Sherr and Roberts 1999: CDK inhibitors as regulators of the G1 phase
The classic review of the brakes on the cell cycle, the proteins that hold back the cyclin-dependent kinases which commit a cell to dividing, and how cancers lose them, the biology behind today's CDK4/6 inhibitors.
Overview
Sherr and Roberts described the two families of cyclin-dependent kinase inhibitors that govern passage through G1: the INK4 proteins (p16, p15, p18 and p19), which specifically block cyclin D-CDK4 and CDK6, and the Cip/Kip proteins (p21, p27 and p57), which act on a broader range of cyclin-CDK complexes. They explained how these inhibitors integrate mitogenic and anti-proliferative signals to control the restriction point, how p21 links p53 to arrest and p27 mediates contact inhibition and TGF-beta responses, and how loss of p16 or p27 and overexpression of cyclin D contribute to cancer.
- INK4 inhibitors (p16, p15, p18, p19) specifically restrain cyclin D-dependent CDK4 and CDK6; Cip/Kip inhibitors (p21, p27, p57) act more broadly.
- These inhibitors integrate growth-promoting and growth-inhibitory signals at the G1 restriction point.
- Loss of p16 (CDKN2A) or p27 and cyclin D overexpression are common in cancer and remove the G1 brake.
This review is the textbook basis for the cyclin D-CDK4/6-RB axis that palbociclib, ribociclib and abemaciclib target in breast cancer, and for reading CDKN2A loss and cyclin D1 amplification in tumour genomes.
- Written before the clinical development of CDK4/6 inhibitors.
- Later work showed CDK2 and cyclin E can bypass the CDK4/6 brake, which underlies resistance.
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