HIPK2 inhibits both MDM2 gene and protein by, respectively, p53-dependent and independent regulations

Valeria Di Stefano, Marina Mattiussi, Ada Sacchi, Gabriella D'Orazi

Research output: Contribution to journalArticlepeer-review

Abstract

We address here the involvement of the homeodomain-interacting protein kinase 2 (HIPK2)/p53 complex on MDM2 regulation following apoptotic DNA damage. Our results provide a plausible transcriptional (p53-dependent) and posttranscriptional (p53-independent) double mechanism by which HIPK2 accomplishes MDM2 downmodulation. First, in wtp53-carrying cells HIPK2-dependent p53Ser46 phosphorylation selectively inhibits MDM2 at transcriptional level. Secondly, HIPK2 interacts with MDM2 in vitro and in vivo and promotes MDM2 nuclear export and proteasomal degradation, in p53-null cellular context. This p53-independent effect is likely mediated by HIPK2 catalytic activity and we found that HIPK2 phosphorylates MDM2 in vitro. In response to DNA damage, depletion of HIPK2 by RNA-interference abolishes MDM2 protein degradation. We propose that HIPK2 contributes to drug-induced modulation of MDM2 activity at transcriptional (through p53Ser46 phosphorylation) and posttranscriptional (through p53-independent subcellular re-localization and proteasomal degradation) levels.

Original languageEnglish
Pages (from-to)5473-5480
Number of pages8
JournalFEBS Letters
Volume579
Issue number25
DOIs
Publication statusPublished - Oct 24 2005

Keywords

  • HIPK2
  • MDM2
  • Nuclear export
  • p53
  • Phosphorylation
  • Proteasomal degradation

ASJC Scopus subject areas

  • Biochemistry
  • Biophysics
  • Molecular Biology

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