Escape from p14ARF cell cycle arrest (premature senescence in MCF-7 breast cancer cells): A proposed model.

P14ARF binds hdm2 and sequesters it to the nucleolus. P53 upregulates p21 and p21 dephosphorylates and downregulates Rb. P21 also binds and inactivates cyclin D1/cdk4/6 complex and induces premature senescence. Two avenues are suggested whereby cells may escape from senescence: ER binds p53 and inactivates p14ARF-p53 inhibitory functions [44]; alternatively ER binds to cyclin D1 with a gain of cell proliferative function [40].