title: Calcium/calmodulin-dependent protein kinase II links ER stress with Fas and mitochondrial apoptosis pathways.
abstract: ER stress-induced apoptosis is implicated in various pathological conditions, but the mechanisms linking ER stress-mediated signaling to downstream apoptotic pathways remain unclear. Using human and mouse cell culture and in vivo mouse models of ER stress-induced apoptosis, we have shown that cytosolic calcium resulting from ER stress induces expression of the Fas death receptor through a pathway involving calcium/calmodulin-dependent protein kinase IIgamma (CaMKIIgamma) and JNK. Remarkably, CaMKIIgamma was also responsible for processes involved in mitochondrial-dependent apoptosis, including release of mitochondrial cytochrome c and loss of mitochondrial membrane potential. CaMKII-dependent apoptosis was also observed in a number of cultured human and mouse cells relevant to ER stress-induced pathology, including cultured macrophages, endothelial cells, and neuronal cells subjected to proapoptotic ER stress. Moreover, WT mice subjected to systemic ER stress showed evidence of macrophage mitochondrial dysfunction and apoptosis, renal epithelial cell apoptosis, and renal dysfunction, and these effects were markedly reduced in CaMKIIgamma-deficient mice. These data support an integrated model in which CaMKII serves as a unifying link between ER stress and the Fas and mitochondrial apoptotic pathways. Our study also revealed what we believe to be a novel proapoptotic function for CaMKII, namely, promotion of mitochondrial calcium uptake. These findings raise the possibility that CaMKII inhibitors could be useful in preventing apoptosis in pathological settings involving ER stress-induced apoptosis.
authors.affiliation: Department of Medicine, Columbia University, 630 West 168th Street, New York, NY 10032, USA.
authors.forename: Jenelle M
authors.initials: JM
authors.lastname: Timmins
authors.forename: Lale
authors.initials: L
authors.lastname: Ozcan
authors.forename: Tracie A
authors.initials: TA
authors.lastname: Seimon
authors.forename: Gang
authors.initials: G
authors.lastname: Li
authors.forename: Cristina
authors.initials: C
authors.lastname: Malagelada
authors.forename: Johannes
authors.initials: J
authors.lastname: Backs
authors.forename: Thea
authors.initials: T
authors.lastname: Backs
authors.forename: Rhonda
authors.initials: R
authors.lastname: Bassel-Duby
authors.forename: Eric N
authors.initials: EN
authors.lastname: Olson
authors.forename: Mark E
authors.initials: ME
authors.lastname: Anderson
authors.forename: Ira
authors.initials: I
authors.lastname: Tabas
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D002118:Calcium / Q000378:metabolism; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000235:genetics / Q000378:metabolism*; D002478:Cells, Cultured; D002784:Cholesterol / Q000378:metabolism; D004721:Endoplasmic Reticulum / Q000378:metabolism*; D004789:Enzyme Activation; D004847:Epithelial Cells / Q000166:cytology / Q000502:physiology; D006801:Humans; D007684:Kidney Tubules / Q000166:cytology; D017737:Macrophages, Peritoneal / Q000166:cytology / Q000378:metabolism; D053078:Membrane Potential, Mitochondrial / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008928:Mitochondria / Q000378:metabolism*; D048056:Mitogen-Activated Protein Kinase 9 / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D050794:STAT1 Transcription Factor / Q000235:genetics / Q000378:metabolism; D013312:Stress, Physiological; D019284:Thapsigargin / Q000378:metabolism; D019014:fas Receptor / Q000235:genetics / Q000378:metabolism*
chemical_list: D034741:RNA, Small Interfering; D050794:STAT1 Transcription Factor; C494080:Stat1 protein, mouse; D019014:fas Receptor; D019284:Thapsigargin; D002784:Cholesterol; D048056:Mitogen-Activated Protein Kinase 9; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D002118:Calcium