Early cell cycle progression in G1 is under the control of the D-type cyclins together with Cdk4 and Cdk6. An important target for these CDKs is the Retinoblastoma (Rb) protein, which when phosphorylated promotes cell cycle progression by releasing E2F transcription factors that transactivate several important genes for later cell cycle events. The formation of Cyclin D - Cdk4/6 complexes is promoted by two proteins, p21Cip1/Waf1 and p27kip1, and their activity can be inhibited by the binding of several small CDK-inhibitory proteins (CKIs): p15INK4B, p16INK4A, p18INK4C and p19INK4D.