The cyclin-dependent kinase pathway moves forward.

The cell cycle of mammalian cells is divided into four phases: G1 (first gap), S (DNA synthesis), G2 (second gap), and M (mitosis). Quiescent cells that have not entered the cell cycle are referred to as being in G0. Progression through the cell cycle requires the activation of cyclindependent kinases (CDKs). CDK activation is dependent on the association of the CDK with a cyclin regulatory subunit. Cyclin D/CDK4, cyclin D/CDK6, and cyclin E/CDK2 regulate transition through G1, cyclin A/CDK2 regulates S phase transition, and cyclin A/CDK2 and cyclin B/CDK2 regulate G2/M transition,1 as shown by the Figure. The activity of CDKs is also regulated by endogenous CDK inhibitors (CKIs) in the cyclin/CDK complex1 (Figure). Two families of CKIs have been characterized according to their structures and CDK targets. Kip/Cip proteins (p21, p27, and p57), which bind to both cyclin and CDK subunits, inhibit cyclin Eand A-dependent kinases but act as positive regulators of cyclin D-dependent kinases. The INK family of proteins (p16, p15, p18, and p19) exclusively binds to and inhibits CDK4 and CDK6.1 Initiation of the cell cycle occurs when a quiescent cell (in G0) is stimulated with appropriate mitogenic stimulus. This event induces expression of D-type cyclins that bind to CDK4 and CDK6, and then enter the nucleus. Active cyclin D-dependent kinases phosphorylate the retinoblastoma protein (Rb) in mid-G1. Rb is then phosphorylated on additional sites by the cyclin E/CDK2 complex, and this event leads to disruption of Rb association with the transcription factor complex E2F, release of active E2F, and subsequent transcription of genes necessary for DNA synthesis, such as DNA polymerase and thymidine kinase.2 Cyclin Aand B-dependent kinases maintain Rb in a hyperphosphorylated form during S, G2, and M.1