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The polycystic kidney disease-1 gene is a target for p53-mediated transcriptional repression

Diederik Van Bodegom1, Zubaida Saifudeen, Susana Dipp

  • 1Department of Pediatrics, Section of Pediatric Nephrology, Tulane University Health Sciences Center, New Orleans, Louisiana 70112, USA.

The Journal of Biological Chemistry
|August 26, 2006
PubMed

Insights

The tumor suppressor protein p53 acts as a transcriptional repressor of PKD1. Loss of this p53-mediated feedback loop may drive cystogenesis in PKD1-related diseases.

Area of Science:

  • Molecular Biology
  • Genetics
  • Cell Biology

Background:

  • Polycystic kidney disease (PKD) involves dysregulated gene expression.
  • The tumor suppressor protein p53 plays a role in cell differentiation and tumor suppression.
  • PKD1 is a key gene implicated in the pathogenesis of PKD.

Purpose of the Study:

  • To investigate the regulatory relationship between p53 and the PKD1 gene.
  • To elucidate the mechanism by which p53 influences PKD1 expression.
  • To explore the potential role of this interaction in cystogenesis.

Main Methods:

  • Comparison of Pkd1 mRNA levels in p53-null and wild-type mice.
  • Analysis of PKD1 gene expression following gamma-irradiation in different p53 genotypes.
  • Chromatin immunoprecipitation assays to detect p53 binding to the PKD1 promoter.
  • Transient transfection assays with PKD1 promoter constructs.
  • Site-directed mutagenesis of p53 domains.
  • Treatment with trichostatin A, a histone deacetylase inhibitor.

Main Results:

  • p53 directly represses PKD1 gene transcription.
  • p53 binds to the proximal promoter region of PKD1.
  • Repression is independent of p21 and requires functional p53 DNA binding and repression domains.
  • Histone deacetylase activity is involved in p53-mediated repression of PKD1.
  • PKD1 signaling appears to activate the p53-p21 pathway, forming a negative feedback loop.

Conclusions:

  • p53 acts as a transcriptional repressor of PKD1, forming a negative feedback loop.
  • This feedback loop involves cooperation between p53 and histone deacetylases.
  • Disruption of this p53-mediated negative feedback loop in PKD1 mutant cells may contribute to aberrant PKD1 expression and cyst formation in polycystic kidney disease.

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