Central role of glycogen synthase kinase-3beta in endoplasmic reticulum stress-induced caspase-3 activation.
Stress of the endoplasmic reticulum (ER), which is associated with many neurodegenerative conditions, can lead to the elimination of affected cells by apoptosis through only partially understood mechanisms. Thapsigargin, which causes ER stress by inhibiting the ER Ca(2+)-ATPase, was found to not only activate the apoptosis effector caspase-3 but also to cause a large and prolonged increase in the activity of glycogen synthase kinase-3beta (GSK3beta). Activation of GSK3beta was obligatory for thapsigargin-induced activation of caspase-3, because inhibition of GSK3beta by expression of dominant-negative GSK3beta or by the GSK3beta inhibitor lithium blocked caspase-3 activation. Thapsigargin treatment activated GSK3beta by inducing dephosphorylation of phospho-Ser-9 of GSK3beta, a phosphorylation that normally maintains GSK3beta inactivated. Caspase-3 activation induced by thapsigargin was blocked by increasing the phosphorylation of Ser-9-GSK3beta with insulin-like growth factor-1 or with the phosphatase inhibitors okadaic acid and calyculin A, but the calcineurin inhibitors FK506 and cyclosporin A were ineffective. Insulin-like growth factor-1, okadaic acid, calyculin A, and lithium also protected cells from two other inducers of ER stress, tunicamycin and brefeldin A. Thus, ER stress activates GSK3beta through dephosphorylation of phospho-Ser-9, a prerequisite for caspase-3 activation, and this process is amenable to pharmacological intervention.
Song
Ling
L
Department of Psychiatry and Behavioral Neurobiology, University of Alabama at Birmingham, Birmingham, Alabama 35294-0017, USA.
De Sarno
Patrizia
P
Jope
Richard S
RS
D000900:Anti-Bacterial Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D020126:Brefeldin A / Q000494:pharmacology; D019703:Calcineurin / Q000378:metabolism; D065095:Calcineurin Inhibitors; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism*; D004721:Endoplasmic Reticulum / Q000378:metabolism*; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D000071679:Glycogen Synthase Kinase 3 beta; D006624:Hippocampus / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000494:pharmacology; D018021:Lithium Chloride / Q000494:pharmacology; D009447:Neuroblastoma; D018696:Neuroprotective Agents / Q000494:pharmacology; D010766:Phosphorylation; D011506:Proteins / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D019284:Thapsigargin / Q000494:pharmacology; D014407:Tumor Cells, Cultured; D014415:Tunicamycin / Q000494:pharmacology
D000900:Anti-Bacterial Agents; D065095:Calcineurin Inhibitors; D004791:Enzyme Inhibitors; D018696:Neuroprotective Agents; D011506:Proteins; D014415:Tunicamycin; D020126:Brefeldin A; D019284:Thapsigargin; D007334:Insulin-Like Growth Factor I; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; D038362:Glycogen Synthase Kinase 3; D019703:Calcineurin; C505407:CASP3 protein, human; D053148:Caspase 3; D020169:Caspases; D018021:Lithium Chloride