The Biology of Cyclins and Cyclin-Dependent Protein Kinases

Abstract

In the 20 yr since the discovery of proteins whose levels oscillate during the cell cycle in marine invertebrate embryos (1), the study of cyclins and their cognate protein kinases has revealed a wealth of information on how eukaryotic cells control cyclical functions connected with cell proliferation and growth. The picture that has emerged from two decades of investigation is intricate and still incomplete. In the simplest possible model, cyclins are critical regulatory subunits of cyclin-dependent protein kinases (CDKs). When cyclin levels rise, they form stable complexes with CDKs, generating enzymatically active heterodimeric complexes. When cyclin levels fall, CDKs lose catalytic activity and are unable to phosphorylate their substrates. This simple model remains fundamentally valid, but it is now clear that the regulation of cyclin/CDKs is exquisitely complex throughout the cell cycle. Moreover, it is now widely recognized that cyclins and CDKs do much more than simply control cell cycle progression. The relatively simple mechanisms discovered in yeast cells, which have one G1 cyclin, one G2 cyclin, and a single CDK, are replaced in mammalian cells by a richly redundant molecular network, including multiple cyclins, CDKs, and regulatory pathways that cross-talk with a dizzying array of cell fate determination molecules. Thus, it is hardly surprising that initial hopes for quick discovery and therapeutic development of highly specific pharmacological inhibitors of cyclin/CDK complexes have not yet been fully realized.