Identification of acetylation-dependent regulatory mechanisms that govern the oncogenic functions of Skp2.
Identification of acetylation-dependent regulatory mechanisms that govern the oncogenic functions of Skp2.
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DOI：
10.18632/oncotarget.740
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发表时间：
2012-11
期刊：
影响因子：
--
通讯作者：
Wei W
中科院分区：
文献类型：
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作者：
Wang Z;Inuzuka H;Zhong J;Liu P;Sarkar FH;Sun Y;Wei W
Skp2(S相蛋白相关蛋白2)癌基因蛋白在人类各种类型的肿瘤中都有高表达。然而，其致癌作用的机制基础以及控制Skp2活性的上游调控途径(S)仍不完全清楚。最近，我们报道了p300乙酰化Skp2在其核定位信号中的两个保守的赖氨酸残基K68和K71处。这种修饰导致Skp2稳定性和细胞质易位的增加，从而导致Skp2致癌潜能的提高。此外，我们还发现SIRT3抑癌基因是一种生理性脱乙酰酶，可以拮抗p300介导的Skp2乙酰化。此外，我们还发现Skp2调控E-钙粘素在胞浆中的泛素化和降解。与此一致，我们观察到临床乳腺肿瘤标本中Skp2和E-cadherin的表达呈负相关。因此，我们的工作阐明了Skp2癌基因功能的一种新的乙酰化依赖的调控机制。
The Skp2 (S-phase kinase associated protein 2) oncoprotein is often highly expressed in various types of human cancers. However, the mechanistic basis of its oncogenic function, as well as the upstream regulatory pathway(s) that control Skp2 activities remains not fully understood. Recently, we reported that p300 acetylates Skp2 at two conserved lysine residues K68 and K71 within its NLS (Nuclear localization signal). This modification leads to increased Skp2 stability and cytoplasmic translocation, thus contributing to elevated Skp2 oncogenic potential. Moreover, we found that the SIRT3 tumor suppressor serves as the physiological deacetylase that antagonizes p300-mediated Skp2 acetylation. Furthermore, we showed that Skp2 governs E-cadherin ubiquitination and degradation in the cytosol. Consistent with this, we observed an inverse correlation between Skp2 and E-cadherin expression in clinical breast tumor samples. Therefore, our work elucidates a novel acetylation-dependent regulatory mechanism for Skp2 oncogenic functions.