MDM2-regulated degradation of HIPK2 prevents p53Ser46 phosphorylation and DNA damage-induced apoptosis.
In response to DNA damage, p53 induces either cell-cycle arrest or apoptosis by differential transcription of several target genes and through transcription-independent apoptotic functions. p53 phosphorylation at Ser46 by HIPK2 is one determinant of the outcome because it takes place only upon severe, nonrepairable DNA damage that irreversibly drives cells to apoptosis. Here, we show that p53 represses its proapoptotic activator HIPK2 via MDM2-mediated degradation, whereas a degradation-resistant HIPK2 mutant has increased apoptotic activity. Upon cytostatic, nonsevere DNA damage, inhibition of HIPK2 degradation is sufficient to induce p53Ser46 phosphorylation and apoptosis, converting growth-arresting stimuli to apoptotic ones. These findings establish HIPK2 as an MDM2 target and support a model in which, upon nonsevere DNA damage, p53 represses its own phosphorylation at Ser46 due to HIPK2 degradation, supporting the notion that the cell-cycle-arresting functions of p53 include active inhibition of the apoptotic ones.
Rinaldo
Cinzia
C
Department of Experimental Oncology, Regina Elena Cancer Institute, Via delle Messi d'Oro 156, 00158 Rome, Italy.
Prodosmo
Andrea
A
Mancini
Francesca
F
Iacovelli
Stefano
S
Sacchi
Ada
A
Moretti
Fabiola
F
Soddu
Silvia
S
D000595:Amino Acid Sequence; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D002352:Carrier Proteins / Q000737:chemistry / Q000378:metabolism*; D002384:Catalysis / Q000187:drug effects; D004249:DNA Damage; D020869:Gene Expression Profiling; D006801:Humans; D008239:Lysine / Q000378:metabolism; D051379:Mice; D008954:Models, Biological; D008969:Molecular Sequence Data; D009153:Mutagens / Q000633:toxicity; D050505:Mutant Proteins / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D010768:Phosphoserine / Q000378:metabolism; D011485:Protein Binding / Q000187:drug effects; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D017346:Protein Serine-Threonine Kinases / Q000737:chemistry / Q000378:metabolism*; D051736:Proto-Oncogene Proteins c-mdm2 / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*
D000970:Antineoplastic Agents; D002352:Carrier Proteins; D009153:Mutagens; D050505:Mutant Proteins; D016159:Tumor Suppressor Protein p53; D010768:Phosphoserine; C497206:MDM2 protein, human; C497207:Mdm2 protein, mouse; D051736:Proto-Oncogene Proteins c-mdm2; C115114:HIPK2 protein, human; C492003:Hipk2 protein, mouse; D017346:Protein Serine-Threonine Kinases; D008239:Lysine