Hedgehog signaling promotes the degradation of tumor suppressor Sufu through the ubiquitin-proteasome pathway
Hedgehog signaling promotes the degradation of tumor suppressor Sufu through the ubiquitin-proteasome pathway
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Hedgehog信号通过泛素-蛋白酶体途径促进肿瘤抑制因子Sufu的降解
DOI：
10.1038/onc.2008.403
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发表时间：
2009-01-29
期刊：
影响因子：
8
通讯作者：
Cheng, S. Y.
中科院分区：
文献类型：
--
作者：
Yue, S.;Chen, Y.;Cheng, S. Y.
持续的声刺猬 (Shh) 通路活性与多种组织中的肿瘤发生有关。 Shh 受体 Patched (Ptch) 和下游基因 Suppressor of fused (Sufu) 的突变失活，两者都是该通路的负调节因子，会增加人类和小鼠患小脑癌的易感性。 Sufu 是 Shh 通路转录因子 Gli 的结合伴侣。最近的数据表明，Sufu 的失活可以通过小鼠体内的基因靶向或培养物中 RNAi 介导的沉默来实现。成纤维细胞，足以开启 Shh 靶基因表达。在这里，我们报告 Sufu 在某些癌细胞中快速降解，并且我们发现 Shh 信号传导促进 Sufu 泛素化，从而导致其在蛋白酶体中被破坏。我们在 Sufu 的 K257 上发现了一个泛素附着位点，并表明 Sufu-K257R 突变体由于稳定性增加，作为转录抑制子和细胞生长抑制剂更有效。这些结果表明，Shh 信号传导通过泛素-蛋白酶体系统诱导 Sufu 的更新来调节 Sufu 活性。
Sustained Sonic hedgehog (Shh) pathway activity is associated with tumorigenesis in a wide variety of tissues. Mutational inactivation of Shh receptor Patched (Ptch) and a downstream gene Suppressor of fused (Sufu), both of which are negative regulators of the pathway, increases susceptibility to cerebellum cancer in humans and mice. Sufu is a binding partner of Shh pathway transcription factor Gli. Recent data indicate that inactivation of Sufu, through either gene targeting in mice or RNAi-mediated silencing in cultured. broblasts, is sufficient to turn on Shh target gene expression. Here, we report that Sufu is degraded rapidly in certain cancer cells and we show that Shh signaling promotes ubiquitination of Sufu, which leads to its destruction in the proteasomes. We identified an ubiquitin attachment site on K257 of Sufu, and showed that Sufu-K257R mutant is more potent as a transcription repressor and cell growth inhibitor because of increased stability. These results indicate that Shh signaling regulates Sufu activity by inducing its turnover via the ubiquitin-proteasome system.