Fig. 1. Schematic representation of the mammalian cell cycle. A, mammalian cell cycle is divided into four phases, G1, S, G2, and M. Progression from one phase to the next is regulated by cdks associated with their cyclin subunits. Inhibition of the cyclin-cdk complexes is mediated by two families of cdk inhibitors, Ink4 proteins (p16Ink4a, p15Ink4b, p18Ink4c, and p19Ink4d) and Cip/Kip proteins (p21Cip1, p27Kip1, and p57Kip2). Whereas Ink4 proteins specifically bind to and inhibit cdk4/6, Cip/Kip family members can inhibit cyclin/cdk complexes including cyclin E-cdk2, cyclin A-cdk2, and cyclin B-cdk1 at a 1:1 stoichiometry. Cip/Kip proteins can also positively regulate cyclin D-cdk4/6 by promoting their assembly. Mitogen stimulation induces synthesis of D-type cyclins and is necessary for cells to proceed through G1 until they reach the restriction point (R), after which cells independently complete the first cell cycle. Cells can exit from the cell cycle and enter a state of quiescence, G0. B, cyclin D-cdk4/6 and cyclin E-cdk2 complexes phosphorylate (P) the pRb, releasing tethered transcription factors including the E2Fs. Free E2Fs (1, 2, or 3) bind to their DP partners and activate the transcription of genes necessary for S phase entry, including cyclin E. C, Ink4 proteins bind cdk4/6, freeing D cyclins that become targeted for ubiquitination (Ub) and proteosomal degradation. Cip/Kip proteins bound to cyclin D-cdk4/6 are released and bind to cyclin E- and cyclin A-cdk2, inhibiting cdk2 activity and prevent cells from entering S phase.