c-Ski inhibits the TGF-β signaling pathway through stabilization of inactive Smad complexes on Smad-binding elements
c-Ski inhibits the TGF-β signaling pathway through stabilization of inactive Smad complexes on Smad-binding elements
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DOI：
10.1038/sj.onc.1207690
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发表时间：
2004-06-24
期刊：
影响因子：
8
通讯作者：
Miyazawa, K
中科院分区：
文献类型：
--
作者：
Suzuki, H;Yagi, K;Miyazawa, K
C-Ski通过与Smad蛋白相互作用抑制转化生长因子-β信号转导。C-Ski抑制Smad介导的转录激活，可能是通过其作为转录共抑制因子发挥作用的。C-Ski还能抑制转化生长因子-β诱导的c-myc等基因的下调。然而，c-Ski对靶基因转录调控的机制尚未完全确定。在这项研究中，我们研究了c-Ski如何抑制转化生长因子-β诱导的转录激活和抑制。DNA亲和沉淀分析表明，c-Ski增强了Smad2和Smad4的结合，并在较小程度上增强了Smad3与cagA和转化生长因子-β1抑制元件探针的结合。一个不能与Smad4相互作用的c-Ski突变体不能增强Smad复合体与这些探针的结合，也不能抑制Smad反应启动子。这些结果表明，失活的Smad复合体在DNA上的稳定是c-Ski介导的抑制转化生长因子-β信号转导的关键事件。
c-Ski inhibits transforming growth factor-beta (TGF-beta) signaling through interaction with Smad proteins. c-Ski represses Smad-mediated transcriptional activation, probably through its action as a transcriptional co-repressor. c-Ski also inhibits TGF-beta-induced downregulation of genes such as c-myc. How ever, mechanisms for transcriptional regulation of target genes by c-Ski have not been fully determined. In this study, we examined how c-Ski inhibits both TGF-beta-induced transcriptional activation and repression. DNA-affinity precipitation analysis revealed that c-Ski enhances the binding of Smad2 and 4, and to a lesser extent Smad3, to both CAGA and TGF-beta1 inhibitory element probes. A c-Ski mutant, which is unable to interact with Smad4, failed to enhance the binding of Smad complex on these probes and to inhibit the Smad-responsive promoter. These results suggest that stabilization of inactive Smad complexes on DNA is a critical event in c-Ski-mediated inhibition of TGF-beta signaling.