{"entity":{"id":"paper-sherr-roberts-cdk-inhibitors-genesdev-1999","kind":"paper","name":"Sherr and Roberts 1999: CDK inhibitors as regulators of the G1 phase","aka":[],"tldr":"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.","asOf":"2026-09-08","links":[{"label":"Full text (DOI)","url":"https://doi.org/10.1101/gad.13.12.1501"}],"tags":[],"related":["paper-el-deiry-waf1-p21-cell-1993"],"cancers":[],"sections":[],"technologies":["cdk46-inhibitor"],"targets":["cdk4-6"],"drugs":[],"companies":[],"institutions":["st-jude"],"pathways":["cell-cycle-engine-cdks","p53-cell-cycle"],"terms":["cell-cycle","tumour-suppressor-gene"],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"journal":"Genes and Development","year":1999,"doi":"10.1101/gad.13.12.1501","authors":"Sherr CJ, Roberts JM.","paperType":"review","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."],"whatItMeans":"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."],"changedPractice":false},"route":"/key-papers/paper-sherr-roberts-cdk-inhibitors-genesdev-1999/","neighbours":{"paper":[{"id":"paper-el-deiry-waf1-p21-cell-1993","kind":"paper","name":"El-Deiry 1993: WAF1, the gene through which p53 stops cell division","route":"/key-papers/paper-el-deiry-waf1-p21-cell-1993/"}],"technology":[{"id":"cdk46-inhibitor","kind":"technology","name":"CDK4/6 inhibitors","route":"/technologies/cdk46-inhibitor/"}],"target":[{"id":"cdk4-6","kind":"target","name":"CDK4/6","route":"/targets/cdk4-6/"}],"institution":[{"id":"st-jude","kind":"institution","name":"St. Jude Children's Research Hospital","route":"/institutions/st-jude/"}],"pathway":[{"id":"p53-cell-cycle","kind":"pathway","name":"p53 / RB / cell-cycle checkpoint","route":"/pathways/p53-cell-cycle/"},{"id":"cell-cycle-engine-cdks","kind":"pathway","name":"The cell-cycle engine (cyclins & CDKs)","route":"/pathways/cell-cycle-engine-cdks/"}],"term":[{"id":"cell-cycle","kind":"term","name":"Cell cycle","route":"/terms/cell-cycle/"},{"id":"tumour-suppressor-gene","kind":"term","name":"Tumour suppressor gene","route":"/terms/tumour-suppressor-gene/"}]}}