p53-dependent induction of p21(Cip1/WAF1/Sdi1) protects against oxygeninduced toxicity

The beneficial effects of supplemental oxygen delivered to pa-tients suffering from acute respiratory distress is offset by its reduction to genotoxic reactive oxygen species (ROS) that inhibit proliferation and kill pulmonary cells. Cells respond to oxygen-induced damage by expressing the tumor suppressor p53 and the cyclin-dependent kinase inhibitor p21Cip1/WAF1/Sdi1 (p21), which lim-its proliferation by blocking entry into S phase. Since preventing DNA synthesis during genotoxic stress may enhance survival, the current study examines whether hyperoxia induces p21 through a p53-dependent pathway and whether p21 protects cells from the toxic effects of oxygen. HCT116 colon carcinoma cells and clonal lines lacking p53 or p21were used in this study because they allow direct cytotoxic comparisons between isogenic cells, without com-plications arising from unknown genetic differences between non-homologous cell lines. Hyperoxia (95 % O2, 5 % CO2) increased p5