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p53 pathway in renal cell carcinoma is repressed by a dominant mechanism

Katerina V Gurova1, Jason E Hill, Olga V Razorenova

  • 1Department of Molecular Biology, Lerner Research Institute, The Cleveland Clinic Foundation, 9500 Euclid Avenue, Cleveland, OH 44195, USA. gurovak@ccf.org

Cancer Research
|March 18, 2004
PubMed

Insights

Renal cell carcinoma (RCC) rarely mutates the p53 gene. Instead, a dominant inhibitor likely represses p53 function, a mechanism also observed in normal kidney cells.

Area of Science:

  • Oncology
  • Molecular Biology
  • Genetics

Background:

  • Renal cell carcinoma (RCC) infrequently harbors p53 mutations.
  • This suggests alternative mechanisms may suppress p53 signaling in RCC.

Purpose of the Study:

  • To investigate the mechanism of p53 repression in renal cell carcinoma.
  • To determine if known p53 regulators are involved in this repression.

Main Methods:

  • Analysis of p53-responsive gene transactivation in RCC cell lines.
  • Assessment of p53 protein response to genotoxic stress.
  • Functional and expression analysis of Mdm2, MdmX, and Arf.
  • Cell fusion experiments with RCC and normal kidney cells.

Main Results:

  • RCC cell lines with wild-type p53 failed to transactivate p53-responsive genes.
  • p53 protein accumulated and translocated normally upon genotoxic stress.
  • Known p53 regulators (Mdm2, MdmX, Arf) were not implicated in the p53 defect.
  • p53 transactivation was restored only at supra-physiological p53 levels, suggesting a dominant inhibitor.
  • Cell fusion experiments indicated a dominant inhibitory mechanism also present in normal kidney epithelium.

Conclusions:

  • p53 signaling is repressed in renal cell carcinoma not by mutation, but by a dominant inhibitor.
  • This dominant repression mechanism appears to be present in normal kidney epithelium as well.
  • Further research is needed to identify the specific inhibitor and its role in both normal and cancerous kidney tissue.

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