Skp2 inhibits FOX01 in tumor suppression through ubiquitin-mediated degradation
Skp2 inhibits FOX01 in tumor suppression through ubiquitin-mediated degradation
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DOI：
10.1073/pnas.0406789102
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发表时间：
2005-02-01
影响因子：
11.1
通讯作者：
Tindall, DJ
中科院分区：
文献类型：
--
作者：
Huang, H;Regan, KM;Tindall, DJ
叉头转录因子FOXO1 （FKHR）、FOXO3a （FKHRL1）和FOXO4 （AFX）通过诱导生长阻滞和细胞凋亡在肿瘤抑制中发挥关键作用。由于磷酸化和蛋白酶体降解，这些因子的功能丧失与细胞转化和恶性肿瘤有关。然而，FOXO因子泛素化所必需的泛素连接酶以及这种调节与肿瘤发生的相关性尚未被表征。我们发现Skp2是Skp1/Cul1/F-box蛋白泛素复合物的一个致癌亚基，与fox01相互作用，泛素化，并促进fox01的降解。Skp2的这种作用需要akt特异性磷酸化fox01的Ser-256位点。此外，Skp2的表达抑制FOXO1的反激活，消除FOXO1对细胞增殖和存活的抑制作用。此外，在Skp2过表达的小鼠淋巴瘤模型中，fox01蛋白的表达缺失。这些数据表明skp2促进的fox01蛋白水解在肿瘤发生中起关键作用。
Forkhead transcription factors FOXO1 (FKHR), FOXO3a (FKHRL1), and FOXO4 (AFX) play a pivotal role in tumor suppression by inducing growth arrest and apoptosis. Loss of function of these factors due to phosphorylation and proteasomal degradation has been implicated in cell transformation and malignancy. However, the ubiquitin ligase necessary for the ubiquitination of the FOXO factors and the relevance of this regulation to tumorigenesis have not been characterized. Here we demonstrate that Skp2, an oncogenic subunit of the Skp1/Cul1/F-box protein ubiquitin complex, interacts with, ubiquitinates, and promotes the degradation of FOXO1. This effect of Skp2 requires Akt-specific phosphorylation of FOXO1 at Ser-256. Moreover, expression of Skp2 inhibits transactivation of FOXO1 and abolishes the inhibitory effect of FOXO1 on cell proliferation and survival. Furthermore, expression of the FOXO1 protein is lost in a mouse lymphoma model, where Skp2 is overexpressed. These data suggest that the Skp2-promoted proteolysis of FOXO1 plays a key role in tumorigenesis.