Transforming growth factor-β suppresses the ability of ski to inhibit tumor metastasis by inducing its degradation
Transforming growth factor-β suppresses the ability of ski to inhibit tumor metastasis by inducing its degradation
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DOI：
10.1158/0008-5472.can-07-6793
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发表时间：
2008-05-01
期刊：
影响因子：
11.2
通讯作者：
Luo, Kunxin
中科院分区：
文献类型：
--
作者：
Le Scolan, Erwan;Zhu, Qingwei;Luo, Kunxin
c-Ski是转化生长因子-β（TGF-β）信号传导的重要辅阻遏物，通过其结合并抑制Smad蛋白的活性的能力。它最初被鉴定为一种癌基因，当过度表达时，它促进鸡和鹌鹑胚胎成纤维细胞的锚定非依赖性生长。虽然在许多人类癌细胞中检测到Ski表达增加，但Ski在哺乳动物致癌作用中的作用尚未确定。在这里，我们报告说，减少乳腺癌和肺癌细胞中的Ski表达不会影响肿瘤生长，但会增强体内肿瘤转移。因此，在这些细胞中，Ski起着抗肿瘤作用。我们还发现，TGF-β，一种在转移性肿瘤中经常高度表达的细胞因子，在恶性人类癌细胞中通过泛素依赖性蛋白酶体诱导Ski降解。在TGF-β处理时，E3泛素连接酶Arkadia以Smad依赖性方式介导Ski的降解。尽管Arkadia在不存在TGF-β的情况下与Ski相互作用，但需要磷酸化Smad 2或Smad 3与Ski的结合来诱导Arkadia对Ski的有效降解。我们的研究结果表明，TGF-β诱导Ski降解的能力可能是其促肿瘤活性的另一种机制。
c-Ski is an important corepressor of transforming growth factor-beta (TGF-beta) signaling through its ability to bind to and repress the activity of the Smad proteins. It was initially identified as an oncogene that promotes anchorage-independent growth of chicken and quail embryo fibroblasts when over-expressed. Although increased Ski expression is detected in many human cancer cells, the roles of Ski in mammalian carcinogenesis have yet to be defined. Here, we report that reducing Ski expression in breast and lung cancer cells does not affect tumor growth but enhances tumor metastasis in vivo. Thus, in these cells, Ski plays an antitumorigenic role. We also showed that TGF-beta, acytokine that is often highly expressed in metastatic tumors, induces Ski degradation through the ubiquitin-dependent proteasome in malignant human cancer cells. On TGF-beta treatment, the E3 ubiquitin ligase Arkadia mediates degradation of Ski in a Smad-dependent manner. Although Arkadia interacts with Ski in the absence of TGF-beta, binding of phosphorylated Smad2 or Smad3 to Ski is required to induce efficient degradation of Ski by Arkadia. Our results suggest that the ability of TGF-beta to induce degradation of Ski could be an additional mechanism contributing to its protumorigenic activity.