HIPK2 contributes to PCAF-mediated p53 acetylation and selective transactivation of p21Waf1 after nonapoptotic DNA damage

Valeria Di Stefano, Silvia Soddu, Ada Sacchi, Gabriella D'Orazi

Research output: Contribution to journalArticle

Abstract

The p53 tumor suppressor gene is activated in response to DNA damage resulting in either growth arrest or apoptosis. We previously demonstrated the specific involvement of homeodomain interacting protein-kinase 2 (HIPK2), a nuclear serine/threonine kinase, in inducing p53-dependent apoptosis through selective p53 phosphorylation at serine 46 after severe genotoxic damage. Here we show that HIPK2 contributes to p53 regulation, independently from serine 46 phosphorylation upon nonapoptotic DNA damage such as that induced by cytostatic doses of cisplatin. We show that HIPK2 depletion by RNA interference inhibits p53 binding to the p21Waf1 promoter affecting its p53-induced transactivation thereby allowing cell proliferation. We found that nonapoptotic DNA damage induces p53 acetylation mediated by the HAT protein PCAF and this p53 posttranslational modification is abolished by HIPK2 depletion. In this regard, we found that HIPK2 cooperates with PCAF to induce selectively p53 transcriptional activity toward the p21Waf1 promoter while depletion of either HIPK2 or PCAF abolished this function. These data show that HIPK2 regulates the p53 growth arrest function through its PCAF-mediated acetylation.

Original languageEnglish
Pages (from-to)5431-5442
Number of pages12
JournalOncogene
Volume24
Issue number35
DOIs
Publication statusPublished - Aug 18 2005

Keywords

  • Acetylation
  • Chromatin immunoprecipitation
  • DNA damage
  • HIPK2
  • p53
  • PCAF

ASJC Scopus subject areas

  • Molecular Biology
  • Cancer Research
  • Genetics

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