Bellail Anita C, Olson Jeffrey J, Hao Chunhai
Department of Neurology and Neurosurgery, Montreal Neurological Institute and Hospital, McGill University, 3801 University Street, Montreal, Quebec, Canada H3A 2B4.
Department of Neurosurgery, Emory University School of Medicine, 1365B Clifton Road, Atlanta, Georgia 30322, USA.
Nat Commun. 2014 Jun 23;5:4234. doi: 10.1038/ncomms5234.
Ubiquitination governs oscillation of cyclin-dependent kinase (CDK) activity through a periodic degradation of cyclins for orderly cell cycle progression; however, the mechanism that maintains the constant CDK protein levels throughout the cell cycle remains unclear. Here we show that CDK6 is modified by small ubiquitin-like modifier-1 (SUMO1) in glioblastoma, and that CDK6 SUMOylation stabilizes the protein and drives the cell cycle for the cancer development and progression. CDK6 is also a substrate of ubiquitin; however, CDK6 SUMOylation at Lys 216 blocks its ubiquitination at Lys 147 and inhibits the ubiquitin-mediated CDK6 degradation. Throughout the cell cycle, CDK1 phosphorylates the SUMO-specific enzyme, ubiquitin-conjugating enzyme9 (UBC9) that in turn mediates CDK6 SUMOylation during mitosis; CDK6 remains SUMOylated in G1 phase and drives the cell cycle through G1/S transition. Thus, SUMO1-CDK6 conjugation constitutes a mechanism of cell cycle control and inhibition of this SUMOylation pathway may provide a strategy for treatment of glioblastoma.
泛素化通过细胞周期蛋白的周期性降解来调控细胞周期蛋白依赖性激酶（CDK）的活性，以实现细胞周期的有序进行；然而，在整个细胞周期中维持CDK蛋白水平恒定的机制仍不清楚。在此，我们表明在胶质母细胞瘤中，CDK6被小泛素样修饰物1（SUMO1）修饰，并且CDK6的SUMO化修饰可使该蛋白稳定，并驱动细胞周期促进癌症的发生和发展。CDK6也是泛素的底物；然而，赖氨酸216处的CDK6 SUMO化修饰会阻断其赖氨酸147处的泛素化修饰，并抑制泛素介导的CDK6降解。在整个细胞周期中，CDK1磷酸化SUMO特异性酶——泛素结合酶9（UBC9），而UBC9又在有丝分裂期间介导CDK6的SUMO化修饰；CDK6在G1期保持SUMO化修饰状态，并驱动细胞周期通过G1/S期转换。因此，SUMO1-CDK6偶联构成了一种细胞周期调控机制，抑制这种SUMO化修饰途径可能为胶质母细胞瘤的治疗提供一种策略。
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