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 accomplishe...

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Bibliographic Details
Published in:FEBS letters 2005-10, Vol.579 (25), p.5473-5480
Main Authors: Di Stefano, Valeria, Mattiussi, Marina, Sacchi, Ada, D’Orazi, Gabriella
Format: Article
Language:English
Subjects:
Active Transport, Cell Nucleus
Apoptosis
Carrier Proteins - genetics
Carrier Proteins - metabolism
Cell Nucleus - chemistry
Cell Nucleus - metabolism
DNA Damage
Gene Expression Regulation
HIPK2
Humans
MDM2
Nuclear export
p53
Phosphorylation
Proteasomal degradation
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
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Summary: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.
ISSN:0014-5793
1873-3468
DOI:10.1016/j.febslet.2005.09.008