Weng Wenjie, Zhang Baozhen, Deng Dajun
Key Laboratory of Carcinogenesis and Translational Research (MOE/Beijing) Division of Etiology, Peking University Cancer Hospital and Institute, Beijing 100142, China.
iScience. 2024 Sep 3;27(10):110882. doi: 10.1016/j.isci.2024.110882. eCollection 2024 Oct 18.
P16 expression is inversely associated with RB1 expression in cancer cells, and P16 inhibits CDK4-catalyzed RB1 phosphorylation. How P16 and RB1 coordinately express and regulate the cell cycle remains to be studied. In the present study, we found that P16 upregulated the E3 ligase UTP14A, which led to the ubiquitination of RB1 at K810 and RB1 degradation. P16 loss consistently disrupted the UTP14A-mediated degradation of RB1 and caused RB1 accumulation. Functionally, P16 loss inhibited RB1 ubiquitination in a cell cycle progression-independent fashion and inhibited proteome-scale ubiquitination in a cell cycle progression-dependent manner. Our findings indicate that there is a negative feedback loop between P16 and RB1 expression and that disruption of this loop may partially rescue the biological outcomes of P16 loss. We also revealed a hitherto unknown function for in regulating proteome-scale ubiquitination by inhibiting cell proliferation, which may be useful for the development of anticancer drugs.
P16表达与癌细胞中RB1表达呈负相关，且P16抑制CDK4催化的RB1磷酸化。P16和RB1如何协同表达并调控细胞周期仍有待研究。在本研究中，我们发现P16上调E3连接酶UTP14A，这导致RB1在K810位点发生泛素化及RB1降解。P16缺失持续破坏UTP14A介导的RB1降解并导致RB1积累。在功能上，P16缺失以不依赖细胞周期进程的方式抑制RB1泛素化，并以依赖细胞周期进程的方式抑制蛋白质组规模的泛素化。我们的研究结果表明，P16和RB1表达之间存在负反馈环，且该环的破坏可能部分挽救P16缺失的生物学后果。我们还揭示了UTP14A在通过抑制细胞增殖来调控蛋白质组规模泛素化方面的一个前所未知的功能，这可能对抗癌药物的开发有用。
