title: Ask1 gene deletion blocks maternal diabetes-induced endoplasmic reticulum stress in the developing embryo by disrupting the unfolded protein response signalosome.
abstract: Apoptosis signal-regulating kinase 1 (ASK1) is activated by various stresses. The link between ASK1 activation and endoplasmic reticulum (ER) stress, two causal events in diabetic embryopathy, has not been determined. We sought to investigate whether ASK1 is involved in the unfolded protein response (UPR) that leads to ER stress. Deleting Ask1 abrogated diabetes-induced UPR by suppressing phosphorylation of inositol-requiring enzyme 1α (IRE1α), and double-stranded RNA-activated protein kinase (PKR)-like ER kinase (PERK) blocked the mitochondrial translocation of proapoptotic Bcl-2 members and ER stress. ASK1 participated in the IRE1α signalosome, and removing ASK1 abrogated the proapoptotic kinase activity of IRE1α. Ask1 deletion suppressed diabetes-induced IRE1α endoriboneclease activities, which led to X-box binding protein 1 mRNA cleavage, an ER stress marker, decreased expression of microRNAs, and increased expression of a miR-17 target, thioredoxin-interacting protein (Txnip), a thioredoxin binding protein, which enhanced ASK1 activation by disrupting the thioredoxin-ASK1 complexes. ASK1 is essential for the assembly and function of the IRE1α signalosome, which forms a positive feedback loop with ASK1 through Txnip. ASK1 knockdown in C17.2 neural stem cells diminished high glucose- or tunicamycin-induced IRE1α activation, which further supports our hypothesis that ASK1 plays a causal role in diabetes-induced ER stress and apoptosis.
authors.affiliation: Department of Obstetrics, Gynecology and Reproductive Sciences, University of Maryland School of Medicine, Baltimore, MD.
authors.forename: Fang
authors.initials: F
authors.lastname: Wang
authors.affiliation: Department of Obstetrics, Gynecology and Reproductive Sciences, University of Maryland School of Medicine, Baltimore, MD.
authors.forename: Yanqing
authors.initials: Y
authors.lastname: Wu
authors.affiliation: Department of Obstetrics, Gynecology and Reproductive Sciences, University of Maryland School of Medicine, Baltimore, MD.
authors.forename: Hui
authors.initials: H
authors.lastname: Gu
authors.affiliation: Department of Obstetrics, Gynecology and Reproductive Sciences, University of Maryland School of Medicine, Baltimore, MD Department of Biochemistry and Molecular Biology, University of Maryland School of Medicine, Baltimore, MD.
authors.forename: E Albert
authors.initials: EA
authors.lastname: Reece
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Maryland School of Medicine, Baltimore, MD Center for Biomedical Engineering and Technology, University of Maryland School of Medicine, Baltimore, MD Department of Physiology, University of Maryland School of Medicine, Baltimore, MD.
authors.forename: Shengyun
authors.initials: S
authors.lastname: Fang
authors.affiliation: Department of Obstetrics, Gynecology and Reproductive Sciences, University of Maryland School of Medicine, Baltimore, MD.
authors.forename: Rinat
authors.initials: R
authors.lastname: Gabbay-Benziv
authors.affiliation: Department of Obstetrics, Gynecology and Reproductive Sciences, University of Maryland School of Medicine, Baltimore, MD.
authors.forename: Graham
authors.initials: G
authors.lastname: Aberdeen
authors.affiliation: Department of Obstetrics, Gynecology and Reproductive Sciences, University of Maryland School of Medicine, Baltimore, MD Department of Biochemistry and Molecular Biology, University of Maryland School of Medicine, Baltimore, MD pyang@fpi.umaryland.edu.
authors.forename: Peixin
authors.initials: P
authors.lastname: Yang
mesh_terms: D000818:Animals; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism; D002478:Cells, Cultured; D016640:Diabetes, Gestational / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D059865:Endoplasmic Reticulum Stress / Q000235:genetics / Q000502:physiology*; D004722:Endoribonucleases / Q000235:genetics / Q000378:metabolism; D005260:Female; D047468:Immunoprecipitation; D020287:In Situ Nick-End Labeling; D048848:MAP Kinase Kinase Kinase 5 / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011247:Pregnancy; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D060888:Real-Time Polymerase Chain Reaction; D013879:Thioredoxins / Q000235:genetics / Q000378:metabolism; D056811:Unfolded Protein Response / Q000235:genetics / Q000502:physiology*
chemical_list: D002352:Carrier Proteins; C445672:Txnip protein, mouse; D013879:Thioredoxins; C510185:Ern1 protein, mouse; D017346:Protein Serine-Threonine Kinases; D048848:MAP Kinase Kinase Kinase 5; C482859:Map3k5 protein, mouse; D004722:Endoribonucleases