FIGURE 24-25 Restriction point control. Nonphosphorylated RB protein binds transcription factors collectively called E2Fs and thereby prevents E2F-mediated transcriptional activation of many genes whose products (e.g., DNA polymerase) are required for DNA synthesis. The kinase activity of cyclin D–CDK4/6 phosphorylates RB, thereby inactivating RB and activating E2Fs; cyclin D–CDK4/6 activity is inhibited by p16. Overproduction of cyclin D, a positive regulator, or loss of the negative regulators p16 and RB commonly occurs in human cancers.