Regulation of the cell cycle by cyclin dependent kinases (cdks).

cdks affect various stages of the cycle by forming complexes with their respective cyclins. The cell cycle begins in G₁ during which there is increased synthesis of D-type cyclins that associate with cdks 4 and 6. When the complex is formed, the cdks are activated and then phosphorylate the retinoblastoma (Rb) protein. The latter is necessary to regulate G₁ through its restriction point. As the cycle goes through G₁, Cyclin E is synthesized and associates with cdk2, which permits the cycle to proceed to S. After cyclin A is synthesized during the G₁/S transition phase, it is associated with cdk2 in early S phase and cdk1 in late S phase and early G₂. Cyclin B is synthesized late in G₂ and M phase and associates with cdk1. The increased cyclins A and B, complexed with cdk1 at the end of M phase, are necessary to move the cell into the next G₁ phase.

The action of cyclins/cdks is regulated on multiple levels. For example, along with cyclin synthesis is the process of cyclin degradation. Cyclin/cdk activity is controlled by two families of inhibitors. The first group includes the cyclin and kinase inhibitory proteins (Cip/Kip) p21^waf1/cip1, p27^kip2 and p57^kip2. These appear to function at several points during the cycle inhibiting cdks 4, 6, and 2. p53 helps regulate the cell cycle through transcription of p21, which retains the cell in G₁ permitting DNA repair. The other group includes p15^ink4a, p15^ink4b, p18^ink4c and p19^ink4d, which specifically inhibit cyclin D-associated cdk4 and cdk6.