Homeodomain-interacting protein kinase-2 phosphorylates p53 at Ser 46 and mediates apoptosis.
Phosphorylation of p53 at Ser 46 was shown to regulate p53 apoptotic activity. Here we demonstrate that homeodomain-interacting protein kinase-2 (HIPK2), a member of a novel family of nuclear serine/threonine kinases, binds to and activates p53 by directly phosphorylating it at Ser 46. HIPK2 localizes with p53 and PML-3 into the nuclear bodies and is activated after irradiation with ultraviolet. Antisense inhibition of HIPK2 expression reduces the ultraviolet-induced apoptosis. Furthermore, HIPK2 and p53 cooperate in the activation of p53-dependent transcription and apoptotic pathways. These data define a new functional interaction between p53 and HIPK2 that results in the targeted subcellular localization of p53 and initiation of apoptosis.
D'Orazi
Gabriella
G
Molecular Oncogenesis Laboratory, Regina Elena Cancer Institute, Via delle Messi d Oro 156, 00158 Rome, Italy.
Cecchinelli
Barbara
B
Bruno
Tiziana
T
Manni
Isabella
I
Higashimoto
Yuichiro
Y
Saito
Shin'ichi
S
Gostissa
Monica
M
Coen
Sabrina
S
Marchetti
Alessandra
A
Del Sal
Giannino
G
Piaggio
Guilia
G
Fanciulli
Maurizio
M
Appella
Ettore
E
Soddu
Silvia
S
D000818:Animals; D017209:Apoptosis / Q000235:genetics* / Q000528:radiation effects; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism* / Q000528:radiation effects; D002467:Cell Nucleus / Q000235:genetics / Q000378:metabolism / Q000648:ultrastructure; D004789:Enzyme Activation / Q000528:radiation effects; D016147:Genes, Tumor Suppressor; D006801:Humans; D051379:Mice; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism; D009687:Nuclear Proteins; D016376:Oligonucleotides, Antisense; D010766:Phosphorylation; D000071156:Promyelocytic Leukemia Protein; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism* / Q000528:radiation effects; D012694:Serine; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D015533:Transcriptional Activation; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000235:genetics* / Q000378:metabolism*; D025521:Tumor Suppressor Proteins; D014466:Ultraviolet Rays
D002352:Carrier Proteins; D009363:Neoplasm Proteins; D009687:Nuclear Proteins; D016376:Oligonucleotides, Antisense; C513293:Pml protein, mouse; D000071156:Promyelocytic Leukemia Protein; D020033:Protein Isoforms; D014157:Transcription Factors; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; C070576:PML protein, human; D012694:Serine; C115114:HIPK2 protein, human; C492003:Hipk2 protein, mouse; D017346:Protein Serine-Threonine Kinases