It is known that p53 induces either cell cycle arrest (with features of senescence) or apoptosis, depending on the type of tumor where restoration takes place. In the lab we’ve been tackling a long-standing question of how p53 can induce two completely different tumor suppressive responses depending on the tumor type. A project in the lab is focused on understanding the action mechanisms of the p53 tumor suppressor gene, which is the most frequently mutated gene in human cancer. Our research has identified the state of mitochondrial priming—a measure of the balance of apoptotic regulators in the cell—as a key determinant of the functional outcome of p53 action. The “cellular decision” between cell cycle arrest and apoptosis following stimulation of the p53 pathway has important implications for tumor progression and therapy.
Restoration of the p53 tumor suppressor gene in established tumors leads to tumor regression. Lung adenocarcinoma cell lines derived from KrasLA2/+; Trp53LSL/LSL; Rosa26CreERT2 mice were stably infected with luciferase. Mice harbor a tamoxifen-inducible Cre recombinase, which restores p53 expression upon deletion of a STOP element in the Trp53 gene. Tumors were formed via tail vein injection in nude mice and allowed to grow for 22 days before tamoxifen administration. p53 restoration was achieved by administering tamoxifen every 2 days for one week.