title: Hypoxic preconditioning decreases nuclear factor κB activity via Disrupted in Schizophrenia-1.
abstract: Nuclear factor κB is a key mediator of inflammation during conditions of hypoxia. Here, we used models of hypoxic pre-conditioning as mechanism to decrease nuclear factor κB activity induced by hypoxia. Our initial studies suggested that Disrupted in Schizophrenia-1 may be induced by hypoxic pre-conditioning and possibly involved in the regulation of nuclear factor κB. In this study we used Disrupted in Schizophrenia-1 exogenous over-expression and knock-down to determine its effect on ataxia telangiectasia mutated--nuclear factor κB activation cascade. Our results demonstrated that hypoxic pre-conditioning significantly increased the expression of Disrupted in Schizophrenia-1 at mRNA and protein levels both in vitro and in vivo. Over-expression of Disrupted in Schizophrenia-1 significantly attenuated the hypoxia-mediated ataxia telangiectasia mutated phosphorylation and prevented its cytoplasm translocation where it functions to activate nuclear factor κB. We further determined that Disrupted in Schizophrenia-1 activated the protein phosphatase 2A, preventing the phosphorylation of ataxia telangiectasia mutated serine-1981, the main regulatory site of ataxia telangiectasia mutated activity. Cellular levels of Disrupted in Schizophrenia-1 protein significantly decreased nuclear factor κB activation profiles and pro-inflammatory gene expression. Taken together, these results demonstrate that hypoxic pre-conditioning decreases the activation of nuclear factor κB through the transcriptional induction of Disrupted in Schizophrenia-1.
authors.affiliation: Department of Anesthesiology, Perioperative and Pain Medicine, Boston Children's Hospital and Harvard Medical School, Boston, MA 02115, United States. Electronic address: Jia-Ren.Liu@childrens.harvard.edu.
authors.forename: Jia-Ren
authors.initials: JR
authors.lastname: Liu
authors.affiliation: Department of Pediatric Surgery, The First Affiliated Hospital of GanNan Medical University, JiangXi 341000, PR China.
authors.forename: Qian
authors.initials: Q
authors.lastname: Liu
authors.affiliation: Department of Anesthesiology, Perioperative and Pain Medicine, Boston Children's Hospital and Harvard Medical School, Boston, MA 02115, United States.
authors.forename: Joseph
authors.initials: J
authors.lastname: Khoury
authors.affiliation: Department of Anesthesiology, Perioperative and Pain Medicine, Boston Children's Hospital and Harvard Medical School, Boston, MA 02115, United States.
authors.forename: Yue-Jin
authors.initials: YJ
authors.lastname: Li
authors.affiliation: Department of Anesthesiology, Perioperative and Pain Medicine, Boston Children's Hospital and Harvard Medical School, Boston, MA 02115, United States.
authors.forename: Xiao-Hui
authors.initials: XH
authors.lastname: Han
authors.affiliation: Laboratory of Stem Cell and Tissue Engineering, Department of Histology and Embryology, Chongqing Medical University, Chongqing 400016, PR China.
authors.forename: Jing
authors.initials: J
authors.lastname: Li
authors.affiliation: Department of Anesthesiology, Perioperative and Pain Medicine, Boston Children's Hospital and Harvard Medical School, Boston, MA 02115, United States. Electronic address: juan.ibla@childrens.harvard.edu.
authors.forename: Juan C
authors.initials: JC
authors.lastname: Ibla
mesh_terms: D000818:Animals; D064007:Ataxia Telangiectasia Mutated Proteins / Q000235:genetics / Q000378:metabolism; D015687:Cell Hypoxia / Q000235:genetics; D045744:Cell Line, Tumor; D004847:Epithelial Cells / Q000378:metabolism* / Q000473:pathology; D005786:Gene Expression Regulation; D006367:HeLa Cells; D006801:Humans; D000860:Hypoxia / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009154:Mutation; D016328:NF-kappa B / Q000235:genetics* / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000235:genetics* / Q000378:metabolism; D010766:Phosphorylation; D054648:Protein Phosphatase 2 / Q000235:genetics / Q000378:metabolism; D021381:Protein Transport; D012333:RNA, Messenger / Q000235:genetics* / Q000378:metabolism; D012694:Serine / Q000378:metabolism; D015398:Signal Transduction
chemical_list: C412476:DISC1 protein, human; D016328:NF-kappa B; D009419:Nerve Tissue Proteins; D012333:RNA, Messenger; D012694:Serine; C576324:ATM protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; D054648:Protein Phosphatase 2
keywords: Ataxia telangiectasia mutated; Disrupted in Schizophrenia-1; Hypoxia; Hypoxic preconditioning; Normoxia; Nuclear factor κB; Protein phosphatase 2A