Regulation of the cell cycle

Abstract The smooth running of the mitotic cell cycle depends on the activity of a family of serine-threonine kinases, the cyclin-dependent kinases (cdks). Agents that regulate the cell cycle ultimately impinge upon the activity of these proteins, either directly (by promoting their degradation or inducing the expression of an inhibitor) or indirectly (by arresting the cell cycle at a point before a particular cdk is active). The cdks are under very strict regulation, as might be expected for enzymes responsible for such a fundamental cellular process. These kinases are activated and inactivated in a sequential manner over the course of the mitotic cycle and their phosphorylation of various substrates allows cells to progress through the mitotic cycle (1). To date, the most extensively characterized of these substrates is the retinoblastoma protein, pRb, whose phosphorylation first by cyclin D/cdk4,6 in early G1 phase and then by cyclin E/cdk2 later in G1 precedes the commencement of DNA synthesis (2, 3) (Figure 1). Other substrates that have been identified are listed in Table 1.