Fig. 4

Crosstalk of cell cycle and p53 pathway. p53 activity is under the direct control of MDM2. When the MDM2-p53 interaction is interrupted via stress signals or specific MDM2 inhibitors, p53 accumulates and activates its direct transcriptional targets, resulting in protein production: p21 involved in cell cycle arrest; PUMA, NOXA, BAX, BAK involved in the intrinsic apoptotic pathway; DR4 and FAS involved in the extrinsic apoptotic pathway; MDM2, WIP1 involved in p53 feedback regulation and many others participating in DNA repair, cell metabolism, autophagy, and translational control. Cell cycle progression is controlled by p53 activity mainly via p21 protein, which associates with and inactivates CDK/cyclin complexes and blocks cell cycle progression. CDK4/6 with cyclin D/E controls the activity of RB and E2F1. When RB is hyperphosphorylated, it is released from binding to E2F1, and E2F1 then activates its transcriptional program, leading to cell cycle progression