Mammalian cyclin-dependent kinases

Cyclin-dependent kinases (Cdks) are the catalytic subunits of a family of mammalian heterodimeric serine/threonine kinases that have been implicated in the control of cell-cycle progression, transcription and neuronal function. Recent genetic evidence obtained with gene-targeted mice has shown that Cdk4 and Cdk6 are not needed for entry into the cell cycle after mitogenic stimuli and organogenesis; however, they are essential for the proliferation of some endocrine and hematopoietic cells. Cdk2 is also dispensable for the mitotic cell cycle. Indeed, mice without Cdk2 are normal except for their complete sterility: unexpectedly, Cdk2 is crucial for the first meiotic division of male and female germ cells. These findings have important implications both for our current understanding of the role of Cdks in regulating the mammalian cell cycle and for their potential use as therapeutic targets in cancer.

Introduction

Cdks are the catalytic subunits of a large family of heterodimeric serine/threonine protein kinases whose best-characterized members are involved in controlling progression through the cell cycle. According to the latest versions of the human and mouse genomes, there are 11 genes encoding Cdks and 9 other genes encoding Cdk-like proteins with conserved primary structure (Figure 1). Because the catalytic activity of these Cdks requires binding of a regulatory subunit, the term Cdk is often used for the active heterodimeric complex. In this review, we have made every effort to avoid this confusing terminology. The activating partners of the cell-cycle Cdks are molecules that are synthesized and degraded during each cell cycle and thus have been designated ‘cyclins’ (see later). Although this property has been used to define this kinase family, not all activating partners of Cdks are synthesized and destroyed in a cyclical fashion. Indeed, the physiological role of most Cdks and their activating partners remains unknown.

In this review, we first summarize the most relevant biochemical information for known Cdks, with a particular emphasis on those involved in regulating the cell cycle. We then discuss this information in view of recent observations derived from genetic studies in mice that have challenged some of the widely accepted models of the mammalian cell cycle. Finally, we consider the implications of these findings for the use of cell-cycle Cdks as targets for the development of selective inhibitors with potential therapeutic value in cancer.