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FLASH GENE
Symbol NOS2 contributors: mct/npt - updated : 10-10-2018
HGNC name nitric oxide synthase 2, inducible
HGNC id 7873
Location 17q11.2      Physical location : 26.083.792 - 26.127.555
Synonym name
  • nitric oxide synthase 2A (inducible, hepatocytes)
  • hepatocyte NOS
  • nitric oxide synthase, macrophage
  • NOS, type II
  • inducible NO synthase
  • Synonym symbol(s) NOS, INOS, NOS2A, HEP-NOS
    EC.number 1.14.13.39
    DNA
    TYPE functioning gene
    STRUCTURE 43.76 kb     27 Exon(s)
    regulatory sequence Promoter
    Binding site   enhancer   hormone
    text structure
  • A-activator binding site (AABS) located at -192 nucleotides in the promoter region
  • NOS2 gene is highly methylated around the NOS2 transcription start site
  • epigenetic regulation of NOS2 by CASP1 involves cleavage of the chromatin regulator PARP1 and chromatin accessibility of the NFKB1 binding sites located at the NOS2 promoter
  • octamer (Oct) element in NOS2 proximal promoter, located close to the TATA box, that constitutively binds POU2F1 and its deletion abrogates cytokine-induced transcription
  • MAPPING cloned Y linked N status confirmed
    RNA
    TRANSCRIPTS type messenger
    identificationnb exonstypebpproduct
    ProteinkDaAAspecific expressionYearPubmed
    27 - 4206 131 1153 - 2016 29637536
    EXPRESSION
    Type widely
       expressed in (based on citations)
    organ(s)
    SystemOrgan level 1Organ level 2Organ level 3Organ level 4LevelPubmedSpeciesStageRna symbol
    Digestiveintestine   highly
     pancreas exocrine   moderately
     pharynx   highly
     stomach   moderately
    Lymphoid/Immune      Homo sapiens
    Nervousbrain     Homo sapiens
    Reproductivefemale systembreastmammary gland moderately
    Respiratorylung    
     respiratory tracttrachea  moderately
    tissue
    SystemTissueTissue level 1Tissue level 2LevelPubmedSpeciesStageRna symbol
    Blood / hematopoietic    
    Connectivebone   
    Connectivecartilage   
    Epithelialbarrier/lining   
    Nervouscentral   
    cells
    SystemCellPubmedSpeciesStageRna symbol
     chondrocyte
    Digestivehepatocyte
    Lymphoid/Immuneactivated B lymphocyte Homo sapiens
    Lymphoid/Immunemacrophage
    Nervousneuron Homo sapiens
    cell lineage
    cell lines
    fluid/secretion
    at STAGE
    PROTEIN
    PHYSICAL PROPERTIES
    STRUCTURE
    motifs/domains
  • a flavodoxin-like domain
  • an FAD/NAD(P) binding FR-type domain
  • an oxidoreductase domain
  • mono polymer homomer , dimer
    HOMOLOGY
    interspecies homolog to rattus Nos2 (80.2 pc)
    homolog to murine Nos2 (81.2 pc)
    intraspecies paralog to nitrite oxide synthases
    homolog to sequences found in the SMS repeat gene clusters SMS-REPD,SMS-REPM,REPP (see symbols)
    Homologene
    FAMILY
  • NOS family
  • CATEGORY enzyme , immunity/defense , transport carrier
    SUBCELLULAR LOCALIZATION     plasma membrane
        intracellular
    intracellular,cytoplasm,organelle,membrane
    intracellular,cytoplasm,organelle,peroxisome
    intracellular,cytoplasm,organelle,endoplasmic reticulum
    intracellular,cytoplasm,cytosolic,vesicle
    intracellular,cytoplasm,cytoskeleton
    intracellular,nucleus
    text
  • cortical cytoskeletal
  • perinuclear region of cytoplasm
  • basic FUNCTION
  • producing nitric oxide synthesis from arginine and molecular oxygen
  • playing a role in neurogenesis
  • role for IDO1 in the regulation of blood pressure, although the contribution of IDO1 to sepsis-induced hypotension is smaller that that of NOS2 (Hofmann 2010)
  • role of NOS2 as a critical host factor regulating apoptosis during respiratory syncytial virus (RSV) infection
  • immune-activated glial cells produced NOS2
  • its expression is restricted to neurons in the healthy brain but is triggered in microglia upon inflammation
  • is an important mediator in high-cholesterol diet (HCD)-induced liver fibrosis
  • NOS2 is calcium-independent and is inducible
  • is a major signaling molecule involved in innate immunity
  • is a novel negative regulator of hematopoietic cell migration and prevents egress of hematopoietic stem/progenitor cells (HSPCs) into peripheral blood (PB) during mobilization
  • crucial role of endogenous NOS2 in promoting optimal IL2 production, proliferation and glycolysis of gamma-delta T cells that may contribute to their regulation at steady state
  • is necessary for the microbicidal activity of macrophages
  • regulates a number of cellular processes in these cell types without exerting toxicity
  • CELLULAR PROCESS
    PHYSIOLOGICAL PROCESS development , immunity/defense , inflammation , electron transport
    text
  • tumoricidal and bactericidal
  • electron carrier
  • neurogenesis
  • PATHWAY
    metabolism aminoacid
    signaling
  • arginine catabolism
  • NOS2 and IDO1 pathways are implicated in antimicrobial activities, antitumor defense, neuropathology and immune regulation (Hofmann 2010)
  • a component
  • specific aminoacids critical for dimerization and catalytic activity (in the domain encoded by exons 8 and 9)
  • dimeric form of the enzyme stabilized by tetrahydrobiopterin (BH4)
  • INTERACTION
    DNA
    RNA
    small molecule cofactor,
  • heme
  • FAD
  • FMN
  • Ca2+
  • Fe2+
  • NADP
  • Zn2+
  • protein
  • calmodulin binding protein, Ca2+ dependent
  • with CEBPB through the AABS promoter response element
  • binding to SLC9A3R1
  • phosphorylated TP63 induces transcription of ADRM1, leading to NOS2 protein degradation
  • POU2F1 cooperates with the TATA binding initiation complex to control rapid transcription of NOS2
  • XPO1 and EIF4E seem to play an important role in the nucleocytoplasmic export of human NOS2 mRNA
  • positive feedback regulation of inducible nitric-oxide synthase expression by RAS protein S-nitrosylation
  • RELA and STAT1 cooperate to control NOS2 gene transcription in response to proinflammatory cytokines by a coactivator exchange mechanism
  • required for plasma cells (PCs)to respond to some prosurvival mediators associated with bone marrow stromal cells and at least one mediator, IL6, fed directly into this pathway by inducing NOS2
  • IGF1 inhibits cells apoptosis in pulmonary artery smooth muscle cells (PASMC) by activating the MAPK14-NOS2 transduction pathway
  • MMP12 regulates adipose tissue expansion, insulin sensitivity, and expression of NOS2
  • coactivator EP300 mediates cytokine-induced NOS2 transactivation by forming a distant DNA loop between its enhancer and core promoter region
  • is a potential target of the histone methyltransferase EZH2 which mediates trimethylation of histone 3 at lysine 27 (H3K27me3)
  • during transdifferentiation, innate immune activation increases NOS2 generation of NO to S-nitrosylate RING1, a key member of the polycomb repressive complex
  • KLF4 is important for regulating the expression of NOS2 by TNF in human synoviocytes
  • FYN has likely a regulatory role in NOS2 expression in astrocytes during neuroinflammatory responses
  • cell & other
    REGULATION
    activated by KLF5 (KLF5 activates NOS2 gene transcription and is involved in vascular inflammatory injury and remodeling)
    induced by endotoxins, cytokines
    HMGA1
    cytokines and endotoxin with IDO1 in the vascular endothelium (Hofmann 2010)
    inhibited by aspirin
    repressed by ELK3
    aspirin
    Other regulated by calcium/calmodulin
    regulation of NOS2 induction by the interaction between the spliced and unspliced forms of XBP1 in response to ER stress
    is regulated on the expressional level mostly by post-transcriptional mechanisms modulating the mRNA stability
    ASSOCIATED DISORDERS
    corresponding disease(s)
    Other morbid association(s)
    TypeGene ModificationChromosome rearrangementProtein expressionProtein Function
    constitutional     --over  
    in astrocytes in the optic nerve head and lamina cribosa of glaucomatous eyes (neurotoxic effect)
    tumoral     --over  
    of NOS2 expression in borderline and malignant epithelial ovarian tumours indicates its involvement in the development and progression of epithelial ovarian cancer (EOC), and its increased expression in less differentiated cancers suggests their association with poor prognosis in this category of tumours
    tumoral     --over  
    in pancreatic ductal adenocarcinoma (PDAC)
    Susceptibility
  • cerebral malaria and severe malarial anemia
  • to multiple sclerosis
  • to pulmonary tuberculosis
  • Variant & Polymorphism SNP
  • promoter C1173T protecting against severe malaria
  • allele 1659 T marker of cerebral malaria
  • variant increasing the risk of multiple sclerosis
  • variants may contribute to TB susceptibility, particularly in individuals of African descent, and may act synergistically with SNPs in TLR4 and IFNGR1 (NOS2A rs2248814 and IFNGR1 rs1327474 and NOS2A rs944722 and IFNGR1 rs1327474 )(Velez 2009)
  • Candidate gene
  • allele sharing with NOS2A and other markers of chromosome 17 (D17S949, D17S799)
  • candidate for MS susceptibility
  • Marker
  • potential relevance of NOS2 as a prognostic factor for glioma malignancy and recurrence
  • NOS2 is a predictor of prognosis in early stage, resected PDAC patients
  • Therapy target
    SystemTypeDisorderPubmed
    cancerdigestivepancreas
    targeting NOS2 may have potential therapeutic value in pancreatic ductal adenocarcinoma
    cancerangiogenesis 
    Therapeutic manipulation of iNOS levels may remove a critical cytoprotective mechanism of importance in tumour angiogenesis
    ANIMAL & CELL MODELS