Homeodomain-interacting protein kinase 2 is the ionizing radiation-activated p53 serine 46 kinase and is regulated by ATM.
Phosphorylation of p53 at Ser(46) is important to activate the apoptotic program. The protein kinase that phosphorylates p53 Ser(46) in response to DNA double-strand breaks is currently unknown. The identification of this kinase is of particular interest because it may contribute to the outcome of cancer therapy. Here, we report that ionizing radiation (IR) provokes homeodomain-interacting protein kinase 2 (HIPK2) accumulation, activation, and complex formation with p53. IR-induced HIPK2 up-regulation strictly correlates with p53 Ser(46) phosphorylation. Down-regulation of HIPK2 by RNA interference specifically inhibits IR-induced phosphorylation of p53 at Ser(46). Moreover, we show that HIPK2 activation after IR is regulated by the DNA damage checkpoint kinase ataxia telangiectasia mutated (ATM). Cells from ataxia telangiectasia patients show defects in HIPK2 accumulation. Concordantly, IR-induced HIPK2 accumulation is blocked by pharmacologic inhibition of ATM. Furthermore, ATM down-regulation by RNA interference inhibited IR-induced HIPK2 accumulation, whereas checkpoint kinase 2 deficiency showed no effect. Taken together, our findings indicate that HIPK2 is the IR-activated p53 Ser(46) kinase and is regulated by ATM.
Dauth
Ilka
I
Research Group Cellular Senescence, German Cancer Research Center, Im Neuenheimer Feld 242, 69120 Heidelberg, Germany.
Krüger
Jana
J
Hofmann
Thomas G
TG
D064007:Ataxia Telangiectasia Mutated Proteins; D002352:Carrier Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism* / Q000502:physiology*; D018797:Cell Cycle Proteins / Q000502:physiology*; D002478:Cells, Cultured; D004249:DNA Damage / Q000528:radiation effects; D004268:DNA-Binding Proteins / Q000502:physiology*; D045325:HCT116 Cells; D006801:Humans; D008954:Models, Biological; D010766:Phosphorylation / Q000528:radiation effects; D011485:Protein Binding; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism* / Q000502:physiology*; D034741:RNA, Small Interfering / Q000494:pharmacology; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism* / Q000528:radiation effects; D025521:Tumor Suppressor Proteins / Q000502:physiology*
D002352:Carrier Proteins; D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D034741:RNA, Small Interfering; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; C115114:HIPK2 protein, human; C576324:ATM protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; D017346:Protein Serine-Threonine Kinases