Affinage

ELANE

Neutrophil elastase · UniProt P08246

Length
267 aa
Mass
28.5 kDa
Annotated
2026-06-09
100 papers in source corpus 20 papers cited in narrative 20 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 5/5 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

ELANE encodes neutrophil elastase (NE), a granule-associated serine protease whose dominant heterozygous mutations cause cyclic and severe congenital neutropenia (PMID:10581030). Its transcription is driven by a network of hematopoietic factors — LEF-1, CBFalpha/AML1, C/EBPalpha, PU.1, and c-Myb — with LEF-1 directly activating the promoter and rescuing granulocytic differentiation in patient CD34+ cells (PMID:14594802, PMID:16247445, PMID:19620402), while the repressor GFI1 directly limits ELANE expression and dominant-negative GFI1 mutations elevate it in vivo (PMID:12778173); post-transcriptionally, miR-608 targets the ELANE 3'UTR to restrain expression (PMID:31749032). The dominant disease mechanism centers on protein misfolding: mutant NE mislocalizes away from primary granules and triggers the unfolded protein response and ER stress in a protease-independent manner, driving CHOP-dependent apoptosis and differentiation arrest of granulocytic precursors (PMID:17761833, PMID:26193632), with distinct mutations engaging distinct UPR arms and modulators such as ATF6 and SLPI (PMID:26567890) and an accompanying oxidative/PML-mediated stress state (PMID:33560392). Pharmacological correction by NE inhibitors (sivelestat, beta-lactam MK0339) restores granule localization, relieves ER stress, and rescues differentiation via C/EBPalpha (PMID:26193632, PMID:28754797), and CRISPR mapping shows that only late-exon frameshifts mimicking SCN alleles impede maturation whereas early-exon disruption triggers nonsense-mediated decay and rescues the phenotype (PMID:33513358). Beyond hematopoiesis, NE has enzymatic substrate roles: in monocytes it cleaves the histone H3 amino terminus (H3ΔN) to regulate chromatin accessibility during macrophage differentiation (PMID:34017121), and in hepatocytes it promotes ferroptosis by stabilizing KEAP1 and suppressing the NRF2/GPX4 pathway (PMID:40204709).

Mechanistic history

Synthesis pass · year-by-year structured walk · 10 steps
  1. 1999 High

    Established the genetic cause of cyclic hematopoiesis, transforming an idiopathic oscillatory blood disorder into a defined single-gene disease.

    Evidence Genome-wide linkage and positional cloning with direct ELA2 sequencing across 13 affected families

    PMID:10581030

    Open questions at the time
    • Did not explain how a protease mutation produces a 21-day oscillation
    • Functional consequence of the mutations on NE protein unresolved
  2. 2003 High

    Defined the transcriptional control of ELANE by placing the repressor GFI1 and the activators LEF-1/CBFalpha upstream within myeloid differentiation, connecting ELANE dysregulation to neutropenia beyond coding mutations.

    Evidence ChIP, EMSA, reporter assays, in vitro interaction mapping, and patient bone marrow expression measurements

    PMID:12778173 PMID:14594802

    Open questions at the time
    • Whether elevated ELANE alone is sufficient to cause neutropenia not established
    • Combinatorial logic among the activators not resolved
  3. 2006 Medium

    Expanded the activating transcription factor set (AML1, C/EBPalpha, PU.1, c-Myb) regulating ELANE in myeloid cells.

    Evidence ChIP, siRNA knockdown, and promoter reporter assays in myeloid cell lines

    PMID:16247445

    Open questions at the time
    • Relative contribution of each factor in vivo not quantified
    • Cell-line context may not reflect primary precursors
  4. 2007 High

    Identified protein misfolding–driven UPR/ER stress and apoptosis as a protease-independent disease mechanism, shifting the model from loss of enzymatic function to a toxic gain-of-function.

    Evidence Mutant vs. wild-type NE expression in cell lines and primary granulocytic precursors with UPR markers and apoptosis assays; functional characterization distinguishing CyN from SCN mutations

    PMID:17436313 PMID:17761833

    Open questions at the time
    • Why specific mutations partition into cyclic versus severe phenotypes incompletely defined
    • Link between mislocalization and UPR not fully separated
  5. 2013 Medium

    Revealed an alternative translation mechanism in which start-site-disrupting mutations use downstream ATGs and an internal ribosome entry site to make truncated NE isoforms, broadening the molecular consequences of ELANE mutations.

    Evidence Patient-derived iPSCs, downstream initiation codon and IRES mapping, clonogenic assays

    PMID:24184683

    Open questions at the time
    • In vivo relevance of truncated isoforms to neutropenia unclear
    • Single-lab characterization
  6. 2015 High

    Demonstrated that restoring NE localization to primary granules with the inhibitor sivelestat relieves ER stress and rescues differentiation via C/EBPalpha, establishing mislocalization as a therapeutically tractable driver, and that distinct mutants engage distinct UPR arms.

    Evidence Genome-edited SCN patient iPSC granulopoiesis with immunofluorescence, UPR markers, pharmacological rescue; mutant-specific ATF6/SLPI UPR analysis

    PMID:26193632 PMID:26567890

    Open questions at the time
    • Whether localization rescue fully accounts for clinical response not established
    • Role of SLPI in patient outcomes unconfirmed
  7. 2020 Medium

    Challenged the universality of the UPR model by showing that the p.G185R mutant impairs differentiation through reduced enzymatic activity and altered myeloid transcription without inducing UPR or apoptosis.

    Evidence Inducible mutant ELANE expression in murine 32D and human NB4 cells with enzymatic assays and gene expression profiling

    PMID:32299910

    Open questions at the time
    • Contradicts UPR findings from other labs; reconciliation across mutant classes unresolved
    • Cell-line model may not capture primary precursor biology
  8. 2021 High

    Defined the allele-specific genetic logic of ELANE-driven maturation arrest and identified an oxidative/PML stress axis, clarifying which lesions cause disease and pointing to gene-editing rescue strategies.

    Evidence Pooled CRISPR screen in human HSPCs with NMD assays and humanized-mouse engraftment; iPSC progenitors with ROS/PML quantification and genetic rescue

    PMID:33513358 PMID:33560392

    Open questions at the time
    • Mechanistic link between PML/ROS state and ELANE expression incomplete
    • Therapeutic translation of early-exon editing not yet clinical
  9. 2021 High

    Assigned a physiological enzymatic substrate role to NE beyond neutropenia: cleavage of histone H3 to regulate chromatin accessibility during monocyte-to-macrophage development.

    Evidence Integrative epigenomics, simultaneous NSP siRNA depletion, and ATAC-seq in primary monocytes/macrophages

    PMID:34017121

    Open questions at the time
    • Specific contribution of NE versus cathepsin G and proteinase 3 not separated
    • Functional consequences for macrophage gene programs broadly defined
  10. 2025 Medium

    Extended NE function to liver disease by showing it promotes hepatocyte ferroptosis through KEAP1 stabilization and NRF2/GPX4 suppression, implicating ELANE in metabolic-associated fatty liver disease.

    Evidence Elane-KO mice, recombinant ELANE on primary hepatocytes, Co-IP for P62-KEAP1, ubiquitination and lysosomal degradation assays

    PMID:40204709

    Open questions at the time
    • Whether the effect requires NE catalytic activity not established
    • Single-lab mechanistic model

Open questions

Synthesis pass · forward-looking unresolved questions
  • How a single protease reconciles its toxic misfolding role in granulocyte precursors with its physiological substrate-cleavage roles in chromatin and ferroptosis, and which mutant class predominates in patients, remains unresolved.
  • No unified model linking UPR-dependent and enzymatic-activity-dependent disease mechanisms
  • Physiological substrate repertoire of NE incompletely mapped

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0016787 hydrolase activity 3 GO:0140096 catalytic activity, acting on a protein 2 GO:0140097 catalytic activity, acting on DNA 1
Localization
GO:0005783 endoplasmic reticulum 2 GO:0031410 cytoplasmic vesicle 1
Pathway
R-HSA-1266738 Developmental Biology 2 R-HSA-168256 Immune System 2 R-HSA-5357801 Programmed Cell Death 2 R-HSA-8953897 Cellular responses to stimuli 2 GO:0140097 catalytic activity, acting on DNA 1
Partners
GFI1KEAP1LEF1PMLSLPI

Evidence

Reading pass · 20 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1999 Heterozygous single-base substitutions in ELA2 (encoding neutrophil elastase, a serine protease of neutrophil and monocyte granules) were identified in all 13 families with cyclic haematopoiesis, establishing that mutations in this gene cause the 21-day oscillation in blood-cell production. Genome-wide linkage screen and positional cloning, followed by direct sequencing of ELA2 in affected families Nature genetics High 10581030
2003 GFI1, a transcriptional repressor, directly represses ELA2 expression; dominant-negative GFI1 zinc-finger mutations in neutropenic patients elevate ELA2 expression in vivo, placing GFI1 upstream of ELA2 in a common myeloid differentiation pathway. Chromatin immunoprecipitation, electrophoretic mobility shift assay, reporter assays, and measurement of elevated ELA2 expression in patient bone marrow Nature genetics High 12778173
2007 Expression of mutant (but not wild-type) NE in granulocytic precursors strongly induces BiP/GRP78 mRNA and XBP1 mRNA splicing (markers of the unfolded protein response), and activates CHOP/apoptosis in a protease-independent fashion; UPR activation and decreased NE protein were confirmed in primary SCN patient granulocytic precursors. Transient expression of mutant vs. wild-type NE in cell lines and primary human granulocytic precursors; quantitative RT-PCR for UPR markers; apoptosis assays Blood High 17761833
2003 LEF-1 and core-binding factor alpha (CBFalpha/AML1) co-activate the human ELA2 promoter; the high-mobility-group domain of LEF-1 physically interacts with the runt DNA-binding and proline/serine/threonine-rich activation domains of CBFalpha; promoter substitutions in SCN patients within the LEF-1 motif correlate with elevated ELA2 transcript levels. In vitro protein-protein interaction assay, promoter reporter assays, bone marrow mRNA quantification from SCN and familial platelet disorder/AML patients The Journal of biological chemistry High 14594802
2006 ELA2 expression is regulated by the hematopoietic transcription factors AML1, C/EBPalpha, PU.1, and c-Myb, as shown by chromatin immunoprecipitation and siRNA knockdown; the leukemic fusion protein AML1-ETO binds the ELA2 promoter but does not significantly repress ELA2 expression. Chromatin immunoprecipitation, siRNA knockdown, promoter reporter assays in myeloid cell lines Oncogene Medium 16247445
2009 LEF-1 directly activates the ELA2 promoter; LEF-1 transduction of hematopoietic cells upregulates ELA2/NE synthesis, while LEF-1 shRNA knockdown markedly reduces ELA2/NE levels; LEF-1 rescue of CD34+ cells from CN patients restores granulocytic differentiation with concomitant increase in functionally active NE. Promoter binding assays, lentiviral overexpression and shRNA knockdown of LEF-1 in hematopoietic cells, primary patient CD34+ cell rescue experiments Blood Medium 19620402
2007 ELA2 mutations that cause cyclic neutropenia versus SCN have different and partly opposing effects on proteolytic activity, subcellular trafficking of NE, and induction of the unfolded protein response; pairs of cis mutations act approximately additively, and disturbed subcellular localization was identified as a potential disease mechanism distinct from the UPR. Functional characterization of mutant NE in transfected cells: protease activity assays, immunofluorescence for subcellular localization, UPR marker induction Human mutation Medium 17436313
2015 ELANE point mutations cause promyelocyte death and differentiation arrest associated with NE mislocalization away from primary granules and activation of UPR/ER stress; sivelestat (an NE-specific inhibitor) corrected dysgranulopoiesis by restoring normal NE localization to primary granules, ameliorating UPR/ER stress, and promoting promyelocyte survival and differentiation via C/EBPalpha (not C/EBPbeta). SCN patient-derived iPSCs with genome editing and granulopoiesis differentiation protocols; immunofluorescence for NE localization; UPR markers; pharmacological inhibition with sivelestat The Journal of clinical investigation High 26193632
2013 ELANE mutations that disrupt the translational start site force translation from downstream in-frame ATGs, producing amino-terminally truncated NE isoforms lacking the ER-localizing (pre) and zymogen-maintaining (pro) sequences but retaining catalytic residues; an internal ribosome entry site (IRES) within ELANE was defined; expression of these truncated isoforms reduces myeloid cell clonogenic capacity. Patient-derived iPSCs recapitulating the hematopoietic phenotype; identification of downstream translation initiation codons; IRES mapping; clonogenic assays in myeloid cells Blood Medium 24184683
2021 ELANE encodes neutrophil elastase which, together with cathepsin G and proteinase 3, catalyzes proteolytic cleavage of histone H3 at the amino terminus (H3ΔN) in human peripheral blood monocytes; this histone mark is repressed as monocytes differentiate into macrophages, and simultaneous NSP depletion causes H3ΔN loss and increased chromatin accessibility, priming chromatin for gene expression reprogramming during macrophage development. Integrative epigenomic analysis; simultaneous siRNA depletion of neutrophil serine proteases in monocytic cells; ATAC-seq for chromatin accessibility; primary monocyte and macrophage analysis Nature immunology High 34017121
2021 ELANE-mutant (misfolding) SCN patient-derived iPSC hematopoietic progenitors display elevated reactive oxygen species and increased numbers of PML nuclear bodies (markers of acute oxidative stress); PML controls the metabolic state of these progenitors and the expression of ELANE itself; both PML deletion and ELANE mutation correction restored normal G-CSF responses. iPSC-derived hematopoietic progenitor cells from SCN patients; ROS measurement; PML nuclear body quantification; PML genetic deletion; ELANE mutation correction; CSF3 response assays Blood advances Medium 33560392
2021 CRISPR-based pooled screen in human hematopoietic stem and progenitor cells established that only -1 frameshift indels in late ELANE exons (mimicking SCN-associated mutations) impede neutrophil maturation, while -2 frame late-exon indels repress translation and support maturation; early exon disruption elicits nonsense-mediated decay, overcomes maturation arrest, and preserves hematopoietic engraftment. Pooled CRISPR screen in human HSPCs; nonsense-mediated decay assays; in vitro neutrophil differentiation; in vivo engraftment in humanized mice Cell stem cell High 33513358
2020 The SCN-associated ELANE mutation p.G185R diminishes NE enzymatic activity and impairs granulocytic differentiation without significantly inducing the unfolded protein response or causing apoptosis in myeloblast cell lines, challenging the prevailing UPR model; impaired differentiation was associated with decreased expression of Gfi1, Cebpd, Cebpe, Spi1, Csf3r, and neutrophil granule protein genes. Inducible expression system for mutant ELANE in murine 32D and human NB4 cells; enzymatic activity assays; UPR marker measurement; gene expression profiling The Journal of biological chemistry Medium 32299910
2015 Different ELANE mutants activate distinct UPR pathways: the CN-specific p.C71R mutant induces ATF6 and its target genes (PPP1R15A, DDIT3, HSPA5), while other mutants do not; secretory leukocyte protease inhibitor (SLPI), a natural NE inhibitor whose levels are reduced in CN but not CyN patients, modulates the extent of ELANE-triggered UPR when co-depleted with the p.S126L mutant. Transduction of hematopoietic cells with specific ELANE mutants; quantitative RT-PCR for UPR markers; shRNA knockdown of SLPI combined with mutant ELANE transduction British journal of haematology Medium 26567890
2017 Cell-permeable beta-lactam inhibitors of NE (particularly MK0339) promote cell survival and increase formation of mature neutrophils in three cellular models expressing mutant ELANE (patient iPSCs, HL60 transient expression, HL60 inducible expression), suggesting that inhibiting NE enzymatic activity or acting as a chaperone can rescue the differentiation defect. Patient-derived iPSCs, HL60 transient and inducible mutant NE expression models; annexin V/FACS viability assay; neutrophil differentiation assessment with NE inhibitor treatment Journal of leukocyte biology Medium 28754797
1998 Mouse proteinase-3 (Prtn3) and neutrophil elastase (Ela2) genes are located within 2.2 kb of each other on mouse chromosome 10C2; each gene has five exons and four introns conserving the typical granule-associated serine proteinase gene structure; the catalytic triad and its placement are conserved; mouse Ela2 promoter contains functional c-myb and ets transcriptional elements. Molecular cloning, gene structure characterization, FISH chromosomal localization, sequence homology analysis, promoter element identification Cytogenetics and cell genetics Medium 9925946
2017 A novel ELANE mutation was found to decrease NE enzymatic activity, impair NETosis (neutrophil extracellular trap formation), and alter neutrophil cytokine production (IL-12, IL-8), without causing neutropenia; 3D structural modeling suggested the mutation alters protein folding and surface charge distribution, potentially perturbing protein trafficking. Scanning electron microscopy of NET formation; flow cytometry for neutrophil activation; fluorescent substrate-based NE activity assay; multiplex cytokine assay; 3D structural modeling Arthritis & rheumatology (Hoboken, N.J.) Medium 28881492
2019 miR-608 directly targets ELANE mRNA: cotransfection of a miR-608 mimic into HEK293T cells inhibited ELANE 3'UTR reporter activity, and mutation of the miRNA seed sequences abolished this repression; decreased miR-608 in monocytes leads to ELANE overexpression at both mRNA and protein levels. Luciferase reporter assay with wild-type and mutant ELANE 3'UTR; lentiviral miR-608 inhibition in U937 cells; cDNA microarray; qRT-PCR and Western blot Journal of clinical immunology Medium 31749032
2025 ELANE (neutrophil elastase) promotes ferroptosis in hepatocytes in the context of MAFLD by enhancing KEAP1 protein stability: recombinant ELANE treatment weakened the binding between P62 and KEAP1, inhibiting lysosomal degradation of KEAP1, thereby increasing KEAP1 levels, enhancing NRF2 ubiquitination, and suppressing the NRF2/GPX4 anti-ferroptosis pathway; ELANE-KO mice showed opposite effects. Elane knockout mice on HFD; primary hepatocyte treatment with recombinant ELANE; Co-IP to assess P62-KEAP1 interaction; Western blot for KEAP1, NRF2, GPX4; ubiquitination assays; lysosomal degradation inhibition experiments Cell death & disease Medium 40204709
2022 ELANE promotes M2 macrophage polarization by down-regulating PTEN expression in THP-1-derived macrophages, leading to increased M2 markers (CD206, CCL22, IL-10, CCL18); ELANE-polarized M2 macrophage conditioned medium enhanced lung cancer cell proliferation, migration, and invasion in vitro and tumor growth in vivo. THP-1 monocyte-to-macrophage differentiation; ELANE overexpression; qRT-PCR, ELISA, flow cytometry for M2 markers; Western blot for PTEN; co-culture conditioned medium assays; xenograft mouse model Immunological investigations Low 36102787

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2013 Cell death and diseases related to oxidative stress: 4-hydroxynonenal (HNE) in the balance. Cell death and differentiation 489 24096871
2014 Role of lipid peroxidation derived 4-hydroxynonenal (4-HNE) in cancer: focusing on mitochondria. Redox biology 414 25598486
1999 Mutations in ELA2, encoding neutrophil elastase, define a 21-day biological clock in cyclic haematopoiesis. Nature genetics 335 10581030
2003 Mutations in proto-oncogene GFI1 cause human neutropenia and target ELA2. Nature genetics 292 12778173
2006 Protein adducts generated from products of lipid oxidation: focus on HNE and one. Drug metabolism reviews 279 17145694
1989 Two epithelial tumor cell lines (HNE-1 and HONE-1) latently infected with Epstein-Barr virus that were derived from nasopharyngeal carcinomas. Proceedings of the National Academy of Sciences of the United States of America 204 2556716
2016 Role of 4-hydroxy-2-nonenal (HNE) in the pathogenesis of alzheimer disease and other selected age-related neurodegenerative disorders. Free radical biology & medicine 203 27789292
2016 4-Hydroxynonenal (HNE) modified proteins in metabolic diseases. Free radical biology & medicine 187 27815191
2022 Oxidative Stress and 4-hydroxy-2-nonenal (4-HNE): Implications in the Pathogenesis and Treatment of Aging-related Diseases. Journal of immunology research 170 35411309
2003 The proteasomal system and HNE-modified proteins. Molecular aspects of medicine 160 12892997
2007 Mutations of the ELA2 gene found in patients with severe congenital neutropenia induce the unfolded protein response and cellular apoptosis. Blood 156 17761833
2016 Antioxidants and HNE in redox homeostasis. Free radical biology & medicine 149 27888001
2004 Mutations in the ELA2 gene correlate with more severe expression of neutropenia: a study of 81 patients from the French Neutropenia Register. Blood 145 14962902
2004 Mass spectrometry for detection of 4-hydroxy-trans-2-nonenal (HNE) adducts with peptides and proteins. Mass spectrometry reviews 140 15133838
2010 Trans-4-hydroxy-2-hexenal, a product of n-3 fatty acid peroxidation: make some room HNE.. Free radical biology & medicine 126 20353821
2015 The diversity of mutations and clinical outcomes for ELANE-associated neutropenia. Current opinion in hematology 124 25427142
2006 Mitogenic responses of vascular smooth muscle cells to lipid peroxidation-derived aldehyde 4-hydroxy-trans-2-nonenal (HNE): role of aldose reductase-catalyzed reduction of the HNE-glutathione conjugates in regulating cell growth. The Journal of biological chemistry 122 16648138
1998 Inhibition of cytochrome c oxidase activity by 4-hydroxynonenal (HNE). Role of HNE adduct formation with the enzyme subunits. Biochimica et biophysica acta 119 9555085
2017 Chemistry and analysis of HNE and other prominent carbonyl-containing lipid oxidation compounds. Free radical biology & medicine 113 28192230
2001 Mutations in the ELA2 gene encoding neutrophil elastase are present in most patients with sporadic severe congenital neutropenia but only in some patients with the familial form of the disease. Blood 103 11675333
2008 Clinical implications of ELA2-, HAX1-, and G-CSF-receptor (CSF3R) mutations in severe congenital neutropenia. British journal of haematology 101 19120359
2001 Overexpression of mitochondrial manganese superoxide dismutase protects against radiation-induced cell death in the human hepatocellular carcinoma cell line HLE. Cancer research 98 11454680
2013 Measurement of HNE-protein adducts in human plasma and serum by ELISA-Comparison of two primary antibodies. Redox biology 92 24024156
2019 Mitochondrial 4-HNE derived from MAO-A promotes mitoCa2+ overload in chronic postischemic cardiac remodeling. Cell death and differentiation 80 31819159
2012 ELANE mutations in cyclic and severe congenital neutropenia: genetics and pathophysiology. Hematology/oncology clinics of North America 80 23351986
2011 Control of protein function by reversible Nɛ-lysine acetylation in bacteria. Current opinion in microbiology 78 21239213
2016 Contribution of the HNE-immunohistochemistry to modern pathological concepts of major human diseases. Free radical biology & medicine 74 27993730
2013 The spectrum of ELANE mutations and their implications in severe congenital and cyclic neutropenia. Human mutation 74 23463630
2024 Monitoring norepinephrine release in vivo using next-generation GRABNE sensors. Neuron 73 38547869
1995 Molecular cloning and functional expression of bacteriophage PK1E-encoded endoneuraminidase Endo NE. Molecular microbiology 68 7565105
2022 What Is Ne, Anyway? The Journal of heredity 63 35532202
1999 Formation and export of the glutathione conjugate of 4-hydroxy-2, 3-E-nonenal (4-HNE) in hepatoma cells. Archives of biochemistry and biophysics 63 9882435
2015 Establishment of NE asymmetry—targeting of membrane proteins to the inner nuclear membrane. Current opinion in cell biology 62 26112002
2015 Pathogenesis of ELANE-mutant severe neutropenia revealed by induced pluripotent stem cells. The Journal of clinical investigation 62 26193632
2021 Repression of CTSG, ELANE and PRTN3-mediated histone H3 proteolytic cleavage promotes monocyte-to-macrophage differentiation. Nature immunology 59 34017121
2011 Mutations in the ELANE gene are associated with development of periodontitis in patients with severe congenital neutropenia. Journal of clinical immunology 58 21796505
2007 The lipid peroxidation end-product 4-HNE induces COX-2 expression through p38MAPK activation in 3T3-L1 adipose cell. FEBS letters 57 17481611
2014 "Stop Ne(c)king around": How interactomics contributes to functionally characterize Nek family kinases. World journal of biological chemistry 55 24921005
2002 Protection of HLE B-3 cells against hydrogen peroxide- and naphthalene-induced lipid peroxidation and apoptosis by transfection with hGSTA1 and hGSTA2. Investigative ophthalmology & visual science 52 11818388
2010 Cyclic neutropenia and severe congenital neutropenia in patients with a shared ELANE mutation and paternal haplotype: evidence for phenotype determination by modifying genes. Pediatric blood & cancer 50 20582973
2003 Genotoxicity of HNE. Molecular aspects of medicine 50 12892993
2003 Proteome analysis of lens epithelia, fibers, and the HLE B-3 cell line. Investigative ophthalmology & visual science 50 14578405
2006 Regulation of CD95 (Fas) expression and Fas-mediated apoptotic signaling in HLE B-3 cells by 4-hydroxynonenal. Biochemistry 48 17014078
2003 HNE--signaling pathways leading to its elimination. Molecular aspects of medicine 47 12892996
2007 Glutathione level regulates HNE-induced genotoxicity in human erythroleukemia cells. Toxicology and applied pharmacology 45 18096195
2001 Mutations in the gene encoding neutrophil elastase (ELA2) are not sufficient to cause the phenotype of congenital neutropenia. British journal of haematology 45 11722436
2021 Dissecting ELANE neutropenia pathogenicity by human HSC gene editing. Cell stem cell 44 33513358
2016 Vitamin C enhances epigenetic modifications induced by 5-azacytidine and cell cycle arrest in the hepatocellular carcinoma cell lines HLE and Huh7. Clinical epigenetics 43 27134688
2017 HNE as an inducer of COX-2. Free radical biology & medicine 41 28192229
2016 HNE-modified proteins in Down syndrome: Involvement in development of Alzheimer disease neuropathology. Free radical biology & medicine 41 27838436
2010 HNE-induced 5-LO expression is regulated by NF-{kappa}B/ERK and Sp1/p38 MAPK pathways via EGF receptor in murine macrophages. Cardiovascular research 41 20554538
2021 On Broken Ne(c)ks and Broken DNA: The Role of Human NEKs in the DNA Damage Response. Cells 40 33673578
2017 HNE and cholesterol oxidation products in colorectal inflammation and carcinogenesis. Free radical biology & medicine 39 28089726
2013 Neutropenia-associated ELANE mutations disrupting translation initiation produce novel neutrophil elastase isoforms. Blood 39 24184683
2007 Inhibition of hepatocellular carcinoma invasion by suppression of claudin-10 in HLE cells. Molecular cancer therapeutics 39 18025272
2020 CRISPR-Cas9-Mediated ELANE Mutation Correction in Hematopoietic Stem and Progenitor Cells to Treat Severe Congenital Neutropenia. Molecular therapy : the journal of the American Society of Gene Therapy 38 32822592
2016 Pro-apoptotic effects of lipid oxidation products: HNE at the crossroads of NF-κB pathway and anti-apoptotic Bcl-2. Free radical biology & medicine 37 27840321
2006 Strong evidence for autosomal dominant inheritance of severe congenital neutropenia associated with ELA2 mutations. The Journal of pediatrics 37 16737875
2009 Effects of HNE-modification induced by Abeta on neprilysin expression and activity in SH-SY5Y cells. Journal of neurochemistry 34 19196432
2015 ELANE mutant-specific activation of different UPR pathways in congenital neutropenia. British journal of haematology 33 26567890
2003 Lymphoid enhancer factor-1 links two hereditary leukemia syndromes through core-binding factor alpha regulation of ELA2. The Journal of biological chemistry 33 14594802
2017 Elastase inhibitors as potential therapies for ELANE-associated neutropenia. Journal of leukocyte biology 31 28754797
2011 Modulation of aldehyde dehydrogenase activity affects (±)-4-hydroxy-2E-nonenal (HNE) toxicity and HNE-protein adduct levels in PC12 cells. Journal of molecular neuroscience : MN 31 22170038
2006 ELA2 is regulated by hematopoietic transcription factors, but not repressed by AML1-ETO. Oncogene 30 16247445
2023 Relationship between 4-Hydroxynonenal (4-HNE) as Systemic Biomarker of Lipid Peroxidation and Metabolomic Profiling of Patients with Prostate Cancer. Biomolecules 29 36671530
2020 How Much Does N Vary Among Species? Genetics 29 32839240
2009 Neutrophil elastase is severely down-regulated in severe congenital neutropenia independent of ELA2 or HAX1 mutations but dependent on LEF-1. Blood 29 19620402
2010 Differential roles of AMPKα1 and AMPKα2 in regulating 4-HNE-induced RPE cell death and permeability. Experimental eye research 28 21029733
2007 Double de novo mutations of ELA2 in cyclic and severe congenital neutropenia. Human mutation 27 17436313
2013 4-HNE increases intracellular ADMA levels in cultured HUVECs: evidence for miR-21-dependent mechanisms. PloS one 25 23717555
2007 HNE produced by the malaria parasite Plasmodium falciparum generates HNE-protein adducts and decreases erythrocyte deformability. Redox report : communications in free radical research 25 17263914
2020 Inducible expression of a disease-associated ELANE mutation impairs granulocytic differentiation, without eliciting an unfolded protein response. The Journal of biological chemistry 24 32299910
2007 Hypothalamic and hindbrain NPY, AGRP and NE increase consummatory feeding responses. Physiology & behavior 24 17289093
1999 Inhibitory role of plasminogen activator inhibitor-1 in invasion and proliferation of HLE hepatocellular carcinoma cells. Japanese journal of cancer research : Gann 23 10470287
2021 Inflammatory signature in acute-on-chronic liver failure includes increased expression of granulocyte genes ELANE, MPO and CD177. Scientific reports 21 34552111
2013 4-Hydroxy-2(E)-nonenal (HNE) catabolism and formation of HNE adducts are modulated by β oxidation of fatty acids in the isolated rat heart. Free radical biology & medicine 21 23328733
2008 Proliferation of human lens epithelial cells (HLE-B3) is inhibited by blocking of voltage-gated calcium channels. Pflugers Archiv : European journal of physiology 21 18446362
2005 In vitro modification of solid phase multiple antigenic peptides/autoantigens with 4-hydroxy-2-nonenal (HNE) provide ideal substrates for detection of anti-HNE antibodies and peptide antioxidants. Journal of immunological methods 21 16055145
2023 Interrelationship of lipid aldehydes (MDA, 4-HNE, and 4-ONE) mediated protein oxidation in muscle foods. Critical reviews in food science and nutrition 20 37589270
2021 A possible pathogenic correlation between neutrophil elastase (NE) enzyme and inflammation in the pathogenesis of coronavirus disease 2019 (COVID-19). International immunopharmacology 20 34536744
2018 Using Pupillometry to Assess the Atypical Pupillary Light Reflex and LC-NE System in ASD. Behavioral sciences (Basel, Switzerland) 20 30469373
2015 4-Hydroxy-2-nonenal (4-HNE) and Its Lipation Product 2-Pentylpyrrole Lysine (2-PPL) in Peanuts. Journal of agricultural and food chemistry 20 25945920
2019 4-HNE Induces Apoptosis of Human Retinal Pigment Epithelial Cells by Modifying HSP70. Current medical science 19 31209817
2016 Immunochemical studies on HNE-modified HSA: Anti-HNE-HSA antibodies as a probe for HNE damaged albumin in SLE. International journal of biological macromolecules 19 26800898
2020 The Appearance of 4-Hydroxy-2-Nonenal (HNE) in Squamous Cell Carcinoma of the Oropharynx. Molecules (Basel, Switzerland) 18 32079077
2020 In silico mapping of microbial communities and stress responses in a porcine slaughterhouse and pork products through its production chain, and the efficacy of HLE disinfectant. Food research international (Ottawa, Ont.) 18 32846568
2017 Brief Report: A Novel ELANE Mutation Associated With Inflammatory Arthritis, Defective NETosis, and Recurrent Parvovirus Infection. Arthritis & rheumatology (Hoboken, N.J.) 18 28881492
2003 Role of PKC-dependent pathways in HNE-induced cell protein transport and secretion. Molecular aspects of medicine 18 12892998
2015 Clinical characteristics of severe congenital neutropenia caused by novel ELANE gene mutations. The Pediatric infectious disease journal 17 25162927
2025 ELANE enhances KEAP1 protein stability and reduces NRF2-mediated ferroptosis inhibition in metabolic dysfunction-associated fatty liver disease. Cell death & disease 15 40204709
2021 PML-controlled responses in severe congenital neutropenia with ELANE-misfolding mutations. Blood advances 15 33560392
2021 He-Ne laser accelerates seed germination by modulating growth hormones and reprogramming metabolism in brinjal. Scientific reports 15 33846419
2024 CRISPR-Cas9n-mediated ELANE promoter editing for gene therapy of severe congenital neutropenia. Molecular therapy : the journal of the American Society of Gene Therapy 14 38556793
2022 ELANE Promotes M2 Macrophage Polarization by Down-Regulating PTEN and Participates in the Lung Cancer Progression. Immunological investigations 14 36102787
1998 Characterization and localization of the genes for mouse proteinase-3 (Prtn3) and neutrophil elastase (Ela2). Cytogenetics and cell genetics 14 9925946
2022 Characterization of an Anti-CD70 Half-Life Extended Bispecific T-Cell Engager (HLE-BiTE) and Associated On-Target Toxicity in Cynomolgus Monkeys. Toxicological sciences : an official journal of the Society of Toxicology 13 35583313
2021 Reduced ELANE and SLPI expression compromises dental pulp cell activity. Cell proliferation 13 34580954
2019 MiR-608 Exerts Anti-inflammatory Effects by Targeting ELANE in Monocytes. Journal of clinical immunology 13 31749032
2016 4-HNE expression in diabetic rat kidneys and the protective effects of probucol. Journal of endocrinological investigation 13 26830905
2003 CYP2E1 overexpression up-regulates both non-specific delta-aminolevulinate synthase and heme oxygenase-1 in the human hepatoma cell line HLE/2E1. International journal of molecular medicine 13 12469218

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