644 The cell cycle, checkpoints, and cancer

Abstract

Studies carried out initially in yeast and marine invertebrate and amphibian eggs, have identified the cyclin dependent kinases (CDKs) as key elements in controlling the cell cycle. In the fission yeast a single CDK p34^cdc2 encoded by ^cdc2 is required to initiate both S-phase and mitosis, the major events common to all eukaryotic cell cycles. This protein kinase is regulated by several mechanisms, including the availability of B-cyclin to form an active complex with p34^cdc2, an inhibitory tyro-sine phosphorylation in the active site of the enzyme, and the action of a specific protein inhibitor. These mechanisms ensure that the p34^cdc2 protein kinase activity is precisely regulated during the cell cycle. Low level activity in G1 is required to bring about S-phase and during G2 to prevent a further round S-phase. Activation to high level in G2 initiates mitosis, and a failure to complete S-phase prevents this activation. Thus p34^cdc2 controls the onset of S-phase and mitosis and ensures they occur in the correct order during the cell cycle. The human <i>CDC2</i> gene was isolated by its ability to substitute for the <i>cdc2</i> gene in fission yeast. It controls the onset of mitosis in human cells indicating that the basic elements of cell cycle control are likely to be conserved in all eukaryotes. Other related CDKs have also been identified in human cells which act in G1, both in mid-G1 and at the onset of S-phase in late G1. These CDKs and their associated regulatory molecules play important roles in controlling cell cycle progression, and so have provided a new set of potential targets for restraining uncontrolled proliferation during malignancy. The CDKs are also important in the checkpoint controls which prevent initiation of S-phase and mitosis if earlier events of the cell cycle have not been properly completed. For example, premature p34^cdc2 activation can lead to mitosis without S-phase and inhibition of p34^cdc2 can lead to S-phase without mitosis. Defects of this sort lead to genomic instability with obvious significance for tumour progression. Understanding these controls may also provide new strategies for treating cancer. Quiescent cells do not have potentially activatable CDKs required for mitosis and so would be resistant to treatments which could activate these protein kinases. Malignant cells which are unable to become properly quiescent could respond to such treatments by a premature entry into mitosis which would be lethal, selectively killing malignant cells. These studies provide a useful example of how work with simple organisms such as yeast and starfish can illuminate fundamental problems in human cells which may ultimately be of practical importance for improving clinical practice.