title: Endoplasmic reticulum stress-induced apoptosis is partly mediated by reduced insulin signaling through phosphatidylinositol 3-kinase/Akt and increased glycogen synthase kinase-3beta in mouse insulinoma cells.
abstract: An imbalance between the rate of protein synthesis and folding capacity of the endoplasmic reticulum (ER) results in stress that has been increasingly implicated in pancreatic islet beta-cell apoptosis and diabetes. Because insulin/IGF/Akt signaling has been implicated in beta-cell survival, we sought to determine whether this pathway is involved in ER stress-induced apoptosis. Mouse insulinoma cells treated with pharmacological agents commonly used to induce ER stress exhibited apoptosis within 48 h. ER stress-induced apoptosis was inhibited by cotreatment of the cells with IGF-1. Stable cell lines were created by small-interfering RNA (siRNA) with graded reduction of insulin receptor expression, and these cells had enhanced susceptibility to ER stress-induced apoptosis and reduced levels of phospho-glycogen synthase kinase 3beta (GSK3beta). In control cells, ER stress-induced apoptosis was associated with a reduction in phospho-Akt and phospho-GSK3beta. To further assess the role of GSK3beta in ER stress-induced apoptosis, stable cell lines were created by siRNA with up to 80% reduction in GSK3beta expression. These cells were found to resist ER stress-induced apoptosis. These results illustrate that ER stress-induced apoptosis is mediated at least in part by signaling through the phosphatidylinositol 3-kinase/Akt/GSK3beta pathway and that GSK3beta represents a novel target for agents to promote beta-cell survival.
authors.affiliation: Division of Endocrinology, Metabolism, and Lipid Research, Washington University School of Medicine, 660 S. Euclid Ave., Campus Box 8127, St. Louis, MO 63110, USA.
authors.forename: Shanthi
authors.initials: S
authors.lastname: Srinivasan
authors.forename: Mitsuru
authors.initials: M
authors.lastname: Ohsugi
authors.forename: Zhonghao
authors.initials: Z
authors.lastname: Liu
authors.forename: Szabolcs
authors.initials: S
authors.lastname: Fatrai
authors.forename: Ernesto
authors.initials: E
authors.lastname: Bernal-Mizrachi
authors.forename: M Alan
authors.initials: MA
authors.lastname: Permutt
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D020126:Brefeldin A / Q000494:pharmacology; D045744:Cell Line, Tumor; D004721:Endoplasmic Reticulum / Q000502:physiology*; D015870:Gene Expression; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000071679:Glycogen Synthase Kinase 3 beta; D007328:Insulin / Q000502:physiology*; D007334:Insulin-Like Growth Factor I / Q000494:pharmacology; D007340:Insulinoma; D007515:Islets of Langerhans / Q000378:metabolism*; D048031:JNK Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors; D048670:MAP Kinase Kinase 4; D020929:Mitogen-Activated Protein Kinase Kinases / Q000037:antagonists & inhibitors; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt; D015398:Signal Transduction; D019284:Thapsigargin / Q000494:pharmacology; D014415:Tunicamycin / Q000494:pharmacology
chemical_list: D020126:Brefeldin A; D038362:Glycogen Synthase Kinase 3; D000071679:Glycogen Synthase Kinase 3 beta; D007328:Insulin; D007334:Insulin-Like Growth Factor I; D048031:JNK Mitogen-Activated Protein Kinases; D048670:MAP Kinase Kinase 4; D020929:Mitogen-Activated Protein Kinase Kinases; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; D019284:Thapsigargin; D014415:Tunicamycin; C000605507:Gsk3b protein, mouse