García-Vázquez Nelson, González-Robles Tania J, Lane Ethan, Spasskaya Daria, Zhang Qingyue, Kerzhnerman Marc A, Jeong YeonTae, Collu Marta, Simoneschi Daniele, Ruggles Kelly V, Róna Gergely, Kaisari Sharon, Pagano Michele
Department of Biochemistry and Molecular Pharmacology, New York University Grossman School of Medicine, New York, United States.
Department of Medicine, New York University Grossman School of Medicine, New York, United States.
Elife. 2025 Apr 24;13:RP101075. doi: 10.7554/eLife.101075.
In healthy cells, cyclin D1 is expressed during the G1 phase of the cell cycle, where it activates CDK4 and CDK6. Its dysregulation is a well-established oncogenic driver in numerous human cancers. The cancer-related function of cyclin D1 has been primarily studied by focusing on the phosphorylation of the retinoblastoma (RB) gene product. Here, using an integrative approach combining bioinformatic analyses and biochemical experiments, we show that GTSE1 (G-Two and S phases expressed protein 1), a protein positively regulating cell cycle progression, is a previously unrecognized substrate of cyclin D1-CDK4/6 in tumor cells overexpressing cyclin D1 during G1 and subsequent phases. The phosphorylation of GTSE1 mediated by cyclin D1-CDK4/6 inhibits GTSE1 degradation, leading to high levels of GTSE1 across all cell cycle phases. Functionally, the phosphorylation of GTSE1 promotes cellular proliferation and is associated with poor prognosis within a pan-cancer cohort. Our findings provide insights into cyclin D1's role in cell cycle control and oncogenesis beyond RB phosphorylation.
在健康细胞中，细胞周期蛋白D1在细胞周期的G1期表达，在该阶段它激活细胞周期蛋白依赖性激酶4（CDK4）和细胞周期蛋白依赖性激酶6（CDK6）。其失调是众多人类癌症中公认的致癌驱动因素。细胞周期蛋白D1的癌症相关功能主要通过关注视网膜母细胞瘤（RB）基因产物的磷酸化来研究。在这里，我们采用生物信息学分析和生化实验相结合的综合方法，表明GTSE1（G2和S期表达蛋白1）是一种正向调节细胞周期进程的蛋白质，在G1期及后续阶段过表达细胞周期蛋白D1的肿瘤细胞中，它是细胞周期蛋白D1 - CDK4/6之前未被识别的底物。细胞周期蛋白D1 - CDK4/6介导的GTSE1磷酸化抑制GTSE1降解，导致在所有细胞周期阶段GTSE1水平都很高。在功能上，GTSE1的磷酸化促进细胞增殖，并与泛癌队列中的不良预后相关。我们的研究结果为细胞周期蛋白D1在细胞周期调控和肿瘤发生中的作用提供了见解，其作用超出了RB磷酸化。
