SUMOylation of Rb enhances its binding with CDK2 and phosphorylation at early G1 phase.
SUMOylation of Rb enhances its binding with CDK2 and phosphorylation at early G1 phase.
复制标题
DOI：
10.1080/15384101.2016.1182267
复制
发表时间：
2016-07-02
期刊：
影响因子：
--
通讯作者：
Xue K
中科院分区：
文献类型：
--
作者：
Meng F;Qian J;Yue H;Li X;Xue K
视网膜母细胞瘤蛋白（Retinoblastoma protein, Rb）是一种典型的肿瘤抑制因子，对细胞周期和肿瘤进展的负调控至关重要。低磷酸化Rb通过抑制E2F转录因子活性与G0/G1阻滞有关，而Rb超磷酸化允许E2F释放和细胞周期从G0/G1期进展到S期。然而，在细胞周期中调控周期蛋白依赖性蛋白激酶（CDK）依赖性Rb超磷酸化的因素仍然不清楚。在这项研究中，我们发现在整个细胞周期中，Rb是特异性的小泛素样修饰因子（SUMO），在G1期早期被酰化。Rb的sumo化通过募集含有sumo相互作用基序（SIM）的激酶CDK2刺激其磷酸化水平，导致Rb超磷酸化和E2F-1释放。相反，sumo缺失的Rb突变体导致sumo化和磷酸化减少，CDK2结合减弱，E2F-1封存减弱。此外，我们发现Rb SUMOylation是细胞增殖所必需的。因此，我们的研究描述了一种在细胞周期进程中调控Rb磷酸化的新机制。
Retinoblastoma protein (Rb) is a prototypical tumor suppressor that is vital to the negative regulation of the cell cycle and tumor progression. Hypo-phosphorylated Rb is associated with G0/G1 arrest by suppressing E2F transcription factor activity, whereas Rb hyper-phosphorylation allows E2F release and cell cycle progression from G0/G1 to S phase. However, the factors that regulate cyclin-dependent protein kinase (CDK)-dependent hyper-phosphorylation of Rb during the cell cycle remain obscure. In this study, we show that throughout the cell cycle, Rb is specifically small ubiquitin-like modifier (SUMO)ylated at early G1 phase. SUMOylation of Rb stimulates its phosphorylation level by recruiting a SUMO-interaction motif (SIM)-containing kinase CDK2, leading to Rb hyper-phosphorylation and E2F-1 release. In contrast, a SUMO-deficient Rb mutant results in reduced SUMOylation and phosphorylation, weakened CDK2 binding, and attenuated E2F-1 sequestration. Furthermore, we reveal that Rb SUMOylation is required for cell proliferation. Therefore, our study describes a novel mechanism that regulates Rb phosphorylation during cell cycle progression.