Regulation of p53 stability and activity in response to genotoxic stress

The p53 tumor suppressor is a universal sensor of genotoxic stress that reg ulates the transcription of genes required for cell-cycle arrest and apopto sis. In response to DN4 damage, the p53 protein is phosphorylated at its am ino-terminus and becomes stabilized upon disruption of an interaction with its negative regulator, MDM2. Subsequent phosphorylation and acetylation of p53 promote different interactions with other proteins and with target gen e regulatory elements to facilitate cell-cycle arrest, apoptosis, or adapta tion in response to DNA damage. Downstream of p53, p21 is responsible for g rowth arrest in G1, but other p53 target genes are responsible for G2 cell- cycle arrest. In response to genotoxic insult, p53-induced apoptosis result s from overlapping downstream pathways that both suppress mitogenic and sur vival signaling and promote pro-apoptotic signaling. Adaptation to DNA dama ge is manifested by p53-mediated expression of its negative regulator, MDM3 . The frequency of observed mutations in p53 predicts that its inactivation is a requisite step in tumorigenesis, as p53 is mutated in approximately 5 0% of human tumors. Thus, it is likely that in the remaining tumors, geneti c aberrations will occur in pathways that regulate p53 or in pathways direc tly downstream of p53. The advances in the understanding of p53 signaling o ver the Fast few years point to many potential overlapping signaling pathwa ys, where mutations may occur as alternative modes to p53 mutation. (C) 200 0 Elsevier Science B.V. All rights reserved.