title: Induction of a unique isoform of the NCOA7 oxidation resistance gene by interferon β-1b.
abstract: We demonstrate that interferon (IFN)-β-1b induces an alternative-start transcript containing the C-terminal TLDc domain of nuclear receptor coactivator protein 7 (NCOA7), a member of the OXR family of oxidation resistance proteins. IFN-β-1b induces NCOA7-AS (alternative start) expression in peripheral blood mononuclear cells (PBMCs) obtained from healthy individuals and multiple sclerosis patients and human fetal brain cells, astrocytoma, neuroblastoma, and fibrosarcoma cells. NCOA7-AS is a previously undocumented IFN-β-inducible gene that contains only the last 5 exons of full-length NCOA7 plus a unique first exon (exon 10a) that is not found in longer forms of NCOA7. This exon encodes a domain closely related to an important class of bacterial aldo-keto oxido-reductase proteins that play a critical role in regulating redox activity. We demonstrate that NCOA7-AS is induced by IFN and LPS, but not by oxidative stress and exhibits, independently, oxidation resistance activity. We further demonstrate that induction of NCOA7-AS by IFN is dependent on IFN-receptor activation, the Janus kinase-signal transducers and activators of transcription (JAK-STAT) signaling pathway, and a canonical IFN-stimulated response element regulatory sequence upstream of exon 10a. We describe a new role for IFN-βs involving a mechanism of action that leads to an increase in resistance to inflammation-mediated oxidative stress.
authors.affiliation: 1 Department of Microbiology and Physiological Systems, University of Massachusetts Medical School , Worcester, Massachusetts.
authors.forename: Lijian
authors.initials: L
authors.lastname: Yu
authors.forename: Ed
authors.initials: E
authors.lastname: Croze
authors.forename: Ken D
authors.initials: KD
authors.lastname: Yamaguchi
authors.forename: Tiffany
authors.initials: T
authors.lastname: Tran
authors.forename: Anthony T
authors.initials: AT
authors.lastname: Reder
authors.forename: Vladimir
authors.initials: V
authors.lastname: Litvak
authors.forename: Michael R
authors.initials: MR
authors.lastname: Volkert
mesh_terms: D000595:Amino Acid Sequence; D002460:Cell Line; D006801:Humans; D007167:Immunotherapy / Q000379:methods*; D016899:Interferon-beta / Q000378:metabolism*; D053612:Janus Kinases / Q000378:metabolism; D007963:Leukocytes, Mononuclear / Q000502:physiology*; D008969:Molecular Sequence Data; D009103:Multiple Sclerosis / Q000276:immunology / Q000628:therapy*; D056918:Nuclear Receptor Coactivators / Q000235:genetics / Q000378:metabolism*; D010084:Oxidation-Reduction; D018384:Oxidative Stress; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism*; D017434:Protein Structure, Tertiary / Q000235:genetics; D017471:Receptors, Interferon / Q000378:metabolism; D050436:Regulatory Elements, Transcriptional / Q000235:genetics; D050791:STAT Transcription Factors / Q000378:metabolism; D015398:Signal Transduction
chemical_list: C455500:NCOA7 protein, human; D056918:Nuclear Receptor Coactivators; D020033:Protein Isoforms; D017471:Receptors, Interferon; D050791:STAT Transcription Factors; D016899:Interferon-beta; D053612:Janus Kinases