DRAM, a p53-induced modulator of autophagy, is critical for apoptosis

Inactivation of cell death is a major step in tumor development, and p53, a tumor suppressor frequently mutated in Cancer, is a critical mediator of cell death. While a role for p53 in Apoptosis is well established, direct links to Other pathways controlling cell death are unknown. Here we describe DRAM (damage-regulated Autophagy modulator), a p53 target gene encoding a lysosomal protein that induces macroautophagy, as an effector of p53-mediated death. We show that p53 induces Autophagy in a DRAM-dependent manner and, while overexpression of DRAM alone causes minimal cell death, DRAM is essential for p53-mediated Apoptosis. Moreover, analysis of DRAM in primary tumors revealed frequent decreased expression often accompanied by retention of wild-type p53. Collectively therefore, these studies not only report a stress-induced regulator of Autophagy but also highlight the relationship of DRAM and Autophagy to p53 function and damage-induced programmed cell death.