Homeodomain-interacting protein kinase-2 activity and p53 phosphorylation are critical events for cisplatin-mediated apoptosis.

HIPK2 is a member of a novel family of nuclear serine-threonine kinases identified through their ability to interact with the Nkx-1.2 homeoprotein. The physiological role of these kinases is largely unknown, but we have recently reported on the involvement of HIPK2 in the induction of apoptosis of tumor cells after UV stress through p53 phosphorylation and transcriptional activation. Here, we demonstrate that the chemotherapeutic drug cisplatin increases HIPK2 protein expression and its kinase activity, and that HIPK2 is involved in cisplatin-dependent apoptosis. Indeed, induction of HIPK2 and of cell death by cisplatin are efficiently inhibited by the serine-threonine kinase inhibitor SB203580 or the transduction of HIPK2-specific RNA-interfering molecules. HIPK2 gene silencing efficiently reduces the p53-mediated transcriptional activation of apoptotic gene promoters as well as apoptotic cell death after treatment with cisplatin. These findings, along with the involvement of p53 phosphorylation at serine 46 (Ser46) in the transcriptional activation of apoptotic gene promoters, suggest a critical role for HIPK2 in triggering p53-dependent apoptosis in response to the antineoplastic drug cisplatin.