Affinage

NOS2

Nitric oxide synthase, inducible · UniProt P35228

Round 2 corrected
Length
1153 aa
Mass
131.1 kDa
Annotated
2026-04-29
130 papers in source corpus 31 papers cited in narrative 32 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

NOS2 (inducible nitric oxide synthase, iNOS) is a calcium-independent homodimeric enzyme that oxidizes L-arginine to nitric oxide (NO) and L-citrulline using FMN, FAD, NADPH, heme, and tetrahydrobiopterin cofactors, with dimer stability maintained by a zinc-tetrathiolate center at the subunit interface (PMID:10074942, PMID:10409685). Transcription of the human NOS2 gene requires cytokine-responsive promoter elements extending up to −16 kb and is driven by NF-κB, STAT-1α, NFAT (via Sur1-Trpm4/calcineurin signaling), and HDAC2–NF-κB complexes, while NOS2-derived NO feeds back to inhibit its own expression through S-nitrosylation of NF-κB p65 at a conserved Rel-domain cysteine (PMID:8577713, PMID:12138131, PMID:27246103, PMID:17720813). NOS2 protein turnover is regulated by proteasomal degradation via the FBXO45/MYCBP2 E3 ubiquitin ligase complex, and NOS2 is targeted to peroxisomes through PEX7 and EBP50 (PMID:23438482, PMID:23474170). Downstream, NOS2-derived NO drives wound healing, collagen synthesis, and fibroblast proliferation (PMID:9486966, PMID:11490353), bridges to polyamine metabolism via LACC1-mediated conversion of L-citrulline to L-ornithine (PMID:35978195), S-nitrosylates RING1A to relieve polycomb-mediated epigenetic repression during transdifferentiation (PMID:27623813), promotes DNMT1 degradation and LINE-1 retrotransposon activation via p38-MAPK/KAT5 (PMID:35584114), and contributes to oncogenesis in KRAS-mutant lung cancer and ER-negative breast cancer (PMID:22618808, PMID:24733928); inherited complete NOS2 deficiency in humans causes selective susceptibility to cytomegalovirus disease (PMID:31995689).

Mechanistic history

Synthesis pass · year-by-year structured walk · 21 steps
  1. 1993 High

    Molecular cloning from multiple human tissues established that a single human iNOS isoform (NOS2) exists, resolving uncertainty about whether humans express a functional inducible NOS and defining its cofactor requirements (FMN, FAD, NADPH) and calcium-independent catalysis.

    Evidence cDNA cloning from hepatocytes, chondrocytes, and DLD-1 cells with heterologous expression in 293 and CHO cells and purified enzyme assays

    PMID:7504305 PMID:7682706 PMID:7692964

    Open questions at the time
    • Calmodulin binding was identified by sequence but its structural role in constitutive activation was not resolved
    • Tissue-specific splice variants were not excluded
  2. 1993 High

    NOS2-derived NO was linked to a specific pathophysiological effector function — cytokine-induced suppression of glucose-stimulated insulin secretion in human islets — establishing NO as a mediator of beta-cell dysfunction.

    Evidence Human islet culture with cytokine stimulation, L-NMMA inhibition, nitrite assay, cGMP measurement, and EPR spectroscopy

    PMID:8383325

    Open questions at the time
    • Downstream NO targets in beta cells not identified
    • Relative contributions of cGMP-dependent vs. cGMP-independent NO signaling not dissected
  3. 1994 High

    Genomic characterization and in vivo expression studies revealed the human NOS2 gene structure (26 exons, chromosome 17q) and showed that constitutive NOS2 expression occurs in airway epithelium and EBV-transformed B cells, overturning the assumption that NOS2 is exclusively inducible.

    Evidence Genomic library screening, FISH mapping, in situ hybridization of airway epithelium, RT-PCR/NOS activity in EBV-transformed B cells

    PMID:7509810 PMID:7528106 PMID:7544004

    Open questions at the time
    • Mechanisms sustaining constitutive expression in airway epithelium not defined
    • Whether constitutive expression reflects tonic cytokine signaling was unresolved
  4. 1996 High

    Systematic promoter analysis revealed that full cytokine inducibility of human NOS2 requires upstream sequences extending to −16 kb — far beyond the ~1 kb murine promoter — identifying three distinct cytokine-responsive regions and explaining prior difficulty in reconstituting human iNOS induction.

    Evidence Nuclear run-on assays and luciferase reporter constructs with deletions up to −16 kb in cytokine-stimulated AKN-1 hepatic cells

    PMID:8577713

    Open questions at the time
    • Specific transcription factors binding the distal elements were not identified
    • Chromatin architecture at the extended locus not characterized
  5. 1999 High

    Crystal structures of the NOS2 heme domain revealed a zinc-tetrathiolate center at the dimer interface that stabilizes intersubunit contacts and maintains the tetrahydrobiopterin binding site, providing the first structural framework for NOS dimerization and cofactor coupling.

    Evidence X-ray crystallography at 2.25 Å of zinc-free and zinc-bound human iNOS heme domains, comparison with eNOS

    PMID:10074942 PMID:10409685

    Open questions at the time
    • Full-length holoenzyme structure was not obtained
    • Conformational dynamics during catalytic cycling not addressed
  6. 1999 Medium

    A polymorphic (CCTTT)n pentanucleotide repeat in the NOS2 promoter was shown to modulate transcriptional output, with the 14-repeat allele conferring maximal IL-1β-inducible activity, linking NOS2 promoter microsatellite variation to functional expression differences.

    Evidence Luciferase reporter assays with different repeat-length constructs in colonic carcinoma cells under IL-1β and high-glucose conditions

    PMID:10506586

    Open questions at the time
    • Single cell type tested
    • In vivo relevance of repeat-length variation not demonstrated
    • Mechanism by which repeat length influences transcription factor binding not defined
  7. 1998 High

    Genetic loss-of-function in mice established that NOS2-derived NO is required for wound healing, directly linking iNOS to collagen synthesis, fibroblast proliferation, and matrix contraction — effects rescued by adenoviral NOS2 gene transfer or NO donors.

    Evidence iNOS knockout mice with wound closure assays, adenoviral rescue, and iNOS−/− fibroblast cultures with NO donor complementation

    PMID:11490353 PMID:9486966

    Open questions at the time
    • Molecular targets of NO in fibroblast collagen synthesis not identified
    • Relative contributions of macrophage vs. fibroblast NOS2 not separated in vivo
  8. 2001 High

    An S714P mutation in NOS2 was shown to reduce enzyme stability by accelerating proteasomal degradation, establishing that post-translational protein turnover is a critical determinant of NOS2 activity levels.

    Evidence Pulse-chase metabolic labeling in COS-7 cells expressing wild-type vs. S714P NOS2, immunoblot, nitrite assay

    PMID:11509447

    Open questions at the time
    • The specific E3 ligase responsible was not identified at this time
    • Whether S714 phosphorylation state regulates wild-type turnover was not tested
  9. 2002 High

    Two post-translational regulatory mechanisms were defined: HDAC2 was identified as a coactivator of NF-κB-dependent NOS2 transcription via direct p65 interaction, and peroxynitrite-mediated tyrosine nitration of NOS2 was shown to decrease its enzymatic activity, establishing auto-inhibitory feedback.

    Evidence Co-IP/GST pull-down for HDAC2–p65, reporter assays; in vitro peroxynitrite treatment with NOS activity assay in human skeletal muscle

    PMID:12097137 PMID:12138131

    Open questions at the time
    • Specific nitrated tyrosine residues not mapped
    • HDAC2 recruitment mechanism to the NOS2 promoter in chromatin context not resolved
  10. 2002 Medium

    Rho/ROCK signaling was identified as a post-transcriptional regulator of NOS2, with ROCK inhibition paradoxically increasing NOS2 mRNA and protein despite reducing promoter activity, revealing a previously unrecognized layer of regulation downstream of transcription.

    Evidence ROCK inhibitor (Y-27632) and HMG-CoA reductase inhibitor in human alveolar epithelial cells, promoter-luciferase vs. mRNA/protein analysis

    PMID:12169580

    Open questions at the time
    • Identity of RNA-binding proteins or mRNA stability factors mediating ROCK effects unknown
    • Not replicated in other cell types
  11. 2006 High

    Genetic deletion of NOS2 in APP transgenic mice caused tau hyperphosphorylation, somatodendritic redistribution, and neurodegeneration, positioning NOS2-derived NO as a suppressor of tau pathology and connecting NO to the intersection of amyloid and tau biology.

    Evidence APP/NOS2−/− bigenic mice, immunohistochemistry, tau phosphorylation and aggregation assays, caspase-3 activation

    PMID:16908860

    Open questions at the time
    • Direct molecular target of NO that modulates tau phosphorylation not identified
    • Whether the effect is cGMP-dependent or S-nitrosylation-mediated was unknown
  12. 2007 High

    S-nitrosylation of NF-κB p65 at a conserved Rel-domain cysteine by NOS2-derived NO was shown to inhibit NF-κB DNA binding and NOS2 promoter activity, establishing the molecular basis of a negative feedback loop through which NOS2 attenuates its own transcription.

    Evidence S-nitrosylation detection, site-directed mutagenesis of p65 cysteine, NF-κB reporter assays, ChIP in respiratory epithelial cells and macrophages

    PMID:17720813

    Open questions at the time
    • Kinetics and reversibility of p65 S-nitrosylation in vivo not determined
    • Whether denitrosylases regulate this feedback is unknown
  13. 2008 High

    Crystal structures of NOS-inhibitor complexes revealed an isoform-specific induced-fit mechanism ('anchored plasticity') involving second- and third-shell residue triads, providing the structural rationale for designing selective iNOS inhibitors.

    Evidence X-ray crystallography of multiple NOS-inhibitor complexes, mutagenesis of specificity-determining residues

    PMID:18849972

    Open questions at the time
    • In vivo pharmacokinetic validation of selectivity not reported
    • Whether the induced-fit mechanism operates similarly in the full-length holoenzyme is unknown
  14. 2011 High

    NOS2 was shown to sustain glioma stem cell proliferation and tumorigenicity, with NOS2 inhibition selectively impairing GSC growth and intracranial tumor formation, identifying NOS2 as a therapeutic vulnerability in glioblastoma.

    Evidence NOS2 inhibitor (1400W) and shRNA in GSC cultures, murine intracranial glioma model, gene expression profiling

    PMID:21729780

    Open questions at the time
    • Direct NO targets in GSC self-renewal not defined
    • Whether NOS2 is essential in non-GSC tumor bulk was not addressed
  15. 2012 High

    Genetic epistasis showed that NOS2 cooperates with oncogenic KRAS to drive lung tumorigenesis via miR-21-dependent Ras signaling amplification, connecting iNOS-derived NO to a specific oncogenic pathway.

    Evidence KRAS(G12D)/NOS2 KO mouse crosses, tumor histology, proliferation assays, miR-21 quantitation

    PMID:22618808

    Open questions at the time
    • Mechanism by which NO upregulates miR-21 not defined
    • Relevance to human KRAS-mutant lung adenocarcinoma not directly tested
  16. 2013 High

    Two key aspects of NOS2 protein regulation were resolved: FBXO45/MYCBP2 was identified as a novel E3 ubiquitin ligase complex targeting NOS2 for proteasomal degradation, and PEX7/EBP50 were shown to mediate NOS2 targeting to peroxisomes, revealing unexpected subcellular compartmentalization.

    Evidence SILAC quantitative MS interactome in airway epithelial cells, Flag-tag Co-IP, siRNA knockdown of PEX7, confocal/immunoelectron microscopy, in vivo LPS model

    PMID:23438482 PMID:23474170

    Open questions at the time
    • Functional consequence of peroxisomal NOS2 on local NO signaling not characterized
    • Whether FBXO45-mediated degradation is regulated by cytokine signaling remains to be dissected
  17. 2014 High

    NOS2 was shown to drive ER-negative breast cancer aggressiveness by upregulating pro-metastatic factors (S100A8, IL-6, IL-8, TIMP-1), enhancing migration, chemoresistance, and brain metastasis, positioning NOS2 as a therapeutic target in aggressive breast cancer.

    Evidence NOS2 inhibitor and shRNA in MDA-MB-231 cells, xenograft model, fat-pad-to-brain metastasis assay, cytokine profiling

    PMID:24733928

    Open questions at the time
    • Direct NO signaling pathway linking NOS2 to S100A8/IL-6 upregulation not defined
    • Patient-derived xenograft validation not reported
  18. 2016 High

    Two new signaling pathways converging on NOS2 were defined: Sur1-Trpm4 channels were shown to regulate NOS2 transcription via calcineurin/NFAT in microglia, and NOS2-derived NO was found to S-nitrosylate RING1A at Cys398 to relieve polycomb repression during fibroblast-to-endothelial transdifferentiation, revealing NOS2 as an epigenetic regulator.

    Evidence Abcc8−/−, Trpm4−/− microglia with patch clamp, calcium imaging, ChIP for NFAT; iNOS KO fibroblasts with mass spectrometry for RING1A S-nitrosylation site, C398A mutagenesis, H3K27me3 ChIP

    PMID:27246103 PMID:27623813

    Open questions at the time
    • Genome-wide targets of RING1A derepression by NO not catalogued
    • Whether Sur1-Trpm4/NFAT axis operates in human microglia not tested
  19. 2018 High

    NOS2 was positioned upstream of an IL-1α→IL-17 innate lymphoid cell axis in psoriatic arthritis, with macrophage NOS2-derived NO triggering IL-1α release that drives pathogenic IL-17 production.

    Evidence Nos2−/− mice, mannan-induced psoriatic arthritis model, pharmacological NOS inhibition, cytokine quantitation, PsA patient monocyte analysis

    PMID:29774240

    Open questions at the time
    • Mechanism of NO-induced IL-1α release from macrophages not molecularly defined
    • Human genetic evidence linking NOS2 variants to PsA not available
  20. 2020 High

    A human NOS2 loss-of-function frameshift mutation causing absent NO production was linked to fatal CMV disease, establishing that NOS2 is essential for anti-CMV immunity in humans while being dispensable for other immune functions.

    Evidence Whole-exome sequencing, functional testing of truncated NOS2 mutant, population-level variant analysis

    PMID:31995689

    Open questions at the time
    • Whether heterozygous NOS2 deficiency confers partial susceptibility unknown
    • Mechanism by which NOS2-derived NO controls CMV replication in humans not defined
  21. 2022 High

    Two downstream effector pathways of NOS2 were elucidated: LACC1 was shown to convert the NOS2 byproduct L-citrulline to L-ornithine, bridging NO synthesis to polyamine metabolism in macrophages, and NOS2-derived NO was found to promote DNMT1 degradation via p38-MAPK/KAT5, causing LINE-1 hypomethylation and genomic instability.

    Evidence Lacc1−/−, Nos2−/−, Odc1−/− macrophages with Salmonella infection and chemical rescue; NOS2 overexpression/KO with DNMT1 stability assay, bisulfite sequencing, LINE-1 assays

    PMID:35584114 PMID:35978195

    Open questions at the time
    • Whether LACC1 pathway is relevant in non-macrophage cell types unknown
    • Quantitative contribution of NOS2-driven DNMT1 loss to cancer initiation vs. progression not separated

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include the full-length holoenzyme structure of human NOS2, the identity of RNA-binding proteins mediating post-transcriptional regulation, the direct NO targets controlling tau phosphorylation, and the mechanism by which NOS2-derived NO triggers IL-1α release from macrophages.
  • No full-length human NOS2 holoenzyme structure available
  • Post-transcriptional regulatory network (RNA-binding proteins, miRNA) incompletely defined
  • Molecular mechanism of NO-mediated suppression of tau hyperphosphorylation unknown

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0016491 oxidoreductase activity 3 GO:0140096 catalytic activity, acting on a protein 2
Localization
GO:0005829 cytosol 3 GO:0005634 nucleus 1 GO:0005777 peroxisome 1
Pathway
R-HSA-168256 Immune System 4 R-HSA-162582 Signal Transduction 3 R-HSA-1643685 Disease 3 R-HSA-4839726 Chromatin organization 2 R-HSA-1430728 Metabolism 1
Partners
FBXO45HDAC2MYCBP2NFKB1PEX7RELARING1SLC9A3R1

Evidence

Reading pass · 32 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1993 Molecular cloning of human inducible NOS (NOS2/iNOS) from hepatocytes revealed an 80% amino acid sequence homology to murine macrophage NOS, with recognition sites for FMN, FAD, and NADPH and a consensus calmodulin binding site; unlike the murine macrophage isoform, the human hepatocyte enzyme showed Ca2+ dependence when expressed in 293 kidney cells. cDNA cloning, heterologous expression in 293 cells, enzymatic assay with Ca2+ chelation and calmodulin antagonist Proceedings of the National Academy of Sciences of the United States of America High 7682706
1993 Cloning of inducible NOS from human chondrocytes confirmed a single human iNOS isoform (1153 amino acids, ~131 kDa); CHO cells transfected with this cDNA expressed NOS activity inhibitable by L-arginine analogues, establishing the catalytic competence of the cloned sequence. cDNA cloning, CHO cell transfection, NOS activity inhibition assay Proceedings of the National Academy of Sciences of the United States of America High 7504305
1993 Purification and cDNA sequencing of cytokine-induced NOS from a human colorectal adenocarcinoma cell line (DLD-1) confirmed that purified human iNOS shares with murine macrophage iNOS a lack of dependence on exogenous calcium and calmodulin for activity, distinguishing it from brain and endothelial NOS isoforms. Enzyme purification, calmodulin-independent activity assay, cDNA sequencing Biochemistry High 7692964
1993 NOS2-derived nitric oxide mediates cytokine-induced inhibition of glucose-stimulated insulin secretion by human islets of Langerhans; this was demonstrated by prevention of both cGMP accumulation and nitrite production, and restoration of insulin secretion, by the NOS inhibitor L-NMMA. Human islet culture, cytokine stimulation, L-NMMA inhibition, nitrite assay, cGMP measurement, insulin secretion assay, EPR spectroscopy Proceedings of the National Academy of Sciences of the United States of America High 8383325
1994 The human NOS2 gene is approximately 37 kb in length, consists of 26 exons and 25 introns, and is located on chromosome 17 at position 17cen-q11.2; primer extension mapped the transcriptional initiation site 30 bp downstream of a TATA sequence, and cytokine-inducible promoter elements reside within a ~400 bp 5'-flanking region. Genomic library screening, exon-intron mapping, primer extension, FISH, somatic cell hybrid PCR panel The Journal of biological chemistry High 7509810
1994 Constitutive NOS2 (iNOS) expression occurs in Epstein-Barr virus-transformed human B lymphocytes; NOS2-derived NO maintains EBV latency by down-regulating expression of the immediate-early EBV transactivator Zta and also inhibits apoptosis in B lymphocyte cell lines through cGMP-independent, redox/sulfhydryl-dependent mechanisms. RT-PCR, NOS activity assay, EBV reactivation assay, apoptosis assay, cGMP-independent pathway analysis Cell High 7528106
1994 Continuous, constitutive expression of NOS2 (iNOS) in normal human airway epithelial cells in vivo was demonstrated by molecular cloning; expression was dependent on the in vivo airway environment, was abolished upon cell removal, and was decreased by inhaled corticosteroids and β-adrenergic agonists. Molecular cloning, in situ hybridization, NOS activity quantitation in epithelial cell lysates, in vivo pharmacological inhibition Proceedings of the National Academy of Sciences of the United States of America High 7544004
1996 Transcriptional activation of the human NOS2 gene by cytokines (TNF-α, IL-1β, IFN-γ) was demonstrated by nuclear run-on analysis; functional cytokine-responsive promoter elements were identified in three distinct regions located between −3.8 and −16 kb upstream of the gene, markedly distinct from the murine iNOS promoter where only 1 kb of 5'-flanking sequence is required. Nuclear run-on transcription assay, luciferase reporter transfection with deletion constructs up to −16 kb Proceedings of the National Academy of Sciences of the United States of America High 8577713
1999 Crystal structures of human iNOS catalytic (heme) domain at 2.25 Å revealed active-site residues nearly identical to those of eNOS; both structures show a structural zinc atom at the dimer interface coordinated by four cysteines (two from each monomer), establishing this zinc-tetrathiolate center as a conserved element of NOS dimer stability. X-ray crystallography at 2.25 Å resolution, comparison with eNOS structure Nature structural biology High 10074942
1999 Crystal structures of the heme domain of human NOS2 in zinc-free and zinc-bound states revealed that: (i) in the zinc-free form, two symmetry-related cysteines form a disulfide bond; (ii) in the zinc-bound form, the same cysteines constitute a ZnS4 (zinc-tetrathiolate) center identical to that in NOS3, which stabilizes intersubunit contacts and maintains the integrity of the tetrahydrobiopterin (BH4) binding site. X-ray crystallography of zinc-free and zinc-bound NOS2 heme domain, structural comparison with NOS3 The Journal of biological chemistry High 10409685
1996 Functional promoter analysis with constructs linked to the thymidine kinase promoter identified that the human NOS2 gene requires promoter sequences up to −16 kb for full cytokine inducibility; the human iNOS promoter architecture contrasts substantially with the murine promoter, which requires only ~1 kb. Luciferase reporter assays with NOS2-TK promoter fusions up to −16 kb in cytokine-stimulated AKN-1 hepatic cells Proceedings of the National Academy of Sciences of the United States of America High 8577713
2002 Histone deacetylase 2 (HDAC2) directly interacts with NF-κB p65 and promotes cytokine-induced NOS2 transcription; HDAC inhibition with trichostatin A suppressed iNOS promoter activity without altering NF-κB DNA binding, and HDAC2 overexpression enhanced both NOS2 and NF-κB element promoter activity. Co-immunoprecipitation, GST pull-down, transient transfection reporter assays, Griess reaction for NO, gel shift/supershift assays Journal of the American Society of Nephrology High 12138131
2002 NOS2 protein expressed in skeletal muscle of septic patients undergoes tyrosine nitration by peroxynitrite on selected tyrosine residues, and in vitro nitration of NOS2 by peroxynitrite decreases its enzymatic activity, identifying tyrosine nitration as a post-translational mechanism of NOS2 self-inhibition. In vitro peroxynitrite treatment, Western blot, immunoprecipitation, NOS activity assay in human skeletal muscle from septic patients The Biochemical journal Medium 12097137
2001 An S714P mutation in NOS2 identified in Dahl/Rapp salt-sensitive rats reduces enzyme stability post-translationally (shorter protein half-life), resulting in decreased NOS2 protein levels and reduced nitrite production; a proteasomal mechanism is implicated, and the functional deficit is overcome by L-arginine supplementation. Transient transfection of COS-7 cells with wild-type and mutant NOS2 cDNA, metabolic labeling (pulse-chase), immunoblot, nitrite production assay Circulation research High 11509447
2007 NOS2-derived NO regulates NF-κB activity by S-nitrosylating the p65 subunit at a conserved cysteine within the Rel homology domain; this inhibits NF-κB-dependent gene transcription, and nuclear levels of S-nitrosylated p65 correlate with decreased p50-p65 DNA binding, establishing a negative feedback loop in which NOS2 attenuates its own expression. S-nitrosylation detection, site-directed mutagenesis of p65 cysteine, NF-κB reporter assays, ChIP for NOS2 promoter binding, cytokine stimulation of respiratory epithelial cells and macrophages The Journal of biological chemistry High 17720813
2008 Crystal structures of NOS isoforms with inhibitor-bound conformations revealed an isozyme-specific induced-fit binding mode: a cascade of conformational changes in second- and third-shell residue triads opens an isoform-specific specificity pocket; this 'anchored plasticity' mechanism provides the structural basis for selective iNOS inhibitor design. X-ray crystallography of NOS-inhibitor complexes, mutagenesis of second/third-shell residues, inhibitor binding assays Nature chemical biology High 18849972
1998 iNOS (NOS2) is required for normal wound closure; iNOS knockout mice show a 31% delay in excisional wound repair that is fully reversed by single topical application of an adenoviral vector expressing human iNOS cDNA, establishing a direct, gene-specific role for iNOS-derived NO in wound healing. iNOS knockout mice, adenoviral gene transfer (AdiNOS), wound closure measurement, RT-PCR for iNOS mRNA, pharmacological iNOS inhibition The Journal of clinical investigation High 9486966
2001 iNOS-deficient fibroblasts exhibit reduced proliferation, decreased collagen synthesis, and slower matrix contraction compared to wild-type; collagen synthesis is restored by NO donors, demonstrating that iNOS-derived NO is required cell-autonomously for fibroblast functions critical to wound healing. iNOS knockout mouse fibroblast explant culture, [3H]-thymidine incorporation, [3H]-proline incorporation into collagenase-sensitive protein, fibroblast-populated collagen lattice contraction assay, NO donor rescue Surgery High 11490353
2006 Genetic deletion of NOS2 in APP Swedish mutant mice results in hyperphosphorylation of mouse tau, its redistribution to somatodendritic compartments, and aggregate formation, as well as increased insoluble Aβ, neuronal degeneration, and caspase-3 activation; NO acts at a junction point connecting Aβ pathology, caspase activation, and tau aggregation. Bigenic mouse model (APP/NOS2−/−), immunohistochemistry, Western blot, tau phosphorylation assays, caspase-3 activation assay Proceedings of the National Academy of Sciences of the United States of America High 16908860
2013 Proteomic analysis of the NOS2 interactome in human airway epithelial cells identified FBXO45 as a novel direct NOS2 interactor that requires Asn27 in the 23DINNN27 motif of NOS2 (same as SPSB proteins) but recruits a distinct E3 ubiquitin ligase complex (MYCBP2/SKP1); cytokine-inducible NOS2 interactions with allosteric activators and the ubiquitin-proteasome system correlated with increased NOS2 ubiquitination and NO output. Flag-tag Co-IP, SILAC quantitative MS, direct interaction validation, cytokine stimulation, NOS2 ubiquitination assay Nitric oxide : biology and chemistry High 23438482
2013 iNOS is targeted to peroxisomes in hepatocytes through interaction with the peroxisomal import protein PEX7 and the adaptor protein EBP50; siRNA knockdown of PEX7 reduced iNOS–peroxisomal colocalization, and iNOS peroxisomal targeting was contingent on EBP50 expression in LPS-treated mice, identifying a novel subcellular targeting pathway for NOS2. siRNA knockdown, confocal microscopy, immunoelectron microscopy, MALDI-MS proteomics, Co-IP, in vivo LPS model Nitric oxide : biology and chemistry High 23474170
2016 iNOS-generated NO is required for transdifferentiation of fibroblasts to endothelial cells; upon NFκB-dependent iNOS induction, iNOS translocates to the nucleus and S-nitrosylates the polycomb repressive complex member RING1A at Cys398, reducing RING1A chromatin binding and global H3K27 trimethylation; expression of a C398A RING1A mutant nearly abolished transdifferentiation. iNOS KO murine embryonic fibroblasts, siRNA knockdown, iNOS overexpression, immunostaining for nuclear iNOS, Co-IP, mass spectrometry for S-nitrosylation site, H3K27me3 ChIP, transdifferentiation efficiency assay Circulation research High 27623813
2016 In TLR4-activated microglia, de novo upregulated Sur1-Trpm4 channels regulate NOS2 transcription via the calcineurin (CN)/NFAT pathway; pharmacological or genetic inhibition of Sur1-Trpm4 increased [Ca2+]i but caused phosphorylation of CaMKII and CN (inactivating CN), reduced NFAT nuclear translocation, and suppressed NOS2 mRNA and protein, as confirmed by chromatin immunoprecipitation. In vivo and in vitro microglia from WT, Abcc8−/−, Trpm4−/− mice; siRNA gene silencing; patch clamp; calcium imaging; ChIP for NFAT at Nos2 promoter; Griess assay; qPCR; Western blot Journal of neuroinflammation High 27246103
2022 LACC1 converts L-citrulline (the NOS2 byproduct) to L-ornithine and isocyanic acid, bridging NOS2 activity to polyamine biosynthesis (via ODC1) in inflammatory macrophages; LACC1 phenotypes in Salmonella-infected bone marrow-derived macrophages required upstream NOS2 and downstream ODC1, and chemical complementation with L-ornithine rescued Lacc1−/− activity. Lacc1−/−, Nos2−/−, Odc1−/− mouse models; bone marrow-derived macrophage Salmonella infection; biochemical enzyme assay; L-ornithine complementation; genetic epistasis Nature High 35978195
2022 NOS2 expression and associated NO signaling induces DNA hypomethylation by promoting degradation of DNMT1 through an NO/p38-MAPK/KAT5-dependent mechanism; this results in LINE-1 retrotransposon hypomethylation, expression, DNA damage, and malignant epithelial transformation. NOS2 overexpression and knockout in human cell lines, NO donor treatment, DNMT1 protein stability assay, p38-MAPK inhibition, KAT5 pathway analysis, bisulfite sequencing, LINE-1 expression and DNA damage assays Proceedings of the National Academy of Sciences of the United States of America High 35584114
1999 A polymorphic (CCTTT)n pentanucleotide repeat in the NOS2A promoter differentially drives NOS2 transcription; the 14-repeat allele showed strongest IL-1β-inducible luciferase activity and was least inhibited by high-glucose conditions, demonstrating that promoter microsatellite length functionally modulates NOS2 expression. Luciferase reporter assay in transfected colonic carcinoma cells with different (CCTTT)n repeat constructs under IL-1β stimulation and high-glucose conditions FASEB journal Medium 10506586
2002 Rho GTPase signaling regulates NOS2 at a post-transcriptional level: inhibition of ROCK (Rho-associated kinase) with Y-27632 decreased NOS2 promoter activity yet increased NOS2 mRNA and protein levels, indicating that ROCK-mediated suppression operates downstream of transcription initiation at the message and protein level, independently of prenylation-mediated effects on the NOS2 promoter. Pharmacological inhibition of HMG-CoA reductase, geranylgeranyl pyrophosphate rescue, ROCK inhibitor (Y-27632), NOS2 promoter-luciferase, NOS2 mRNA and protein quantitation in human alveolar epithelial cells American journal of physiology. Lung cellular and molecular physiology Medium 12169580
2020 A homozygous frameshift mutation in NOS2 causing a truncated, catalytically inactive NOS2 protein (no NO production) was identified in a human patient with fatal CMV disease, establishing that inherited NOS2 deficiency causes selective susceptibility to CMV in humans while being otherwise clinically silent. Whole-exome sequencing, functional testing of truncated mutant (no NO production), population-level analysis of NOS2 homozygous variants in public databases The New England journal of medicine High 31995689
2012 NOS2 enhances KRAS-driven lung tumorigenesis: KRAS(G12D);NOS2 knockout mice showed delayed lung tumor development, reduced tumor cell proliferation, suppressed macrophage recruitment, and markedly decreased miR-21 expression in lung carcinomas compared to KRAS(G12D);NOS2 wild-type controls, demonstrating cooperative action of NOS2 and oncogenic KRAS in driving lung cancer via miR-21-dependent Ras signaling amplification. Genetic crosses of NOS2 KO with KRAS(G12D) mouse model, tumor histology, proliferation assays, macrophage infiltration analysis, qRT-PCR, in situ hybridization for miR-21 International journal of cancer High 22618808
2018 In a mannan-induced psoriatic arthritis mouse model, macrophage NOS2-derived NO promotes arthritis by triggering IL-1α release from skin macrophages, which then drives IL-17 production by innate lymphoid cells; Nos2 deletion or pharmacological NOS inhibition (L-NAME) suppressed disease, placing NOS2 upstream of IL-1α and the IL-17 innate lymphocyte axis. Nos2−/− mice, mannan-induced psoriatic arthritis model, Nos2-selective and general NOS inhibitors, IL-1α and IL-17 quantitation, monocyte subset analysis from PsA patients Science advances High 29774240
2014 NOS2 in ER-negative breast cancer cells is feed-forward regulated by hypoxia, serum withdrawal, IFN-γ, and exogenous NO; NOS2-derived NO upregulates S100A8, IL-6, IL-8, and TIMP-1, enhances cellular migration and chemoresistance to Taxol, and promotes brain metastasis; NOS2 inhibition in MDA-MB-231 xenografts suppressed tumor growth and metastasis. NOS2 inhibitor treatment and shRNA knockdown in ER− breast cancer cells, xenograft mouse model, fat-pad-to-brain metastasis assay, cytokine/chemokine profiling, Taxol chemoresistance assay Proceedings of the National Academy of Sciences of the United States of America High 24733928
2011 NOS2-derived NO mediates glioma stem cell (GSC) proliferation and tumorigenicity; NOS2 is elevated in GSCs relative to non-GSCs and normal progenitors, NOS2 inhibition selectively impairs GSC growth and intracranial tumor formation, and NOS2-regulated genes include the cell-cycle inhibitor CDA1. NOS2 inhibitor (1400W) treatment, NOS2 shRNA in GSC cultures, murine intracranial glioma model, gene expression profiling, CDA1 identification Cell High 21729780

Source papers

Stage 0 corpus · 130 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2012 Host-microbe interactions have shaped the genetic architecture of inflammatory bowel disease. Nature 3725 23128233
2002 Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences. Proceedings of the National Academy of Sciences of the United States of America 1479 12477932
1993 Molecular cloning and expression of inducible nitric oxide synthase from human hepatocytes. Proceedings of the National Academy of Sciences of the United States of America 828 7682706
2021 Dual proteome-scale networks reveal cell-specific remodeling of the human interactome. Cell 705 33961781
2011 Phylogenetic-based propagation of functional annotations within the Gene Ontology consortium. Briefings in bioinformatics 656 21873635
1994 Constitutive and inducible nitric oxide synthase gene expression, regulation, and activity in human lung epithelial cells. Proceedings of the National Academy of Sciences of the United States of America 507 7524082
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