Regulation of the p53 tumor suppressor protein.

Mutations in the p53 tumor suppressor gene occur in about 50% of all human tumors, making it the most frequent target for genetic alterations in cancer (for recent reviews on p53 see Refs. 1–5). Such mutations probably facilitate carcinogenesis primarily through abrogating the tumor suppressor activities of the wild type p53 protein, although at least some forms of tumor-associated mutant p53 proteins may also contribute overt oncogenic activities (gain of function). Excessive wild type p53 activity gives rise to a variety of cellular outcomes, most notably cell cycle arrest and apoptosis. These cellular effects of wild type p53 can reduce cancer incidence through elimination of cancer-prone cells from the replicative pool. However, such effects might become very undesirable if occurring in a normal, unperturbed cell. p53 activity must therefore be kept under tight control, being unleashed only when a cell accumulates lesions that may otherwise drive it into a cancerous state. The signals and mechanisms that regulate p53 activity, maintaining it at low levels under normal conditions and turning it on in cancerprone cells, are the subject of this review.