 1Department of Biochemistry and Molecular Biology, University of Texas M.D. Anderson Cancer Center, Houston, TX 77030, USA.

Molecular and Cellular Biology
|January 20, 2005
PubMed

Insights

The oncoprotein SnoN acts as a tumor suppressor by repressing alpha-fetoprotein (AFP) gene transcription. This function is dependent on its interaction with p53, a key tumor suppressor protein.

Area of Science:

  • Molecular Biology
  • Oncology
  • Gene Regulation

Background:

  • The oncoprotein SnoN's role in tumor suppression is not fully understood.
  • Alpha-fetoprotein (AFP) is a key tumor marker gene in liver cancer.
  • The tumor suppressor p53 is a critical regulator of cell growth and tumor suppression.

Purpose of the Study:

  • To investigate the function of SnoN in regulating the hepatic alpha-fetoprotein (AFP) tumor marker gene.
  • To elucidate the interaction between SnoN and the tumor suppressor p53 in AFP gene regulation.
  • To understand the role of transforming growth factor-beta1 (TGF-beta1) signaling in AFP repression.

Main Methods:

  • Purification of the oncoprotein SnoN.
  • Chromatin immunoprecipitation (ChIP) assays in wild-type and p53-null mouse liver tissue.
  • Small interfering RNA (siRNA) mediated depletion of SnoN and p53 in hepatoma cells.
  • Analysis of histone modifications and protein binding at the AFP gene locus.

Main Results:

  • SnoN functions as a corepressor of the tumor suppressor p53 in regulating AFP gene transcription.
  • p53 facilitates the interaction of SnoN with histone deacetylases at the AFP gene.
  • Absence of p53 leads to loss of SnoN binding and AFP gene repression.
  • TGF-beta1 treatment induces SnoN, activates Smad2, and represses AFP transcription.
  • TGF-beta1 signaling promotes p53, Smad4, and P-Smad2 binding, and histone deacetylation at the AFP locus.
  • Depletion of SnoN or p53 disrupts AFP gene repression.

Conclusions:

  • SnoN and p53 cooperate to repress AFP transcription through chromatin modification.
  • The p53-SnoN complex plays a critical role in the developmental repression of the AFP tumor marker gene.
  • These findings reveal a novel mechanism of tumor suppression involving p53 and TGF-beta signaling in regulating oncodevelopmental genes.

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