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Nuclear receptor hepatocyte nuclear factor 4alpha1 competes with oncoprotein c-Myc for control of the p21/WAF1

Wendy W Hwang-Verslues1, Frances M Sladek

  • 1Environmental Toxicology Graduate Program, University of California, Riverside, California 92521, USA.

Molecular Endocrinology (Baltimore, Md.)
|September 22, 2007
PubMed

Insights

Hepatocyte nuclear factor 4alpha1 (HNF4alpha1) activates p21 gene expression by interacting with Sp1, not direct DNA binding. It competes with c-Myc, a proliferation factor, for gene regulation in differentiation and proliferation.

Area of Science:

  • Molecular biology
  • Cell biology
  • Genetics

Background:

  • Cellular differentiation and proliferation are key processes in development and cancer.
  • The molecular mechanisms governing the balance between these processes are not fully understood.
  • Nuclear receptors, like HNF4alpha1, play crucial roles in cellular functions.

Purpose of the Study:

  • To elucidate the mechanism by which HNF4alpha1 regulates the expression of the p21/WAF1 (CDKN1A) gene.
  • To investigate the interaction between HNF4alpha1, Sp1, and c-Myc in gene regulation.
  • To understand the role of HNF4alpha1 in the dichotomy between cell differentiation and proliferation.

Main Methods:

  • Investigated HNF4alpha1's regulation of p21 gene expression.
  • Utilized reporter assays to assess promoter activity.
  • Performed co-immunoprecipitation to study protein-protein interactions (HNF4alpha1 and c-Myc).
  • Analyzed gene expression of APOC3.

Main Results:

  • HNF4alpha1 activates p21 expression primarily through interaction with Sp1, independent of direct DNA binding.
  • HNF4alpha1 interacts with c-Myc both in vitro and in vivo.
  • HNF4alpha1 and c-Myc compete for Sp1 interaction and regulation of p21.
  • c-Myc competes with HNF4alpha1 for the control of APOC3, a differentiation-associated gene.

Conclusions:

  • HNF4alpha1 acts as a differentiation factor that activates p21 expression by cooperating with Sp1.
  • A competition exists between the differentiation factor HNF4alpha1 and the proliferation factor c-Myc for binding to Sp1.
  • This competition influences the regulation of genes involved in both cell proliferation and differentiation, offering a model for their opposing roles.

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