ABSTRACT

Cell cycle progression provides a mechanism that allows both normal and neoplastic cells to proliferate and grow. The cell cycle is divided into four distinct but closely related phases, i.e., DNA synthesis (S phase) and mitosis (M phase), which are separated by two gaps (phases G1 and G2). Following growth stimuli, cells traverse the cell cycle through G1→S→G2→M phases and then divide to produce two daughter cells, which then enter G1 phase once again to initiate the next cycle, or exit from the cell cycle into a quiescent G0 phase. The G1 phase contains a transition point referred to as “the restriction point,” which determines whether the cell cycle progression is independent of exogenous stimuli. Cell cycle progression is tightly controlled by the cyclin-dependent kinase (CDK) complex consisting of a catalytic (CDK) and a regulatory (cyclin) subunit, which exist in a 1:1 ratio. CDKs are serine/threonine kinases that are 354activated by their regulatory partners (members of the cyclin family). Binding of cyclins to this complex induces a conformational change in the CDK structure producing a basal, active state (1). CDK complexes are activated by phosphorylation of CDKs at specific, conserved threonine (Thr) residues (e.g., Thrl61 in cell division cycle (CDC)2/CDK1, threonine (Thr)160 in CDK2, Thrl72 in CDK4, Thrl77 in CDK6) catalyzed by the CDK-activator kinase (CAK), and dephosphorylated at conserved tyrosine and Thr residues (Thr 14 and Tyrl5 in CDK1 and CDK2, which are phosphorylated by mixed-lineage kinases Weel and/or Myt1), events catalyzed by the dual-specificity phosphatases CDC25 (A, B, and C) (2). CDK activity is inhibited by interactions with endogenous CDK inhibitors, which are divided into two families—the INK4 (inhibitor of CDK4) family, including p16INK4A, p15INK4B, p18INK4C, and p19INK4D, which inhibits cyclin D–associated kinases (CDKs 4 and 6), and the CIP/KIP (kinase inhibitor protein) family, comprising p21CIP1/WAF1, p27KIP1, and p57KIP2, which inhibit most CDKs (3). Cyclin expression fluctuates through the cell cycle and influences progression from one phase to the next. Cyclins B, A, and E are regulated by an ubiquitin/proteasome-dependent degradation pathway, whereas cyclin D is primarily regulated by transcriptional and translational mechanisms.