The p53 Signaling Pathway

The tumor-suppressor protein p53 exhibits sequence-specific DNA-binding, directly interacts with various cellular and viral proteins, and induces cell cycle arrest in response to DNA damage. In response to signals generated by a variety of genotoxic stresses, e.g, UV irradiation or DNA damage, p53 is expressed and undergoes post-translational modification that results in its accumulation in the nucleus. The p53-dependent pathways help to maintain genomic stability by eliminating damaged cells either by arresting them permanently or through apoptosis. For example, g -irradiation activates p53 to turn on the transcription of p21 CIP1 , which, in turn, binds to and inhibits cyclin-dependent kinases, causing hypophosphorylation of retinoblastoma (Rb), thus preventing the release of E2F and blocking the G 1 -S transition. Some of the cellular effects of p53 can be blocked by the deregulated expression of c-Myc, Bcl-2, or E2F. p53 activity is controlled through an autoregulatory loop involving Mdm2. The binding of Mdm2 to p53 targets p53 for degradation and inhibits p53-induced cell-cycle arrest and apoptosis.