title: Endoplasmic reticulum stress-induced cell death mediated by the proteasome.
abstract: Cells exposed to sustained endoplasmic reticulum (ER) stress undergo programmed cell death and display features typical of apoptosis, such as cysteine aspartyl protease (caspase) activation, cytochrome c release, and DNA fragmentation. Here, we show that the execution of cell death induced by ER stress is mediated via the proteasome. Inhibition of the proteasome by lactacystin prevented ER stress-induced degradation of Bcl-2, release of cytochrome c, processing of effector caspase-3, and exposure of phosphatidylserine. Owing to the ability of lactacystin to inhibit cytochrome c release, we propose that the pro-apoptotic activity of the proteasome lies upstream of mitochondrial activation. Thus, the proteasome serves as a principal mediator of ER stress-induced cell death in this system.
authors: The Buck Institute for Age Research, Novato, CA 94945, USA. lotti.egger@bluemail.ch
authors: L
authors: L
authors: Egger
authors: D T
authors: DT
authors: Madden
authors: C
authors: C
authors: Rhême
authors: R V
authors: RV
authors: Rao
authors: D E
authors: DE
authors: Bredesen
mesh_terms: D000111:Acetylcysteine / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D015153:Blotting, Western; D020126:Brefeldin A / Q000494:pharmacology; D053148:Caspase 3 / Q000378:metabolism; D002478:Cells, Cultured; D002710:Chlorhexidine / Q000494:pharmacology; D045304:Cytochromes c / Q000378:metabolism; D053938:DNA Fragmentation / Q000187:drug effects; D004591:Electrophoresis, Polyacrylamide Gel; D004721:Endoplasmic Reticulum / Q000187:drug effects / Q000378:metabolism*; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D051336:Mitochondrial Membranes / Q000378:metabolism; D008954:Models, Biological; D010718:Phosphatidylserines / Q000378:metabolism; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism*; D061988:Proteasome Inhibitors; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D051381:Rats; D013450:Sulfones / Q000494:pharmacology; D013696:Temperature; D044764:Ubiquitin-Activating Enzymes / Q000235:genetics / Q000378:metabolism
chemical_list: D010718:Phosphatidylserines; D061988:Proteasome Inhibitors; D019253:Proto-Oncogene Proteins c-bcl-2; D013450:Sulfones; C067713:lactacystin; D020126:Brefeldin A; C002010:4-(2-aminoethyl)benzenesulfonylfluoride; D045304:Cytochromes c; D053148:Caspase 3; D046988:Proteasome Endopeptidase Complex; D044764:Ubiquitin-Activating Enzymes; D002710:Chlorhexidine; D000111:Acetylcysteine