Figure 2.

In the p16/pRB pathway, p16 inhibits Cdk4/6–cyclin D complex formation and induces subsequent pRB hypophosphorylation. Similarly, in the p53/p21 pathway, p19ARF traps MDM2 and prevents p53 degradation, which consequently activates p21. This works similarly as p16 but by inhibiting Cdk2–cyclin E complex, and, therefore, induces pRB phosphorylation. Dephosphorylated pRB binds E2F transcription factor at the E2F sites and blocks G1–S phase transition, blocking the cell cycle. However, in the absence of p16 and p21, hyperphosphorylated pRB detaches from E2F transcription factors, which consequently activates S-phase genes and induces progression of the cell cycle.