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Homeodomain-Interacting Protein Kinase 2 Is the Ionizing Radiation–Activated p53 Serine 46 Kinase and Is Regulated by ATM

¹ Research Group Cellular Senescence, German Cancer Research Center, Heidelberg, Germany and ² Heinrich-Pette-Institut for Experimental Virology and Immunology, Hamburg, Germany

Requests for reprints: Thomas G. Hofmann, Research Group Cellular Senescence, German Cancer Research Center, Im Neuenheimer Feld 242, 69120 Heidelberg, Germany. Phone: 49-6221-424631; Fax: 49-6221-424902; E-mail: t.hofmann{at}dkfz.de.

Phosphorylation of p53 at Ser⁴⁶ is important to activate the apoptotic program. The protein kinase that phosphorylates p53 Ser⁴⁶ 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 Ser⁴⁶ phosphorylation. Down-regulation of HIPK2 by RNA interference specifically inhibits IR-induced phosphorylation of p53 at Ser⁴⁶. 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 Ser⁴⁶ kinase and is regulated by ATM. [Cancer Res 2007;67(5):2274–9]

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