Degradation of Tob1 mediated by SCF Skp2-dependent ubiquitination
Degradation of Tob1 mediated by SCF Skp2-dependent ubiquitination
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DOI：
10.1158/0008-5472.can-06-1603
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发表时间：
2006-09-01
期刊：
影响因子：
11.2
通讯作者：
Kitagawa, Masatoshi
中科院分区：
文献类型：
--
作者：
Hiramatsu, Yoshihiro;Kitagawa, Kyoko;Kitagawa, Masatoshi
to1是Tob/BTG家族的成员，通过抑制cyclin D1的表达参与G(I)-S进展的控制，并作为肿瘤抑制基因。据报道，to1通过泛素-蛋白酶体途径进行快速周转，但参与该过程的蛋白质尚不清楚。我们发现Skp2，一个SCF （Skp1/Cul1/F-box蛋白）泛素连接酶复合物的底物靶向亚基，参与了to1的泛素依赖性降解。Skp2与Tob1相互作用，促进了Tob1在完整细胞和体外的泛素化。没有F-box或富含亮氨酸重复序列的Skp2突变体不能与Tob1结合，也不能增强Tob1的泛素化。在Skp2（-/-）小鼠成纤维细胞和Skp2敲低的HeLa细胞中，Tob1都是稳定的。此外，Skp2敲低的HeLa细胞中cyclin D1的表达受到抑制。这些数据表明，to1是SCF-Skp2泛素连接酶降解的新靶标。
Tob1, a member of the Tob/BTG family, is involved in the control of G(I)-S progression by suppressing cyclin D1 expression and acts as a tumor suppressor gene. Tob1 was reported to have a quick turnover through the ubiquitin-proteasome pathway, but proteins involved in this process are still unknown. We showed that Skp2, a substrate-targeting subunit of the SCF (Skp1/Cul1/F-box protein) ubiquitin ligase complex, was involved in ubiquitin-dependent degradation of Tob1. Skp2 interacted with Tob1 and facilitated ubiquitination of Tob1 in intact cells as well as in vitro. Skp2 mutants without the F-box or leucine rich repeat were not able to bind to Tob1 and did not enhance ubiquitination of Tob1. Tob1 was stabilized in both Skp2(-/-) mouse fibroblasts and Skp2 knockdown HeLa cells. Moreover, cyclin D1 expression was suppressed in Skp2 knockdown HeLa cells. These data suggest that Tob1 is a novel target for degradation by the SCF-Skp2 ubiquitin ligase.