The p21Cip1 and p27Kip1 CDK `inhibitors' are essential activators of cyclin D-dependent kinases in murine fibroblasts

Abstract

The widely prevailing view that the cyclin‐dependent kinase inhibitors (CKIs) are solely negative regulators of cyclin‐dependent kinases (CDKs) is challenged here by observations that normal up‐regulation of cyclin D–CDK4 in mitogen‐stimulated fibroblasts depends redundantly upon p21^Cip1 and p27^Kip1. Primary mouse embryonic fibroblasts that lack genes encoding both p21 and p27 fail to assemble detectable amounts of cyclin D–CDK complexes, express cyclin D proteins at much reduced levels, and are unable to efficiently direct cyclin D proteins to the cell nucleus. Restoration of CKI function reverses all three defects and thereby restores cyclin D activity to normal physiological levels. In the absence of both CKIs, the severe reduction in cyclin D‐dependent kinase activity was well tolerated and had no overt effects on the cell cycle.