HIPK2 inhibits both MDM2 gene and protein by, respectively, p53‐dependent and independent regulations

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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.