Progression through the cell cycle depends upon the activation of cyclin-dependent kinases (CDK), whose activity requires the binding of specific regulatory subunits, known as cyclins. CDK4/6 is activated by the binding of D-type cyclins, whose expression are controlled by mitogenic growth factors. CDK2 is activated by E-type cyclins, known transcriptional targets of E2F. The activity of both CDK4/6 and CDK2 complexes are opposed by CIP/KIP CDK inhibitors, including p21, p27, and p57, while INK4 inhibitors like p16 exclusively bind CDK4/6, preventing cyclin D-CDK4/6 interaction. CDK activity promotes cell-cycle entry through the phosphorylation and inactivation of the transcriptional repressor, Rb. Following phosphorylation of Rb, E2F transcription is activated, promoting cell-cycle progression.