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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Skp2 inhibits FOXO1 in tumor suppression through ubiquitin-mediated degradation.
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Skp2 inhibits FOXO1 in tumor suppression through ubiquitin-mediated degradation.

机译：Skp2通过泛素介导的降解抑制FOXO1抑制肿瘤。

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摘要

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.
机译：前叉转录因子FOXO1（FKHR），FOXO3a（FKHRL1）和FOXO4（AFX）通过诱导生长停滞和凋亡而在肿瘤抑制中起关键作用。由于磷酸化和蛋白酶体降解，这些因素的功能丧失与细胞转化和恶性肿瘤有关。然而，尚未表征FOXO因子的泛素化所必需的泛素连接酶以及该调节与肿瘤发生的相关性。在这里，我们证明了Skp1 / Cul1 / F-box蛋白泛素复合物的致癌亚基Skp2与泛素相互作用并促进了FOXO1的降解。 Skp2的这种作用需要在Ser-256处FOXO1的Akt特异性磷酸化。此外，Skp2的表达可抑制FOXO1的反式激活，并消除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，FOXO1蛋白的表达丢失。这些数据表明，Skop2促进的FOXO1蛋白水解在肿瘤发生中起关键作用。

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