HIPK2 inhibits both MDM2 gene and protein by, respectively, p53-dependent and independent regulations.
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.
Mesh Terms:
Active Transport, Cell Nucleus, Apoptosis, Carrier Proteins, Cell Nucleus, DNA Damage, Gene Expression Regulation, Humans, Phosphorylation, Proteasome Endopeptidase Complex, Protein-Serine-Threonine Kinases, Proto-Oncogene Proteins c-mdm2, RNA Interference, Serine, Tumor Suppressor Protein p53
Active Transport, Cell Nucleus, Apoptosis, Carrier Proteins, Cell Nucleus, DNA Damage, Gene Expression Regulation, Humans, Phosphorylation, Proteasome Endopeptidase Complex, Protein-Serine-Threonine Kinases, Proto-Oncogene Proteins c-mdm2, RNA Interference, Serine, Tumor Suppressor Protein p53
FEBS Lett.
Date: Oct. 24, 2005
PubMed ID: 16212962
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