Hofmann Thomas G, Stollberg Nicole, Schmitz M Lienhard, Will Hans
Heinrich-Pette-Institut für Experimentelle Virologie und Immunologie an der Universität Hamburg, Hamburg, Germany.
Cancer Res. 2003 Dec 1;63(23):8271-7.
Homeodomain-interacting protein kinase 2 (HIPK2) is a serine/threonine kinase involved in transcriptional regulation and apoptosis. Here we demonstrate that HIPK2 regulates transforming growth factor (TGF) beta-induced c-Jun NH(2)-terminal kinase (JNK) activation and apoptosis. HIPK2 colocalizes with Daxx, a protein acting in TGF-beta-induced JNK activation and apoptosis, in promyelocytic leukemia (PML) nuclear bodies, and triggers PML-nuclear body disruption and release of Daxx. HIPK2 interacts in vitro and in vivo via its kinase domain with Daxx, and a fraction of Daxx coprecipitates with HIPK2 under physiological conditions. Moreover, overexpression of HIPK2 leads to Daxx phosphorylation, and ectopic expression of HIPK2 activates the JNK signaling pathway, which is enhanced by coexpression of Daxx. HIPK2 signals to JNK via a pathway using Daxx and the mitogen-activated protein kinase kinases MKK4/SEK1 and MKK7. Ectopic expression of HIPK2 and Daxx potentiates TGF-beta-induced apoptosis in human p53-deficient hepatocellular carcinoma cells. Finally, we demonstrate that knockdown of endogenous HIPK2 using RNA interference inhibits TGF-beta-induced JNK activation and apoptosis. Taken together, our findings indicate that HIPK2 participates in the TGF-beta signaling pathway leading to JNK activation and apoptosis.
同源结构域相互作用蛋白激酶2（HIPK2）是一种参与转录调控和细胞凋亡的丝氨酸/苏氨酸激酶。在此我们证明，HIPK2调节转化生长因子（TGF）β诱导的c-Jun氨基末端激酶（JNK）激活及细胞凋亡。HIPK2与Daxx共定位于早幼粒细胞白血病（PML）核体中，Daxx是一种在TGF-β诱导的JNK激活和细胞凋亡中起作用的蛋白质，HIPK2可触发PML核体的破坏及Daxx的释放。HIPK2在体外和体内通过其激酶结构域与Daxx相互作用，并且在生理条件下，一部分Daxx可与HIPK2共沉淀。此外，HIPK2的过表达导致Daxx磷酸化，HIPK2的异位表达激活JNK信号通路，Daxx的共表达可增强该通路。HIPK2通过使用Daxx以及丝裂原活化蛋白激酶激酶MKK4/SEK1和MKK7的途径向JNK发出信号。HIPK2和Daxx的异位表达增强了TGF-β诱导的人p53缺陷型肝癌细胞的凋亡。最后，我们证明使用RNA干扰敲低内源性HIPK2可抑制TGF-β诱导的JNK激活和细胞凋亡。综上所述，我们的研究结果表明，HIPK2参与了导致JNK激活和细胞凋亡的TGF-β信号通路。
