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Regulation of the cyclin-dependent kinase inhibitor p57Kip2 expression by p63

Chiara Beretta1, Anna Chiarelli, Barbara Testoni

  • 1Department of Biomolecular and Biotechnological Sciences, University of Milan, Milan, Italy.

Cell Cycle (Georgetown, Tex.)
|November 1, 2005
PubMed

Insights

The p63 protein regulates cell proliferation by controlling the p57Kip2 gene. Certain p63 mutations disrupt this regulation, impacting human development and disease.

Area of Science:

  • Molecular Biology
  • Genetics
  • Developmental Biology

Background:

  • p57Kip2 is a cyclin-dependent kinase (CDK) inhibitor that negatively regulates cell proliferation.
  • p57Kip2 was previously identified as a target gene of p73beta, a member of the p53 family.
  • Phenotypic similarities between p57Kip2 null mice and p63 null mice suggest p57Kip2 may be a downstream target of p63.

Purpose of the Study:

  • To investigate the role of p63 in regulating p57Kip2 gene expression.
  • To determine if p63 directly binds to and activates the p57Kip2 gene promoter.
  • To examine the impact of natural p63 mutants on p57Kip2 promoter activity.

Main Methods:

  • Chromatin immunoprecipitation (ChIP) to identify p63 binding sites on the p57Kip2 gene.
  • Reporter gene assays using a p57Kip2 promoter fragment to assess transactivation by p63.
  • Analysis of p63 mutants associated with human syndromes (AEC, EEC, LMS, SHFM-4).

Main Results:

  • DeltaNp63alpha protein directly associates with three regions of the p57Kip2 gene in HaCaT cells.
  • DeltaNp63alpha activates both the endogenous p57Kip2 gene and a reporter construct containing the p57Kip2 promoter.
  • p63 mutants linked to AEC syndrome exhibit significantly reduced or abolished transactivation of the p57Kip2 promoter, while other mutants show less impairment.

Conclusions:

  • p63 plays a crucial role in regulating p57Kip2 expression.
  • The regulatory relationship between p63 and p57Kip2 is disrupted in p63 mutants associated with AEC syndrome.
  • These findings highlight the importance of p63-mediated p57Kip2 regulation in development and disease.

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