Hofmann Thomas G, Möller Andreas, Sirma Hüaeyin, Zentgraf Hanswalter, Taya Yoichi, Dröge Wulf, Will Hans, Schmitz M Lienhard
Division of Immunochemistry (G0200) German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69120 Heidelberg, Germany.
Nat Cell Biol. 2002 Jan;4(1):1-10. doi: 10.1038/ncb715.
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.
p53是控制细胞增殖和凋亡的网络中的核心调控开关，其转录活性受蛋白质稳定性以及包括磷酸化和乙酰化在内的翻译后修饰的调节。在此，我们证明人类丝氨酸/苏氨酸激酶同源结构域相互作用蛋白激酶2（HIPK2）在早幼粒细胞白血病（PML）核体中与p53和CREB结合蛋白（CBP）共定位并相互作用。HIPK2被紫外线（UV）辐射激活，并选择性地在Ser 46位点磷酸化p53，从而促进CBP介导的p53在Lys 382位点的乙酰化，并促进p53依赖的基因表达。因此，HIPK2的激酶功能介导了p53靶基因表达的增加，这导致细胞生长停滞并增强UV诱导的细胞凋亡。用反义寡核苷酸干扰HIPK2表达会损害UV诱导的细胞凋亡。我们的结果表明，HIPK2是参与细胞生长、增殖和凋亡的p53效应子功能的新型调节因子。
