HIPK2 Inhibits Both MDM2 Gene and Protein By, Respectively, p53-dependent and Independent Regulations

FEBS Lett. 2005 Oct 24;579(25):5473-80. doi: 10.1016/j.febslet.2005.09.008. Epub 2005 Sep 27.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Active Transport, Cell Nucleus
  • Apoptosis
  • Carrier Proteins / genetics
  • Carrier Proteins / metabolism*
  • Cell Nucleus / chemistry
  • Cell Nucleus / metabolism
  • DNA Damage
  • Gene Expression Regulation*
  • Humans
  • Phosphorylation
  • Proteasome Endopeptidase Complex / metabolism
  • Protein-Serine-Threonine Kinases / genetics
  • Protein-Serine-Threonine Kinases / metabolism*
  • Proto-Oncogene Proteins c-mdm2 / analysis
  • Proto-Oncogene Proteins c-mdm2 / genetics*
  • Proto-Oncogene Proteins c-mdm2 / metabolism*
  • RNA Interference
  • Serine / metabolism
  • Tumor Suppressor Protein p53 / metabolism*

Substances

  • Carrier Proteins
  • Tumor Suppressor Protein p53
  • Serine
  • MDM2 protein, human
  • Proto-Oncogene Proteins c-mdm2
  • HIPK2 protein, human
  • Protein-Serine-Threonine Kinases
  • Proteasome Endopeptidase Complex