CELL DEATH Connecting Autophagy to p53-Mediated Cell Death

The role of autophagy in cell death and cell survival is the subject of debate, with reports for a cell-survival role when nutrients are limiting and a role in cell death under other conditions (see Green and Chipuk). Crighton et al. describe damage-regulated autophagy modulator (DRAM), the abundance of which is increased by transcriptional regulation by p53. DRAM is a transmembrane protein that colocalizes with lysosomes and appears to be required for the formation of autophagosomes in response to p53 activation. Knockdown with siRNA of DRAM or ATG5, which is required for autophagy, inhibited the p53-stimulated turnover of long-lived proteins and inhibited cell death after p53 activation (forced expression of p53 or activation of p53 by actinomycin D). Overexpression of DRAM in the absence of p53 activation did not increase cell death despite an increase in autophagosomes under both conditions. Therefore, DRAM appears to be necessary for cell death but not sufficient to induce cell death in the absence of proapoptotic signals. DRAM may be a tumor suppressor, and several cancer cell lines exhibited decreased DRAM mRNA compared with normal cells. These results connect autophagy to p53-mediated cell death.

D. R. Green, J. E. Chipuk, p53 and metabolism: Inside the TIGAR. Cell 126, 30-32 (2006). [Online Journal]

D. Crighton, S. Wilkinson, J. O'Prey, N. Syed, P. Smith, P. R. Harrison, M. Gasco, O. Garrone, T. Crook, K. M. Ryan, DRAM, a p53-induced modulator of autophagy, is critical for apoptosis. Cell 126, 121-134 (2006). [Online Journal]