Cell cycle control as a basis for cancer drug development (review)

Normal cell cycle progression relies on the cell's ability to translate ext racellular signals such as mitogenic stimuli and intact extracellular matri ces in order to efficiently replicate DNA and divide. Cyclin dependent kina ses (CDKs) respond to these signals and are largely responsible for positiv ely pushing cells through the cell cycle. Due to their pivotal role in cell division, nature has evolved elaborate mechanisms to regulate the kinase a ctivity of cdks. Cyclins are cdk binding partners which are required for ki nase activity and their protein levels are intimately linked to the cell cy cle stage. A variety of other cdk regulators such as phosphorylation events , natural inhibitors and complex stability are discussed. Phosphorylation o f various cdk substrates results in diverse outcomes such as changes in gen e expression, formation of prereplicative complexes and breakdown of the nu clear envelope. Cancer cells evolve in part by over-riding normal cell cycl e regulation Abnormal cdk activity is accomplished by cyclin amplification, cdk or substrate mutation as well as inactivation of inhibitors. The selec tive growth advantage of cancer cells also stems from amplification of posi tive growth signals, mutation of checkpoint and surveillance genes as well as deregulation of programmed cell death or apoptosis. The full potential o f cancer therapies, such as small molecule inhibitors and gene therapy amon g others, focusing on our knowledge of cell cycle regulation has yet to be reached.