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Title: Atg5 is a shared mediator of autophagy and apoptosis after oxidative stress to the ER
Authors: Dewaele, Michael
Buytaert, Esther
Van Kelst, Sofie
de Witte, Peter
Martinet, Wim
Agostinis, Patrizia #
Issue Date: 2008
Conference: International Meeting on Yeast Apoptosis edition:6 location:Leuven, Belgium date:30 April - 4 May
Abstract: atg5 is a shared mediator of autophagy and apoptosis after oxidative stress to the ER

Michael Dewaele1, Esther Buytaert2, Sofie Van Kelst2, Peter de Witte3, Wim Martinet4 and Patrizia Agostinis2

1 Department of Molecular Cell Biology, Lab for Cell Death Research and Therapy, Catholic University of Leuven, Herestraat 49, Box 901, O&N1, 3000 Leuven, Belgium Michael.Dewaele@med.kuleuven.be 2 Department of Molecular Cell Biology, Lab for Cell Death Research and Therapy, Catholic University of Leuven, Belgium 3 Department of Pharmaceutical Science, Laboratory for Pharmaceutical Biology, Catholic University of Leuven, Belgium 4 Department of Pharmaceutical Sciences, University of Antwerp, Belgium

Autophagy is a conserved lysosomal pathway for the degradation of long-lived proteins and organelles, which has been extensively studied in yeast following nutrient deprivation. In mammalian cells autophagy is stimulated by a variety of cellular insults, developmental remodeling, organelle homeostasis and disease pathophysiology and may serve as a pro-survival or pro-death pathway, depending on factors which are not completely understood. Recently, we showed that photo-oxidative stress to the endoplasmic reticulum (ER) (e.g. photochemically induced by light-activation of the ER-localizing photosensitizer hypericin) results in loss of ER Ca2+-homeostasis causing ER stress. In the presence of pro-apoptotic Bax and Bak mitochondrial apoptosis is rapidly induced whereas doubly bax/bak deficient fibroblasts succumb through an autophagic cell death mechanism1.
In order to clarify the role of autophagy in our paradigm and its cross-talk with the apoptotic machinery, we used cells with genetic blockage in either apoptosis or autophagy pathways.
This study reveals that in apoptosis-competent cells stimulation of the autophagic flux is a general response to ER stress that precedes caspase-signaling. Apoptosis defects, caused by Bax/Bak- or Apaf-1 deficiency or inhibition of caspases, enhance autophagic signaling and result in cell death. Intriguingly, in apoptosis-competent cells knock-out of the essential autophagy gene, ATG5, obliterates the induction autophagy and impedes mitochondrial apoptosis following ER stress. These results identify Atg5 as key upstream regulator of autophagy and apoptosis signaling following ROS-induced ER stress. We are currently investigating the relevance of this process for the antitumoral efficacy of hypericin-based photodynamic therapy in wt- or Atg5-/- tumor-bearing mice.


1. E.Buytaert, G.Callewaert, N.Hendrickx, L.Scorrano, D.Hartmann, L.Missiaen, J.R.Vandenheede, I.Heirman, J.Grooten, and P.Agostinis (2006) Role of endoplasmic reticulum depletion and multidomain proapoptotic BAX and BAK proteins in shaping cell death after hypericin-mediated photodynamic therapy, FASEB J. 20:756-758.
Publication status: accepted
KU Leuven publication type: IMa
Appears in Collections:Laboratory of Cell Death Research & Therapy
Laboratory of Dermatology
Laboratory for Pharmaceutical Biology (-)
Laboratory for Molecular Cancer Biology
# (joint) last author

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