title: High Glucose-Repressed CITED2 Expression Through miR-200b Triggers the Unfolded Protein Response and Endoplasmic Reticulum Stress.
abstract: High glucose in vivo and in vitro induces neural tube defects (NTDs). CITED2 (CBP/p300-interacting transactivator with ED-rich tail 2) is essential for neural tube closure. We explored the regulatory mechanism underlying CITED2 expression and its relationship with miRNA and endoplasmic reticulum (ER) stress. miR-200b levels were increased by maternal diabetes or high glucose in vitro, and this increase was abrogated by transgenic overexpression of superoxide dismutase 1 (SOD1) or an SOD1 mimetic. CITED2 was the target of miR-200b and was downregulated by high glucose. Two miR-200b binding sites in the 3'-untranslated region of the CITED2 mRNA were required for inhibiting CITED2 expression. The miR-200b mimic and a CITED2 knockdown mimicked the stimulative effect of high glucose on unfolded protein response (UPR) and ER stress, whereas the miR-200b inhibitor and CITED2 overexpression abolished high glucose-induced UPR signaling, ER stress, and apoptosis. The ER stress inhibitor, 4-phenylbutyrate, blocked CITED2 knockdown-induced apoptosis. Furthermore, the miR-200b inhibitor reversed high glucose-induced CITED2 downregulation, ER stress, and NTDs in cultured embryos. Thus, we showed a novel function of miR-200b and CITED2 in high glucose-induced UPR and ER stress, suggesting that miR-200b and CITED2 are critical for ER homeostasis and NTD formation in the developing embryo.
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.
authors.forename: Jingwen
authors.initials: J
authors.lastname: Yu
authors.affiliation: Department of Obstetrics, Gynecology, and Reproductive Sciences, University of Maryland School of Medicine, Baltimore, MD.
authors.forename: Daoyin
authors.initials: D
authors.lastname: Dong
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Maryland School of Medicine, Baltimore, MD.
authors.forename: Qun
authors.initials: Q
authors.lastname: Zhou
authors.affiliation: Cell Biology Group, Department of Surgery, University of Maryland School of Medicine, Baltimore, MD.
authors.forename: Jian-Ying
authors.initials: JY
authors.lastname: Wang
authors.affiliation: Center for Biomedical Engineering and Technology, 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 Department of Biochemistry and Molecular Biology, University of Maryland School of Medicine, Baltimore, MD pyang@upi.umaryland.edu.
authors.forename: Peixin
authors.initials: P
authors.lastname: Yang
mesh_terms: D020413:3' Untranslated Regions; D000818:Animals; D017209:Apoptosis / Q000235:genetics; D001786:Blood Glucose / Q000378:metabolism; D003921:Diabetes Mellitus, Experimental / Q000196:embryology* / Q000235:genetics / Q000378:metabolism; D004622:Embryo, Mammalian; D059865:Endoplasmic Reticulum Stress / Q000235:genetics*; D005260:Female; D055785:Gene Knockdown Techniques; D015151:Immunoblotting; D020287:In Situ Nick-End Labeling; D066298:In Vitro Techniques; D051379:Mice; D008822:Mice, Transgenic; D035683:MicroRNAs / Q000235:genetics*; D058953:Neural Stem Cells; D009436:Neural Tube Defects / Q000196:embryology* / Q000235:genetics / Q000378:metabolism; D010654:Phenylbutyrates / Q000494:pharmacology; D011247:Pregnancy; D012333:RNA, Messenger / Q000378:metabolism*; D012097:Repressor Proteins / Q000235:genetics* / Q000378:metabolism; D013482:Superoxide Dismutase / Q000235:genetics; D000072105:Superoxide Dismutase-1; D015534:Trans-Activators / Q000235:genetics* / Q000378:metabolism; D056811:Unfolded Protein Response / Q000235:genetics*
chemical_list: D020413:3' Untranslated Regions; D001786:Blood Glucose; C110087:Cited2 protein, mouse; D035683:MicroRNAs; C543719:Mirn200 microRNA, mouse; D010654:Phenylbutyrates; D012333:RNA, Messenger; D012097:Repressor Proteins; D015534:Trans-Activators; C075773:4-phenylbutyric acid; C000606291:Sod1 protein, mouse; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1