Cypermethrin blocks a mitochondria-dependent apoptotic signal initiated by deficient N-linked glycosylation within the endoplasmic reticulum.
The endoplasmic reticulum (ER) serves as a critical site of protein synthesis and processing. The temperature-sensitive hamster fibroblast cell line (tsBN7) displays deficient N-linked glycosylation activity at the restrictive temperature and activates cellular apoptosis. Temperature-shifted tsBN7 cells display induction of Grp78 and Gadd153, genes known to be induced by ER stress, and activate apoptosis via the release of cytochrome c from the mitochondria. Cyclosporin A (CsA), a potent blocker of the mitochondrial permeability transition pore (PTP), was sufficient to block cytochrome c release and to rescue tsBN7 cells from apoptosis. CsA-treated cells displayed Grp78 induction at the restrictive temperature, consistent with an ER stress signal being carried to the nucleus, while the apoptosis-associated transcription factor, Gadd153, displayed only a mild induction. Cypermethrin, a type II pyrethroid known to perturb Ca(2+) signaling in neuronal cells, was sufficient to arrest apoptosis under these conditions. This work identifies type II pyrethroids as a valuable new tool in the characterization of cellular stress signaling pathways.
Niederer
Katherine E
KE
Natural Science Division, Pepperdine University, 24255 Pacific Coast Highway, Malibu, CA 90263, USA.
Morrow
Daniel K
DK
Gettings
Justin L
JL
Irick
Molly
M
Krawiecki
Alexander
A
Brewster
Jay L
JL
D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D015153:Blotting, Western; D022762:CCAAT-Enhancer-Binding Proteins / Q000378:metabolism; D053454:Caspase 12; D061945:Caspase Inhibitors; D020169:Caspases / Q000378:metabolism; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D006224:Cricetinae; D016572:Cyclosporine / Q000494:pharmacology; D045304:Cytochromes c / Q000378:metabolism; D004721:Endoplasmic Reticulum / Q000378:metabolism*; D000091342:Endoplasmic Reticulum Chaperone BiP; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism / Q000528:radiation effects; D006031:Glycosylation / Q000187:drug effects; D006360:Heat-Shock Proteins / Q000378:metabolism; D020287:In Situ Nick-End Labeling; D007306:Insecticides / Q000494:pharmacology; D007473:Ion Channels / Q000187:drug effects / Q000378:metabolism; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D048670:MAP Kinase Kinase 4; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism*; D033681:Mitochondrial Membrane Transport Proteins; D000083162:Mitochondrial Permeability Transition Pore; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism; D018832:Molecular Chaperones / Q000378:metabolism; D009570:Nitriles; D010766:Phosphorylation / Q000187:drug effects; D011722:Pyrethrins / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects*; D016559:Tacrolimus / Q000494:pharmacology; D013696:Temperature; D019284:Thapsigargin / Q000494:pharmacology; D051742:Transcription Factor CHOP; D014157:Transcription Factors / Q000378:metabolism; D014415:Tunicamycin / Q000494:pharmacology; D014466:Ultraviolet Rays; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
D022762:CCAAT-Enhancer-Binding Proteins; D061945:Caspase Inhibitors; D000091342:Endoplasmic Reticulum Chaperone BiP; D006360:Heat-Shock Proteins; D007306:Insecticides; D007473:Ion Channels; D033681:Mitochondrial Membrane Transport Proteins; D000083162:Mitochondrial Permeability Transition Pore; D018832:Molecular Chaperones; D009570:Nitriles; D011722:Pyrethrins; D014157:Transcription Factors; D014415:Tunicamycin; D051742:Transcription Factor CHOP; C017160:cypermethrin; D019284:Thapsigargin; D016572:Cyclosporine; D045304:Cytochromes c; D048031:JNK Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D048670:MAP Kinase Kinase 4; D020929:Mitogen-Activated Protein Kinase Kinases; D053454:Caspase 12; D020169:Caspases; D016559:Tacrolimus; C017690:fenvalerate