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Nature Cell Biology 4, 1–10 (1 January 2002) | doi:10.1038/ncb715

Regulation of p53 activity by its interaction with homeodomain-interacting protein kinase-2

Thomas G. Hofmann , Andreas M|[ouml]|ller , H|[uuml]|seyin Sirma , Hanswalter Zentgraf , Yoichi Taya , Wulf Dr|[ouml]|ge , Hans Will & M. Lienhard Schmitz

Transcriptional activity of p53, a central regulatory switch in a network controlling cell proliferation and apoptosis, is modulated by protein stability and post-translational modifications including phosphorylation and acetylation. Here we demonstrate that the human serine/threonine kinase homeodomain-interacting protein kinase-2 (HIPK2) colocalizes and interacts with p53 and CREB-binding protein (CBP) within promyelocytic leukaemia (PML) nuclear bodies. HIPK2 is activated by ultraviolet (UV) radiation and selectively phosphorylates p53 at Ser 46, thus facilitating the CBP-mediated acetylation of p53 at Lys 382, and promoting p53-dependent gene expression. Accordingly, the kinase function of HIPK2 mediates the increased expression of p53 target genes, which results in growth arrest and the enhancement of UV-induced apoptosis. Interference with HIPK2 expression by antisense oligonucleotides impairs UV-induced apoptosis. Our results imply that HIPK2 is a novel regulator of p53 effector functions involved in cell growth, proliferation and apoptosis.