Cell cycle regulation by Rb and p53 tumor suppressor proteins. A) Inactivation of Rb and p53 proteins occurs by phosphorylation for the progression of the cell cycle from the G1 to the S phase. Kinase function of CDK4 is activated by cyclin D1 and inactivated by p16 proteins. Cyclin E and p21 control the activation and inactivation of CDK2, respectively. Ubiquitination of p53 takes place by complexing with MDM2 that is blocked by p14ARF (ARF, alternative reading frame). B) Inactivation of p16 by deletion, methylation, or mutation and/or by amplified expression of cyclin D1 leads to increased phosphorylation of Rb resulting in the activation of E2F mediated transcription. However, increased expression of p16 and reduced expression of cyclin D1 results in hypophosphorylated Rb binding to E2F transcription factor leading to the inactivation of transcription.