# Sherr and Roberts 1999: CDK inhibitors as regulators of the G1 phase

Source: https://onco.cc/key-papers/paper-sherr-roberts-cdk-inhibitors-genesdev-1999/  
OnCo record `paper-sherr-roberts-cdk-inhibitors-genesdev-1999` (Key paper). Data CC BY-NC 4.0, attribute "Data from OnCo (onco.cc)"; commercial use needs a licence.

## TL;DR

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.

## Summary

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.

## Fields

- Kind: Key paper
- Last checked: 2026-09-08
- Journal: Genes and Development
- Year: 1999
- DOI: 10.1101/gad.13.12.1501
- Authors: Sherr CJ, Roberts JM.
- Findings: 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.
- What it means: 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.
- Caveats: 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.

## Sources

- Full text (DOI): https://doi.org/10.1101/gad.13.12.1501

## Connected records

- key papers: [El-Deiry 1993: WAF1, the gene through which p53 stops cell division](https://onco.cc/key-papers/paper-el-deiry-waf1-p21-cell-1993/)
- technologies: [CDK4/6 inhibitors](https://onco.cc/technologies/cdk46-inhibitor/)
- targets: [CDK4/6](https://onco.cc/targets/cdk4-6/)
- institutions: [St. Jude Children's Research Hospital](https://onco.cc/institutions/st-jude/)
- pathways: [p53 / RB / cell-cycle checkpoint](https://onco.cc/pathways/p53-cell-cycle/), [The cell-cycle engine (cyclins & CDKs)](https://onco.cc/pathways/cell-cycle-engine-cdks/)
- terms: [Cell cycle](https://onco.cc/terms/cell-cycle/), [Tumour suppressor gene](https://onco.cc/terms/tumour-suppressor-gene/)

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