It is 3 years since our minireview on cyclins and cancer (Hunter and Pines, 1991), and in that time the number of connections between oncogenesis and the components that regulate the cell cycle has increased dramatically. Perhaps the most significant development has been the isolation of a family of small cyclin-cyclin-dependent kinase (CDK) inhibitor proteins (CDls) that bind and inactivate the CDKs. Individual inhibitor proteins are often absent from transformed cells, marking them out as potential tumor suppressors. Recent developments have also deepened our understanding of the role played by cell cycle components in regulating the known tumor suppressors, such as the retinoblastoma protein (Rb) and~ 53. The current model of cell cycle control holds that the transitions between different cell cycle states are regulated at checkpoints (see Nurse, 1994 [this issue of Cc//j). Examples of these are the initiation and the completion of DNA replication (S phase) and of cell division (mitosis). Several checkpoints are regulated by a family of protein kinases, the CDKs, and their obligate activating partners, the cyclins. One of the most important checkpoints is START (also known as the restriction point in mammalian ceils) in late Gl, at which the cell commits itself to another round of DNA replication and at which both positive and negative external signals are integrated into the cell cycle. Many checkpoints are deregulated in oncogenesis, and this is often due to changes in cyclin-CDK complexes (see Figure 1). In particular, the deregulation of START may allow cell growth and division to become insensitive to external cues. This can be a consequence of either the aberrant expression of positive regulators, such as the cyclins, or the loss of negative regulators, such as the CDls. Both types of change have been documented in tumor cells. Another consequence of abnormal START checkpoint control is that cells can bypass the normal restriction on entry into S phase imposed by damaged DNA, and this may allow the cells to replicate unrepaired mutations and thus accumulate genetic changes that contribute to the tumor phenotype.

The START Checkpoint In mammalian cells, the cyclin-CDK complexes most closely linked to the regulation of START are the D-type cyclins and their partner CDKs, primarily CDK4. There are three types of D cyclin (Dl, D2, and D3), and they are in part cell type specific, with most cells expressing D3 and either Dl or D2 (reviewed by Sherr, 1993). The D-type cyclins activate CDK4 and in some cells also CDK6 (Bates et al., 1994a; Meyerson and Harlow, 1994) to drive the