Cyclin Dependent Kinase (Cdk) Inhibitors

This volume constitutes a comprehensive collection of acticles on cyclin-dependent kinase inhibitors. The topics covered range from the basic biology and biochemistry of these proteins to their roles in development and carcinogensis. All the organisms where cyclin-dependent kinase inhibitors have been intensively studied, including yeast, mouse and man, are represented in the discussion. All of the articles have been contributed by experts in their respective discipline and provide up-to-date views of the field from the perspective of working scientists. As this is the first comprehensive volume strictly dedicated to the topics CDK inhibitors, it will be a valuable resource for anyone who needs or wishes to familiarize themselves with current thought on cell cycle regulation.

More than 10 years ago, the discovery of cyclin-dependent ki- nases (Cdks) ushered in a new era in the understanding of cell proliferation and its control. Not only were both of the known cell cycle transitions, from G 1 to S phase and G2 to M phase, found to be dependent on these protein kinases, but the reg- ulatory assumption intrinsic to cyclin-dependent kinases, a stable inactive catalytic subunit (the Cdk) and an unstable requisite positive regulatory activating subunit (the cyclin), led to a simple model for cell cycle control. Modulation of cyclin accumulation, and thereby Cdk activation, was proposed to be the overarching principle governing the passage through cell cycle phases. An- other reality to emerge from the discovery of Cdks was the ex- ceptional degree of evolutionary conservation maintained in the machinery and organization of proliferation control. Not only were Cdks shown to be structurally conserved between yeast and man, but mammalian Cdks could substitute functionally for the endogenous enzymes in a yeast cell. The problem of cell cycle control was thought to have been virtually solved. The ensuing years have provided a much more complex view of cell cycle control and the role and regulation of Cdks. The uncritical enthusiasm with which many of the ideas were em- braced has required tempering. For example, although Cdks appear to be highly conserved phylogenetically, cyclins are much less so.

Cyclin-Dependent Kinase Inhibitors of Saccharomyces cerevisiae and Schizosaccharomyces pombe.-Inhibitors of the Cip/Kip Family.-The INK4 Family of CDK Inhibitors.-Role of Cyclin-Dependent Kinases and Their Inhibitors in Celluar Differentiation and Development.-Roles of CDK Inhibitors: Lessons from Knockout Mice.-p21/p53, Cellular Growth Control and Genomic Integrity.-CDK Inhibitors and Human Cancer.- Small-Molecule Inhibitors of Cyclin-Dependent Kinases: Molecular Tools and Potential Therapeutics