Three D-type cyclins are essential for progression from G1 to S-phase. These D cyclins bind to and activate both CDK4 and CDK6. The formation of all possible complexes between the D-type cyclins and CDK4/6 is promoted by the proteins, p21(CIP1/WAF1) and p27(KIP1). The cyclin-dependent kinases are then activated due to phosphorylation by CAK. The cyclin dependent kinases phosphorylate the RB1 protein and RB1-related proteins p107 (RBL1) and p130 (RBL2). Phosphorylation of RB1 leads to release of activating E2F transcription factors (E2F1, E2F2 and E2F3). After repressor E2Fs (E2F4 and E2F5) dissociate from phosphorylated RBL1 and RBL2, activating E2Fs bind to E2F promoter sites, stimulating transcription of cell cycle genes, which then results in proper G1/S transition. The binding and sequestration of p27Kip may also contribute to the activation of CDK2 cyclin E/CDK2 cyclin A complexes at the G1/S transition (Yew et al., 2001).