PMID: 18414028Apr 17, 2008Paper

Switching cyclin D-Cdk4 kinase activity on and off

Cell Cycle
Stacy W Blain

Abstract

The cyclin-cdks are master regulators of cell proliferation. These serine/threonine kinases are the motors that both start and stop the cell cycle in response to proliferative or antiproliferative signals. They phosphorylate substrates required to trigger orderly cell cycle progression, and thus their activity is tightly regulated in order to prevent inappropriate activation. One of the main interfaces between the extraceullar environment and the cell cycle machinery is the interaction of the cyclin-cdks with two families of stoichiometric cyclin kinase inhibitors (CKIs), the Ink4s and the Cip/Kips. As their name suggests, the CKIs have historically been considered negative regulators of the cyclin-cdks, responsible for rapidly and effectively turning off cyclin-cdk activity. However, the interaction of cyclin D-cdk4 with the Cip/Kip family, and with p27Kip1 in particular, appeared complex. In addition to its ability to inhibit cyclin D-cdk4, p27 appeared to be a required assembly factor for the complex, binding in a non-inhibitory mode at least some of the time. Whether p27 was a cyclin D-cdk4/6 inhibitor or not was controversial, and how it might switch between these two modes was unknown. Arguing for a two state mechanism, w...Continue Reading

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