This work was supported by the National Institutes of Health (R01 DK051496; sub award to J.D.S.).
Journal of Cell Science
Ubiquitin, Protein binding, Cyclin-dependent kinases, Proteins -- Metabolism, Cancer
mammalian cells. Increased levels of cyclin E are found in some cancers. Additionally, proteolytic removal of the cyclin E N-terminus occurs in some cancers and is associated with increased cyclin E–Cdk2 activity and poor clinical prognosis. Cyclin E levels are tightly regulated and controlled in part through ubiquitin-mediated degradation initiated by one of two E3 ligases, Cul1 and Cul3. Cul1 ubiquitylates phosphorylated cyclin E, but the mechanism through which Cul3 ubiquitylates cyclin E is poorly understood. In experiments to ascertain how Cul3 mediates cyclin E destruction, we identified a degron on cyclin E that Cul3 targets for ubiquitylation. Recognition of the degron and binding of Cul3 does not require a BTB domain-containing adaptor protein. Additionally, this degron is lacking in N-terminally truncated cyclin E. Our results describe a mechanism whereby N-terminally truncated cyclin E can avoid the Cul3-mediated degradation pathway. This mechanism helps to explain the increased activity that is associated with the truncated cyclin E variants that occurs in some cancers.
Davidge, B., de Oliveira Rebola, K. G., Agbor, L. N., Sigmund, C. D., & Singer, J. D. (2019). Cul3 regulates cyclin E1 protein abundance via a degron located within the N-terminal region of cyclin E. Journal of cell science, 132(21).
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