Regulation of CIP/KIP cell cycle inhibitors and their biological implications

The cell cycle regulation is a key homeostatic device upon the cellular decision during the multi processes like proliferation, differentiation, survival and death. Human cancers can arise from the result of functional failure in cell cycle regulators. Therefore, activity of the major cell cycle regulator, cyclin-dependent kinase (CDK), is tightly regulated by cyclin dependent kinase inhibitors (CKIs) such as the p21CIP1 and p27KIP1. These CKIs, mainly functioning as a cyclinE/CDK2 complex inhibitor during the G₁ cell cycle, have been reported to play disparate roles including the assembly of cyclinD/CDK4, 6 and others that apparently assist cell growth if not help carcinogenesis. While their genetic disruptions are rarely found in human cancers, low expression levels or cytoplasmic mislocalizations of the p21CIP1 and p27KIP1 often correlate with human malignancies. Recent studies show that signalling kinases can directly phosphorylate these proteins as a substrate and change their activities in the role of a cell cycle inhibitor by switching interacting partner proteins after the phosphorylation-driven structural modifications. This report will discuss the complex regulatory mechanisms of p21CIP1 and p27KIP1 proteins on the cue of extracellular signals and their indications of functional importance to carcinogenesis.