Published March 7, 2022
| Version v1
Dataset
Open
Cyclin F drives proliferation through SCF-dependent degradation of the retinoblastoma-like tumor suppressor p130/RBL2
Creators
- 1. University of North Carolina at Chapel Hill
- 2. University of California, Santa Cruz
Description
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.
Notes
Funding provided by: National Institute of General Medical Sciences
Crossref Funder Registry ID:
Award Number: R01GM120309
Funding provided by: National Institute of General Medical Sciences
Crossref Funder Registry ID:
Award Number: R01GM134231
Funding provided by: National Institute of General Medical Sciences
Crossref Funder Registry ID:
Award Number: R35GM128855
Funding provided by: American Cancer Society
Crossref Funder Registry ID:
Award Number: RSG-18-220-01-TBG
Funding provided by: National Cancer Institute
Crossref Funder Registry ID:
Award Number: R01CA163834
Funding provided by: National Institute of General Medical Sciences
Crossref Funder Registry ID:
Award Number: R01GM127707
Funding provided by: National Institute of General Medical Sciences
Crossref Funder Registry ID:
Award Number: GM138834
Funding provided by: National Institute of General Medical Sciences
Crossref Funder Registry ID:
Award Number: DP2-HD091800
Funding provided by: National Science Foundation
Crossref Funder Registry ID:
Award Number: 1845796
Funding provided by: National Institute of General Medical Sciences
Crossref Funder Registry ID:
Award Number: T32 GM007040
Funding provided by: National Institute of General Medical Sciences
Crossref Funder Registry ID:
Award Number: T32 GM007040
Files
README.txt
Files
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Additional details
Related works
- Is cited by
- 10.7554/elife.70691 (DOI)