Counteracting MDM2-induced HIPK2 downregulation restores HIPK2/p53 apoptotic signaling in cancer cells

Lavinia Nardinocchi, Rosa Puca, David Givol, Gabriella D'Orazi

Research output: Contribution to journalArticle

Abstract

Homeodomain-interacting protein kinase-2 (HIPK2) is a crucial regulator of p53 apoptotic function by phosphorylating serine 46 (Ser46) in response to DNA damage. In tumors with wild-type p53, its tumor suppressor function is often impaired by MDM2 overexpression that targets p53 for proteasomal degradation. Likewise, MDM2 targets HIPK2 for protein degradation impairing p53-apoptotic function. Here we report that zinc antagonised MDM2-induced HIPK2 degradation as well as p53 ubiquitination. The zinc inhibitory effect on MDM2 activity leads to HIPK2-induced p53Ser46 phosphorylation and p53 pro-apoptotic transcriptional activity. These results suggest that zinc derivatives are potential molecules to target the MDM2-induced HIPK2/p53 inhibition.

Original languageEnglish
Pages (from-to)4253-4258
Number of pages6
JournalFEBS Letters
Volume584
Issue number19
DOIs
Publication statusPublished - Oct 2010

Keywords

  • Apoptosis
  • HIPK2
  • MDM2
  • P53 transcriptional activity
  • Zinc supplementation

ASJC Scopus subject areas

  • Biochemistry
  • Biophysics
  • Cell Biology
  • Genetics
  • Molecular Biology
  • Structural Biology

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