Research Center on Aging, Department of Biochemistry and Molecular Biology, Peking University, Health Science Center, Beijing 100191, China.
J Biol Chem. 2011 Sep 23;286(38):33447-56. doi: 10.1074/jbc.M111.225565. Epub 2011 Jul 27.
WW domain-containing E3 ubiquitin protein ligase 1 (WWP1) plays an important role in the proliferation of tumor cells and the lifespan of Caenorhabditis elegans. However, the role of WWP1 in cellular senescence is still unknown. Here, we show that the expression patterns of p27(Kip1) and WWP1 are inversely correlated during cellular senescence. Moreover, the overexpression of WWP1 delayed senescence, whereas the knockdown of WWP1 led to premature senescence in human fibroblasts. Furthermore, we demonstrate that WWP1 repressed endogenous p27(Kip1) expression through ubiquitin-proteasome-mediated degradation. Additionally, WWP1 had a strong preference for catalyzing the Lys-48-linked polyubiquitination of p27(Kip1) in vitro. Finally, we demonstrate that WWP1 markedly inhibited the replicative senescence induced by p27(Kip1) by promoting p27(Kip1) degradation. Therefore, our study provides a new molecular mechanism for the regulation of cellular senescence.
WW 结构域包含 E3 泛素蛋白连接酶 1（WWP1）在肿瘤细胞的增殖和秀丽隐杆线虫的寿命中发挥着重要作用。然而，WWP1 在细胞衰老中的作用尚不清楚。在这里，我们显示在细胞衰老过程中 p27(Kip1) 和 WWP1 的表达模式呈负相关。此外，WWP1 的过表达延迟了衰老，而 WWP1 的敲低则导致人成纤维细胞过早衰老。此外，我们证明 WWP1 通过泛素蛋白酶体介导的降解来抑制内源性 p27(Kip1) 的表达。此外，WWP1 体外强烈偏好催化 p27(Kip1) 的 Lys-48 连接多泛素化。最后，我们证明 WWP1 通过促进 p27(Kip1) 的降解显著抑制了由 p27(Kip1) 诱导的复制性衰老。因此，我们的研究为细胞衰老的调控提供了一个新的分子机制。
