title: Glycogen synthase kinase-3 regulates endoplasmic reticulum (ER) stress-induced CHOP expression in neuronal cells.
abstract: Endoplasmic reticulum (ER) stress, often resulting from cellular accumulation of misfolded proteins, occurs in many neurodegenerative disorders, in part because of the relatively long lifetime of neurons. Excessive accumulation of misfolded proteins activates the unfolded protein response (UPR) that dampens protein synthesis and promotes removal of misfolded proteins to support survival of ER-stressed cells. However, the UPR also initiates apoptotic signaling to kill cells if recovery is not achieved. Thus, there is much interest in identifying determinants of the life-death switch and interventions that promote recovery and survival. One intervention that has consistently been shown to protect cells from ER stress-induced apoptosis is application of inhibitors of glycogen synthase kinase-3 (GSK3). Therefore, we examined where in the UPR pathway GSK3 inhibitors intercede to impede signaling towards apoptosis. Apoptosis following UPR activation can be mediated by activation of two transcription factors, ATF4 and ATF6, that activate expression of the death-inducing transcription factor C/EBP homologous protein (CHOP/GADD153) following ER stress. We found that ER stress activated ATF6 and ATF4, but these responses were not inhibited by pretreatment with GSK3 inhibitors. However, inhibition of GSK3 effectively reduced the expression of CHOP, and this was apparent in several types of neural-related cells and was evident after application of several structurally diverse GSK3 inhibitors. Therefore, reduction of CHOP activation provides one mechanism by which inhibitors of GSK3 are capable of shifting cell fate towards survival instead of apoptosis following ER stress.
authors.affiliation: Department of Psychiatry and Behavioral Neurobiology, University of Alabama at Birmingham, AL 35294-0017, USA.
authors.forename: Gordon P
authors.initials: GP
authors.lastname: Meares
authors.forename: Marjelo A
authors.initials: MA
authors.lastname: Mines
authors.forename: Eléonore
authors.initials: E
authors.lastname: Beurel
authors.forename: Tae-Yeon
authors.initials: TY
authors.lastname: Eom
authors.forename: Ling
authors.initials: L
authors.lastname: Song
authors.forename: Anna A
authors.initials: AA
authors.lastname: Zmijewska
authors.forename: Richard S
authors.initials: RS
authors.lastname: Jope
mesh_terms: D051701:Activating Transcription Factor 4 / Q000235:genetics / Q000378:metabolism; D051702:Activating Transcription Factor 6 / Q000235:genetics / Q000378:metabolism; D017209:Apoptosis; D015153:Blotting, Western; D004721:Endoplasmic Reticulum / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008156:Luciferases / Q000378:metabolism; D009447:Neuroblastoma / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D051742:Transcription Factor CHOP / Q000235:genetics / Q000378:metabolism*; D014407:Tumor Cells, Cultured; D056811:Unfolded Protein Response
chemical_list: C497109:ATF4 protein, human; C497111:ATF6 protein, human; D051702:Activating Transcription Factor 6; C497249:DDIT3 protein, human; D004791:Enzyme Inhibitors; D012333:RNA, Messenger; D051701:Activating Transcription Factor 4; D051742:Transcription Factor CHOP; D008156:Luciferases; D038362:Glycogen Synthase Kinase 3