Acetylation-dependent regulation of Skp2 function.
Acetylation-dependent regulation of Skp2 function.
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DOI：
10.1016/j.cell.2012.05.038
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发表时间：
2012-07-06
期刊：
影响因子：
64.5
通讯作者：
Wei W
中科院分区：
文献类型：
--
作者：
Inuzuka H;Gao D;Finley LW;Yang W;Wan L;Fukushima H;Chin YR;Zhai B;Shaik S;Lau AW;Wang Z;Gygi SP;Nakayama K;Teruya-Feldstein J;Toker A;Haigis MC;Pandolfi PP;Wei W
异常的Skp 2信号转导被认为是肿瘤发生中的驱动事件。尽管潜在的分子机制仍然难以捉摸，但细胞质Skp 2与更具侵袭性的乳腺癌和前列腺癌相关。在这里，我们报告说，Skp 2是乙酰化的p300在K68和K71，这是一个过程，可以拮抗SIRT 3脱乙酰酶。SIRT 3的失活导致Skp 2乙酰化水平升高，这通过损害Cdh 1介导的蛋白水解途径导致Skp 2稳定性增加。结果，Skp 2致癌功能增加，由此表达乙酰化模拟突变体的细胞在体内显示增强的细胞增殖和肿瘤发生。此外，Skp 2在核定位信号（NLS）中的乙酰化促进其胞质滞留，胞质Skp 2通过泛素化和破坏E-cadherin增强细胞迁移。因此，我们的研究确定了乙酰化依赖的调节机制Skp 2致癌功能，并提供了深入了解细胞质Skp 2如何控制细胞迁移。
Aberrant Skp2 signaling has been implicated as a driving event in tumorigenesis. Although the underlying molecular mechanisms remain elusive, cytoplasmic Skp2 correlates with more aggressive forms of breast and prostate cancers. Here, we report that Skp2 is acetylated by p300 at K68 and K71, which is a process that can be antagonized by the SIRT3 deacetylase. Inactivation of SIRT3 leads to elevated Skp2 acetylation, which leads to increased Skp2 stability through impairment of the Cdh1-mediated proteolysis pathway. As a result, Skp2 oncogenic function is increased, whereby cells expressing an acetylation-mimetic mutant display enhanced cellular proliferation and tumorigenesis in vivo. Moreover, acetylation of Skp2 in the nuclear localization signal (NLS) promotes its cytoplasmic retention, and cytoplasmic Skp2 enhances cellular migration through ubiquitination and destruction of E-cadherin. Thus, our study identifies an acetylation-dependent regulatory mechanism governing Skp2 oncogenic function and provides insight into how cytoplasmic Skp2 controls cellular migration.
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