Cell cycle arrest at G1/S, mediated by cdk inhibitors. Cyclin D–dependent kinases, assembled with a Cip/Kip protein, and cyclin E–cdk2 complexes are principal holoenzymes that phosphorylate Rb, allowing E2F activation and S phase entry. The induction of INK4 proteins (by TGF-β or during senescence) and their association with cdks 4 and 6 result in decreased affinity for cyclin D, which is ultimately degraded. Displaced Cip/Kip proteins, now free to complex with cyclin E-cdk2, promote cdk2 inhibition and G1 arrest. Replacement of p16^INK4A in a tumor cell lacking it only leads to G1 arrest in cells expressing Rb. Antiproliferative signals, including serum starvation, differentiation signals, or DNA damage (which stabilizes p53, resulting in transcriptional induction of p21^Waf1/Cip1) can induce high levels of Cip/Kip proteins, which also cause cdk2 inhibition. Ectopic expression of Cip/Kip proteins causes G1 arrest independent of Rb.