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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

Tumour suppressor p53 down-regulates the expression of the human hepatocyte nuclear factor 4alpha (HNF4alpha) gene

Yutaka Maeda1, Wendy W Hwang-Verslues, Gang Wei

  • 1Department of Cell Biology and Neuroscience, University of California, Riverside, CA 92521, USA.

The Biochemical Journal
|August 10, 2006
PubMed

Insights

The tumor suppressor p53 reduces the expression of hepatocyte nuclear factor 4alpha (HNF4alpha) in liver cells. This p53-mediated repression of HNF4alpha is crucial for cellular stress responses.

Area of Science:

  • Hepatology
  • Molecular Biology
  • Cellular Stress Response

Background:

  • The liver encounters toxins that damage DNA, increasing tumor suppressor p53 levels.
  • p53 is known to inhibit the transactivation of hepatocyte nuclear factor 4alpha1 (HNF4alpha1).
  • HNF4alpha is critical for liver development and differentiation.

Purpose of the Study:

  • To investigate whether p53 down-regulates the expression of the human HNF4alpha gene.
  • To elucidate the mechanism by which p53 affects HNF4alpha expression.
  • To understand the role of p53-mediated HNF4alpha repression in cellular stress.

Main Methods:

  • Overexpression of wild-type and mutant p53 in Hep3B and HepG2 cells.
  • Exposure of HepG2 cells to UV irradiation and doxorubicin.
  • Analysis of HNF4alpha mRNA and protein levels.
  • Reporter assays for HNF4alpha P1 promoter activity.
  • Chromatin immunoprecipitation (ChIP) assays.
  • In vitro and in vivo binding assays with HNF6alpha.
  • Histone deacetylase (HDAC) inhibition.

Main Results:

  • Overexpression of wild-type p53 decreased endogenous HNF4alpha mRNA and protein levels.
  • UV irradiation and doxorubicin treatment increased p53 and decreased HNF4alpha levels in HepG2 cells.
  • p53 bound the HNF4alpha P1 promoter and repressed its activity, dependent on DNA binding.
  • p53 interacted with HNF6alpha, preventing HNF6alpha from binding DNA and repressing P1 promoter stimulation.
  • HDAC inhibition partially recovered HNF4alpha expression, suggesting a role for histone modification.

Conclusions:

  • p53 actively down-regulates HNF4alpha gene expression via the proximal P1 promoter.
  • The repression mechanism involves p53 binding to the promoter and interacting with HNF6alpha.
  • p53-mediated repression of HNF4alpha is a component of the cellular response to DNA damage and stress.

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