Requirement of the co-repressor homeodomain-interacting protein kinase 2 for Ski-mediated inhibition of bone morphogenetic protein-induced transcriptional activation
Requirement of the co-repressor homeodomain-interacting protein kinase 2 for Ski-mediated inhibition of bone morphogenetic protein-induced transcriptional activation
复制标题
DOI：
10.1074/jbc.m307112200
复制
发表时间：
2003-10-03
影响因子：
4.8
通讯作者：
Ishii, S
中科院分区：
文献类型：
--
作者：
Harada, J;Kokura, K;Ishii, S
多种共阻遏物如N-CoR/SMRT、mSin 3和c-ski原癌基因产物（c-Ski）通过募集组蛋白脱乙酰酶复合物介导由Mad和甲状腺激素受体诱导的转录阻遏。c-Ski还直接与Smad蛋白结合，Smad蛋白是转化生长因子-β（TGF-β）/骨形态发生蛋白（BMP）信号通路中的转录激活因子，并抑制TGF-β/BMP诱导的转录激活。然而，仍不清楚其他共阻遏物是否也与Ski一起参与TGF-β/BMP信号传导途径的负调控。在这里，我们报告说，共阻遏同源域相互作用蛋白激酶2（HIPK 2）直接结合到c-Ski和Smad 1。HIPK 2有效地抑制了Smad 1/4诱导的含Smad位点启动子的转录。HIPK 2的显性负性形式，其中激酶结构域中的ATP结合基序和推定的磷酸化位点发生突变，增强了Smad 1/4依赖的转录和BMP诱导的碱性磷酸酶表达。此外，C-Ski诱导的Smad 1/4依赖性转录抑制被HIPK 2的显性负性形式抑制。HIPK 2共阻遏物活性可由未表征的HIPK 2激酶调节。这些结果表明HIPK 2与c-Ski一起在BMP诱导的转录激活的负调控中起重要作用。
Multiple co-repressors such as N-CoR/SMRT, mSin3, and the c-ski proto-oncogene product (c-Ski) mediate the transcriptional repression induced by Mad and the thyroid hormone receptor by recruiting the histone deacetylase complex. c-Ski also binds directly to Smad proteins, which are transcriptional activators in the transforming growth factor-beta (TGF-beta)/bone morphogenetic protein (BMP) signaling pathways, and inhibits TGF-beta/BMP-induced transcriptional activation. However, it remains unknown whether other co-repressor(s) are also involved with Ski in the negative regulation of the TGF-beta/BMP signaling pathways. Here, we report that the co-repressor homeodomain-interacting protein kinase 2 (HIPK2) directly binds to both c-Ski and Smad1. HIPK2 efficiently inhibited Smad1/4-induced transcription from the Smad site-containing promoter. A dominant negative form of HIPK2, in which the ATP binding motif in the kinase domain and the putative phosphorylation sites were mutated, enhanced Smad1/4-dependent transcription and the BMP-induced expression of alkaline phosphatase. Furthermore, the c-Ski-induced inhibition of the Smad1/4-dependent transcription was suppressed by a dominant negative form of HIPK2. The HIPK2 co-repressor activity may be regulated by an un-characterized HIPK2 kinase. These results indicate that HIPK2, together with c-Ski, plays an important role in the negative regulation of BMP-induced transcriptional activation.