CDK4 and neoplasm: In particular, Cyclin-E activates CDK2 and initiates the transition from G1 phase to S phase, and its expression is dependent on E2F transcription factors [32]; Rb protein is a tumor suppressor that binds to transcription factor E2F to make it non-transactivated in G0/G1 phase [33]; Cyclin D-CDK4/6 and Cyclin E-CDK2 complexes phosphorylate Rb protein, which then to dissociate from E2F, and consequently promote expression of Cyclin E and other S phase-related genes [34].