Cyclin F drives proliferation through SCF-dependent degradation of the retinoblastoma-like tumor suppressor p130/RBL2

eLife

Seth M Rubin¹  Peter Ngoi¹  Wayne Stallaert²  Taylor P Enrico³  Elizaveta T Wick³  Nicholas G Brown³  Michael J Emanuele³  Xianxi Wang⁴  Jeremy E Purvis⁵ 

[1]Department of Chemistry and Biochemistry. University of California at Santa Cruz, Santa Cruz, United States

[2]Department of Genetics. The University of North Carolina at Chapel Hill, Chapel Hill, United States

[3]Department of Pharmacology. The University of North Carolina at Chapel Hill, Chapel Hill, United States

[4]Lineberger Comprehensive Cancer Center. The University of North Carolina at Chapel Hill, Chapel Hill, United States

[5]Lineberger Comprehensive Cancer Center. The University of North Carolina at Chapel Hill, Chapel Hill, United States

[6]Lineberger Comprehensive Cancer Center. The University of North Carolina at Chapel Hill, Chapel Hill, United States

[7]Department of Genetics. The University of North Carolina at Chapel Hill, Chapel Hill, United States

关键词: ubiquitin;    cell cycle;    retinoblastoma;    SCF;    cyclin F;    RBL2/p130;    Human;   

DOI  :  10.7554/eLife.70691

来源: eLife Sciences Publications, Ltd

【 摘 要 】

Cell cycle gene expression programs fuel proliferation and are universally dysregulated in cancer. The retinoblastoma (RB)-family of proteins, RB1, RBL1/p107, and RBL2/p130, coordinately represses cell cycle gene expression, inhibiting proliferation, and suppressing tumorigenesis. Phosphorylation of RB-family proteins by cyclin-dependent kinases is firmly established. Like phosphorylation, ubiquitination is essential to cell cycle control, and numerous proliferative regulators, tumor suppressors, and oncoproteins are ubiquitinated. However, little is known about the role of ubiquitin signaling in controlling RB-family proteins. A systems genetics analysis of CRISPR/Cas9 screens suggested the potential regulation of the RB-network by cyclin F, a substrate recognition receptor for the SCF family of E3 ligases. We demonstrate that RBL2/p130 is a direct substrate of SCFcyclin F. We map a cyclin F regulatory site to a flexible linker in the p130 pocket domain, and show that this site mediates binding, stability, and ubiquitination. Expression of a mutant version of p130, which cannot be ubiquitinated, severely impaired proliferative capacity and cell cycle progression. Consistently, we observed reduced expression of cell cycle gene transcripts, as well a reduced abundance of cell cycle proteins, analyzed by quantitative, iterative immunofluorescent imaging. These data suggest a key role for SCFcyclin F in the CDK-RB network and raise the possibility that aberrant p130 degradation could dysregulate the cell cycle in human cancers.

【 授权许可】

CC BY