P53/MDM2 regulation [8]. (a) Regulation p53/MDM2. MDM2 inhibits p53 through an autoregulatory loop MDM2 directly binds to the transactivation domain of p53 and inhibits its transcriptional activity, inducing the ubiquitination and proteasomal degradation of p53, by exporting p53 out of the nucleus. ARF binds to MDM2 and sequesters MDM2 into the nucleolus, leading to the stabilization of p53. (b) P53 can lead to induction of apoptosis via intrinsic (mitochondrial) and extrinsic (death receptor) apoptosis pathways. (c) P53 activation can halt cell-cycle progression in G1-S and G2-M phase through p21, Gadd45, and 14-3-3-σ proteins. (d) P53 regulates senescence through p21-Rb-E2f signaling pathway. (e) P53 can suppress angiogenesis through the downregulation of antiangiogenenic proteins. (f) P53 plays a critical role in DNA damage repair. DNA damage and replication errors can activate ataxia telangiectasia mutated (ATM) and activate ataxia teleangiectasia and Rad kinases.
