Wang Yang, Zhi Qiaoming, Ye Qin, Zhou Chengyuan, Zhang Lei, Yan Wei, Wu Qun, Zhang Di, Li Pu, Huo Keke
State Key Laboratory of Genetic Engineering, Fudan University, 2005 Songhu Rd, Shanghai 200433, China.
Anticancer Agents Med Chem. 2016;16(4):440-6. doi: 10.2174/1871520615666150518093814.
The cell cycle is regulated via important biological mechanisms. Controlled expression of cell cycle regulatory proteins is crucial to maintain cell cycle progression. However, unbalanced protein expression leads to many diseases, such as cancer. Previous research suggests that SCYL1-BP1 function might be related to cell cycle progression and SCYL1-BP1 dysfunction to diseases through undefined mechanisms. In this research, an unbiased yeast two-hybrid screen was used to find protein(s) with potential biological relevance to SCYL1-BP1 function, and a novel interaction was recognized between SCYL1-BP1 and Cyclin F. This interaction was chosen as a paradigm to study SCYL1-BP1 function in cell cycle progression and its possible role in tumorigenesis. We found that SCYL1-BP1 binds to Cyclin F both in vivo and in vitro. SCYL1-BP1 overexpression promoted expression of the CCNF gene and simultaneously delayed Cyclin F protein degradation. SCYL1-BP1 knockdown reduced the expression of endogenous Cyclin F. It was also demonstrated in functional assays that SCYL1-BP1 overexpression induces G2/M arrest in cultured liver cells. Furthermore, SCYL1-BP1 sustained RRM2 protein expression by reducing its ubiquitination. Thus, we propose that SCYL1- BP1 affects the cell cycle through increasing steady state levels of Cyclin F and RRM2 proteins, thus constituting a dual regulatory circuit. This study provides a possible mechanism for SCYL1-BP1-mediated cell cycle regulation and related diseases.
细胞周期通过重要的生物学机制进行调控。细胞周期调节蛋白的可控表达对于维持细胞周期进程至关重要。然而，蛋白质表达失衡会导致许多疾病，如癌症。先前的研究表明，SCYL1 - BP1的功能可能与细胞周期进程有关，而SCYL1 - BP1功能障碍与疾病的关系机制尚不明确。在本研究中，我们利用无偏向性酵母双杂交筛选来寻找与SCYL1 - BP1功能具有潜在生物学相关性的蛋白质，并发现了SCYL1 - BP1与细胞周期蛋白F之间的一种新的相互作用。我们选择这种相互作用作为范例来研究SCYL1 - BP1在细胞周期进程中的功能及其在肿瘤发生中的可能作用。我们发现SCYL1 - BP1在体内和体外均能与细胞周期蛋白F结合。SCYL1 - BP1的过表达促进了CCNF基因的表达，同时延迟了细胞周期蛋白F的蛋白质降解。敲低SCYL1 - BP1可降低内源性细胞周期蛋白F的表达。功能试验还表明，SCYL1 - BP1的过表达在培养的肝细胞中诱导G2/M期阻滞。此外，SCYL1 - BP1通过减少RRM2的泛素化来维持其蛋白质表达。因此，我们提出SCYL1 - BP1通过增加细胞周期蛋白F和RRM2蛋白的稳态水平来影响细胞周期，从而构成一个双重调节回路。本研究为SCYL1 - BP1介导的细胞周期调控及相关疾病提供了一种可能的机制。
