DRAM, a p53-Induced Modulator of Autophagy,

Is Critical for Apoptosis

Cell 126, 121-134 (2006)

Speaker: 蔡志文                                                     Time: 15:10-16:00, Oct. 4, 2006

Commentator: 賴明德 老師                                  Place: Room 601

Abstract:

    Inactivation of cell death is a crucial step during cancer progression.  Autophagy is a conserved lysosomal-mediated degradation process involved in the turnover of long-lived proteins and organelles.  In response to nutrient deprivation, autophagy has been suggested to help cell survival (1).  Interestingly, when undergoing programmed cell death, the accumulation of autophagosomes was observed within cells, implicating that autophagy has a role in controling cell death (2).  p53 induces apoptotic cell death and plays a critical role in the prevention of tumor formation.  Its inactivation occurs in a high percentage of human cancers.  Previous study demonstrated that p53 activation increases autophagy levels (3).  In this paper, the authors identified DRAM (damage-regulated autophagy modulator), a novel p53 target gene encoding a lysosomal protein that induces autophagosome formation.  Their results revealed that p53 induced autophagy in a DRAM-dependent manner.  DRAM-dependent induction of autophagy was important for p53-mediated apoptosis, but overexpression of DRAM alone was not sufficient for cell death. Moreover, in some human cancers, DRAM mRNA was downregulated by methylation-dependent transcriptional silencing at the CpG island within its promoter, and decreased DRAM expression often accompanied by retention of wild-type p53.  Together, the finding of DRAM suggests that induction of autophagy by p53 via DRAM contributes to cell death.  Further investigation of DRAM function may aid our understanding of tumor suppression and lead to the development of novel agents for cancer therapy.

References:

1.      Meijer, A.J. et al. Regulation and role of autophagy in mammalian cells. Int. J. Biochem. Cell Biol. 36, 2445-2462 (2004).

2.      Baehrecke, E.H. Autophagy: dual roles in life and death? Nat. Rev. Mol. Cell Biol. 6, 505–510 (2005).

3.      Feng, Z. et al. The coordinate regulation of the p53 and mTOR pathways in cells. Proc. Natl. Acad. Sci. USA 102, 8204–8209 (2005).