HIPK2 neutralizes MDM2 inhibition rescuing p53 transcriptional activity and apoptotic function.
The p53 oncosuppressor protein is subject to negative regulation by MDM2, which efficiently inhibits its activity through an autoregulatory loop. In response to stress, however, p53 undergoes post-translational modifications that allow the protein to escape MDM2 control, accumulate, and become active. Recent studies have shown that, following DNA damage, the HIPK2 serine/threonine kinase binds and phosphorylates p53, inducing p53 transcriptional activity and apoptotic function. Here, we investigated the role of HIPK2 in the activation of p53 in the presence of MDM2. We found that HIPK2 rescues p53 transcriptional activity overcoming MDM2 inhibition, and that restoration of this p53 function induces apoptosis. Recovery of p53-dependent apoptosis is achieved by preventing p53 nuclear export and ubiquitination mediated by MDM2 in vitro and in vivo following genotoxic stress. These results shed new light on the mechanisms by which the HIPK2/p53 pathway promotes apoptosis and suppression of tumorigenesis.
Di Stefano
Valeria
V
Department of Experimental Oncology, Molecular Oncogenesis Laboratory, Regina Elena Cancer Institute, Rome 00158, Italy.
Blandino
Giovanni
G
Sacchi
Ada
A
Soddu
Silvia
S
D'Orazi
Gabriella
G
D000230:Adenocarcinoma / Q000378:metabolism / Q000473:pathology; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000235:genetics; D015153:Blotting, Western; D002352:Carrier Proteins / Q000187:drug effects / Q000378:metabolism*; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000378:metabolism; D002945:Cisplatin / Q000494:pharmacology; D003110:Colonic Neoplasms / Q000378:metabolism / Q000473:pathology; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology; D004249:DNA Damage; D006801:Humans; D007976:Leupeptins / Q000494:pharmacology; D008156:Luciferases / Q000378:metabolism; D008175:Lung Neoplasms / Q000378:metabolism / Q000473:pathology; D009687:Nuclear Proteins / Q000037:antagonists & inhibitors* / Q000187:drug effects; D012516:Osteosarcoma / Q000378:metabolism / Q000473:pathology; D011233:Precipitin Tests; D017346:Protein Serine-Threonine Kinases / Q000187:drug effects / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors* / Q000187:drug effects; D051736:Proto-Oncogene Proteins c-mdm2; D015533:Transcriptional Activation; D016159:Tumor Suppressor Protein p53 / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D025801:Ubiquitin / Q000378:metabolism
D000970:Antineoplastic Agents; D002352:Carrier Proteins; D015853:Cysteine Proteinase Inhibitors; D007976:Leupeptins; D009687:Nuclear Proteins; D011518:Proto-Oncogene Proteins; D016159:Tumor Suppressor Protein p53; D025801:Ubiquitin; D008156:Luciferases; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2; C115114:HIPK2 protein, human; D017346:Protein Serine-Threonine Kinases; D002945:Cisplatin; C072553:benzyloxycarbonylleucyl-leucyl-leucine aldehyde