The p53-pRB pathway of senescence control. Senescence signaling induces ARF and p16. ARF inhibits HDM2, a down-regulator of p53. Activation of p53 by HDM inhibition or ATM, or DNA-PK and BARD1 results in p21 induction and cell cycle arrest. Both p21 and p16 inhibit CDKs. Without phosphorylation of pRB by cyclins, E2F is repressed. Active E2F can induce transcription of ARF. RAS signaling can induce p16. BMI1 acts as inhibitor of p16-induced senescence signaling.