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 language | English |
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Pages (from-to) | 5473-5480 |
Number of pages | 8 |
Journal | FEBS Letters |
Volume | 579 |
Issue number | 25 |
DOIs | |
Publication status | Published - Oct 24 2005 |
Keywords
- HIPK2
- MDM2
- Nuclear export
- p53
- Phosphorylation
- Proteasomal degradation
ASJC Scopus subject areas
- Biochemistry
- Biophysics
- Molecular Biology