Endoplasmic reticulum stress-induced cell death mediated by the proteasome.
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.
Egger
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The Buck Institute for Age Research, Novato, CA 94945, USA. lotti.egger@bluemail.ch
Madden
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Rhême
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Rao
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Bredesen
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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
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