Department of Biochemistry and Molecular Genetics, University of Virginia, Charlottesville, VA 22908, USA.
Mol Cell. 2013 Mar 28;49(6):1147-58. doi: 10.1016/j.molcel.2013.02.003. Epub 2013 Mar 7.
The Cul4-Cdt2 (CRL4(Cdt2)) E3 ubiquitin ligase is a master regulator of cell-cycle progression and genome stability. Despite its central role in the degradation of many cell-cycle regulators, e.g., Cdt1, p21, and Pr-Set7/Set8, little is known about the regulation of its activity. We report that Cdt2 is autoubiquitylated by the CRL4A E3 ubiquitin ligase. Cdt2 is additionally polyubiquitylated and degraded by Cul1-FBXO11 (CRL1(FBXO11)). CRL1(FBXO11)-mediated degradation of Cdt2 stabilizes p21 and Set8, and this is important during the response to TGF-β, with the Set8 induction being important for turning off the activation of Smad2. The migration of epithelial cells is also stimulated by CRL1(FBXO11)-mediated downregulation of Cdt2 and the consequent stabilization of Set8. This is an interesting example of cross-regulation between specific Cullin 4 and Cullin 1 E3 ubiquitin ligases and highlights the role of ubiquitylation in regulating cellular responses to TGF-β and the migration of epithelial cells.
Cul4-Cdt2 (CRL4(Cdt2)) E3 泛素连接酶是细胞周期进程和基因组稳定性的主要调节剂。尽管它在降解许多细胞周期调节剂（如 Cdt1、p21 和 Pr-Set7/Set8）方面发挥着核心作用，但对于其活性的调节却知之甚少。我们报告 Cdt2 可被 CRL4A E3 泛素连接酶自身泛素化。Cdt2 还可被 Cul1-FBXO11 (CRL1(FBXO11)) 多泛素化和降解。CRL1(FBXO11)介导的 Cdt2 降解稳定了 p21 和 Set8，这在 TGF-β 反应中很重要，Set8 的诱导对于关闭 Smad2 的激活很重要。上皮细胞的迁移也受到 CRL1(FBXO11)下调 Cdt2 和随后稳定 Set8 的刺激。这是特定 Cullin 4 和 Cullin 1 E3 泛素连接酶之间交叉调节的一个有趣例子，突出了泛素化在调节细胞对 TGF-β 的反应和上皮细胞迁移中的作用。
