The p21(Cip1) and p27(Kip1) CDK 'inhibitors' are essential activators of cyclin D-dependent kinases in murine fibroblasts

The widely prevailing view that the cyclin-dependent kinase inhibitors (CKI s) are solely negative regulators of cyclin-dependent kinases (CDKs) is cha llenged here by observations that normal up-regulation of cyclin D-CDK4 in mitogen-stimulated fibroblasts depends redundantly upon p21(Cip1) and p27(K ip1). Primary mouse embryonic fibroblasts that lack genes encoding both p21 and p27 fail to assemble detectable amounts of cyclin D-CDK complexes, exp ress cyclin D proteins at much reduced levels, and are unable to efficientl y direct cyclin D proteins to the cell nucleus. Restoration of CKI function reverses all three defects and thereby restores cyclin D activity to norma l physiological levels. In the absence of both CKIs, the severe reduction i n cyclin D-dependent kinase activity was well tolerated and had no overt ef fects on the cell cycle.