Cip/Kip cyclin-dependent kinase inhibitors: Brakes of the cell cycle engine during development

Precise control of cell-cycle progression is believed to be critical for normal development, while oncogenesis may be a direct result of its disturbance. Cell-cycle progression is regulated predominantly by a series of serine/threonine kinases, the cyclin-dependent kinases (CDKs). The activities of the CDKs are controlled by a variety of mechanisms, and a group of molecules that inhibit CDK activity, CDK inhibitors (CKIs), has recently become the focus of interest, particularly in the fields of development and tumorigenesis. To date, seven CKIs have been identified in mammals and categorized into two families, the Cip/Kip and Ink4 families. The Cip/Kip family is well conserved phylogenetically, suggesting that it is biologically important. Despite the structural and biochemical similarities among the Cip/Kip members, the phenotypes of knockout mice of each Cip/Kip member are surprisingly different, which suggests that the Cip/Kip CKIs have a variety of physiological functions. In this review, the biological roles of Cip/Kip CKIs in development and tumor suppression are discussed.