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Congratulations to Taylor Enrico on publishing a first author paper in eLIfe describing non-canonical control mechanism for the Retinoblastoma tumor suppressor family!

Taylor Enrico

Taylor Enrico, a graduate student in the Emanuele Lab and this year’s co-recipient of the departmental Butler Award, published a first author paper in eLife describing a non-canonical control mechanism for the Retinoblastoma tumor suppressor family. This work suggests new and unforeseen mechanisms of proliferative control that are likely to be highly significant in the context of cancer. She was joined in this work by collaborators in Nick Brown’s Lab (UNC Pharmacology), Jeremy Purvis’s lab (UNC Genetics) and Seth Rubin’s lab (UCSC). 


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. (~excerpt from the eLife article)