Affinage

ATF3

Cyclic AMP-dependent transcription factor ATF-3 · UniProt P18847

Length
181 aa
Mass
20.6 kDa
Annotated
2026-06-09
100 papers in source corpus 53 papers cited in narrative 54 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 7/7 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

ATF3 is a stress-inducible bZIP transcription factor that integrates inflammatory, metabolic, and DNA-damage signals to control cell fate, functioning predominantly as a homodimeric transcriptional repressor at ATF/CRE sites but switching to an activator when partnered with other factors (PMID:7515060, PMID:31273299, PMID:34551291). As a repressor it binds promoter ATF/CRE elements to silence metabolic and inflammatory targets including AdipoR1, PDX-1, PPARγ2, Cox-2 (Ptgs2), IFN-β, MCP-1, and the cystine antiporter SLC7A11 (PMID:20696134, PMID:21821004, PMID:25445599, PMID:25619459, PMID:26416280, PMID:31273299); repression of SLC7A11 depletes glutathione and drives ferroptosis in cancer and stressed tissues (PMID:31273299, PMID:36210815, PMID:38764128). In innate immunity ATF3 forms negative-feedback and feed-forward loops, terminating Cox-2 and IFN-β transcription, mediating itaconate-driven IκBζ suppression of secondary inflammatory genes, and modulating NF-κB-dependent cytokine output (PMID:25619459, PMID:26416280, PMID:29670287, PMID:27159257). Acting as an activator, ATF3 cooperates with ATF4 and recruits p300 to enhance serine-synthesis and one-carbon/nucleotide metabolism genes (PHGDH, PSAT1, PSPH) that fuel proliferation in AML (PMID:34551291, PMID:34081901), and directly activates targets such as Rab7b, H2B genes, FANCD2, and LRG1 to support injury-induced cell plasticity, satellite-cell genome stability, anti-ferroptotic cardioprotection, and angiogenesis (PMID:34309175, PMID:37591871, PMID:35843476, PMID:35094168). In the DNA-damage response ATF3 binds the Tip60 acetyltransferase adjacent to its catalytic domain, stimulating its activity and stabilizing it through USP7-mediated deubiquitination to sustain ATM signaling (PMID:25865756, PMID:26994140). ATF3 protein abundance is itself tightly regulated: PXR stabilizes ATF3 by disrupting its interaction with MDM2 and blocking MDM2-dependent ubiquitination (requiring ATF3 K42), while chromatin-bound ATF3 turnover depends on the CSA/CSB Cockayne syndrome factors (PMID:35372071, PMID:31980658). Across tissues these activities position ATF3 as a central node governing ferroptosis, inflammatory resolution, metabolic reprogramming, regeneration, and senescence (PMID:31273299, PMID:34551291, PMID:37233732, PMID:39543280).

Mechanistic history

Synthesis pass · year-by-year structured walk · 10 steps
  1. 1994 High

    Established the core molecular logic of ATF3 as a homodimeric repressor at ATF sites and revealed that a leucine-zipper-deleted isoform inverts this activity, framing ATF3 function around dimerization and co-factor sequestration.

    Evidence in vitro transcription assays and domain-deletion analysis in transfected cells

    PMID:7515060

    Open questions at the time
    • Did not identify the inhibitory co-factors stabilized at the promoter
    • No physiological inducer or target gene defined
  2. 1996 Medium

    Defined how ATF3 transcription is induced under stress, linking JNK/SAPK signaling and ATF2/c-Jun to ATF3 promoter activation and mRNA stabilization.

    Evidence genomic cloning, promoter reporter and co-transfection assays, mRNA stability analysis

    PMID:8576171

    Open questions at the time
    • Promoter element usage in physiological stress not dissected
    • Did not establish downstream targets
  3. 2003 Medium

    Showed ATF3 can act as a partner-dependent activator by physically associating with c-Jun to promote neurite sprouting, demonstrating context-dependent positive function.

    Evidence co-IP and neurite sprouting assay in neuronal cell lines

    PMID:14667575

    Open questions at the time
    • Direct target genes of the ATF3–c-Jun complex not defined
    • Single cell-line context
  4. 2010 High

    Defined a direct repressive ATF/CRE target (AdipoR1) and an in vivo role in mast cell survival/maturation, extending ATF3 to metabolic signaling and immune cell biology.

    Evidence ChIP/EMSA/promoter mutagenesis for AdipoR1; ATF3-knockout mice and mast-cell cultures with kinase readouts

    PMID:20203264 PMID:20696134

    Open questions at the time
    • Mechanism linking ATF3 loss to Akt/Bad signaling not resolved
    • Promoter binding and cellular phenotype studied separately
  5. 2015 High

    Resolved how ATF3 enforces inflammatory resolution and connects to DNA-damage signaling, repressing Cox-2 and IFN-β while directly binding and activating the Tip60 acetyltransferase to sustain ATM signaling.

    Evidence ChIP with Atf3-knockout macrophages (Ptgs2, Ifnb1); co-IP, acetyltransferase and ubiquitination assays for Tip60/USP7

    PMID:25619459 PMID:25865756 PMID:26416280

    Open questions at the time
    • How a repressor at gene promoters also acts as a Tip60 co-activator at chromatin not unified
    • USP7 recruitment mechanism to Tip60 incomplete
  6. 2018 High

    Positioned ATF3 as the effector arm of immunometabolic signaling, mediating itaconate-driven IκBζ suppression of secondary inflammatory genes and repressing PINK1 to control mitochondrial quality and fibrosis.

    Evidence itaconate/DI treatment with knockdown and IκBζ readout; PINK1 promoter reporter plus ATF3 conditional KO in lung epithelium

    PMID:29363258 PMID:29670287

    Open questions at the time
    • Direct vs indirect regulation of IκBζ not fully separated
    • Selectivity for secondary over primary genes mechanistically unexplained
  7. 2019 High

    Identified ATF3 repression of SLC7A11 as a p53-independent driver of ferroptosis, establishing the central ferroptosis axis later generalized across tissues.

    Evidence ChIP for SLC7A11 promoter binding, gain/loss-of-function with GSH and lipid peroxidation readouts in an erastin model

    PMID:31273299

    Open questions at the time
    • Determinants of pro- vs anti-ferroptotic ATF3 output across cell types not defined
    • Upstream inducers of ATF3 in ferroptosis context not resolved here
  8. 2021 High

    Defined ATF3 as a metabolic activator that, with ATF4 and p300, drives serine synthesis and nucleotide metabolism, and as a direct activator of regeneration genes (Rab7b, H2B, FANCD2).

    Evidence ATF4/ATF3 co-IP and ChIP at SSP gene enhancers with metabolic tracing; conditional KO with lysosomal, satellite-cell, and cardiac ferroptosis phenotypes

    PMID:34081901 PMID:34309175 PMID:34551291 PMID:35843476 PMID:37591871

    Open questions at the time
    • Structural basis of ATF3–ATF4 cooperative activation unresolved
    • Switch between activator and repressor programs in the same cell not defined
  9. 2022 High

    Established how ATF3 protein stability is controlled, with PXR blocking MDM2-dependent ubiquitination via ATF3 K42, and mapped broad immune/metabolic transcriptional programs (RIPK3, CH25H, P4HA1).

    Evidence co-IP, K42R mutagenesis and ubiquitination/half-life assays for PXR-MDM2; hepatocyte- and CTL-specific genetic models with ChIP/LC-MS for RIPK3, CH25H, P4HA1

    PMID:35372071 PMID:36070682 PMID:36690638 PMID:38441561

    Open questions at the time
    • Which E3/DUB pathways dominate ATF3 turnover in vivo not settled
    • Crosstalk between stability control and target gene selection unaddressed
  10. 2024 High

    Extended ATF3 to senescence and aging biology, showing it activates senescence-associated endogenous retroviruses to trigger interferon responses and drives osteocyte ferroptosis via TFR1 and SLC7A11.

    Evidence ATF3 gain/loss in senescent fibroblasts with dsRNA and RIG-I/MDA5-MAVS analysis; single-cell and in vivo ATF3 inhibition in aged osteocytes

    PMID:38764128 PMID:39543280

    Open questions at the time
    • How ATF3 selects ERV loci for bidirectional activation unknown
    • Relationship between senescence-associated and stress-induced ATF3 programs unclear

Open questions

Synthesis pass · forward-looking unresolved questions
  • What determines whether ATF3 acts as a repressor or partner-dependent activator at a given locus, and how its post-translational stability control integrates with target-gene selection, remains unresolved.
  • No structural model of ATF3 dimer/partner-specific DNA engagement
  • Rules governing pro- vs anti-ferroptotic output across tissues undefined

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140110 transcription regulator activity 7 GO:0003677 DNA binding 6 GO:0098772 molecular function regulator activity 2
Localization
GO:0005634 nucleus 4 GO:0000228 nuclear chromosome 1
Pathway
R-HSA-168256 Immune System 4 R-HSA-5357801 Programmed Cell Death 4 R-HSA-74160 Gene expression (Transcription) 4 R-HSA-1430728 Metabolism 3 R-HSA-73894 DNA Repair 2
Partners
ATF4EP300JUNKAT5MDM2NR1I2PPARGUSP7

Evidence

Reading pass · 54 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1994 ATF3 represses transcription from promoters with ATF sites as a homodimer, likely by stabilizing inhibitory co-factors at the promoter. An alternatively spliced isoform, ATF3 delta Zip, lacks the leucine zipper domain, cannot bind DNA, and instead activates transcription by sequestering inhibitory co-factors away from the promoter. Transient transfection, in vitro transcription assays, domain deletion analysis The Journal of biological chemistry High 7515060
1996 The ATF3 gene is organized into four exons spanning ~15 kb; its promoter contains ATF/CRE, AP-1, NF-κB, E2F, and Myc/Max binding sites. Co-transfection of ATF2 and c-Jun activates the ATF3 promoter, implicating the JNK/SAPK pathway in stress-induced ATF3 transcription. Anisomycin both activates the ATF3 promoter and stabilizes ATF3 mRNA. Genomic cloning, promoter reporter assays, co-transfection, mRNA stability analysis The Journal of biological chemistry Medium 8576171
2003 ATF3 physically associates with c-Jun and enhances c-Jun-mediated neurite sprouting in neuronal cell lines; the enhancement depends on this physical interaction between the two transcription factors. Co-expression in neuronal cell lines, neurite sprouting assay, co-immunoprecipitation to demonstrate physical association Brain research. Molecular brain research Medium 14667575
2010 ATF3 is required for IL-3-induced mast cell maturation; ATF3-deficient mast cells show increased apoptosis, diminished Akt kinase activation, and decreased phosphorylation of the pro-apoptotic protein Bad. ATF3-null mice lacked peritoneal and dermal mast cells. Additionally, ATF3-null mast cells showed significantly inhibited high-affinity IgE receptor-mediated degranulation, while IL-4 and IL-6 expression was enhanced. ATF3 knockout mice, bone marrow-derived mast cell cultures, flow cytometry, kinase phosphorylation assays Blood High 20203264
2010 ATF3 directly binds to an ATF/CRE site (−248 to −224) in the human AdipoR1 promoter and represses AdipoR1 expression, thereby attenuating adiponectin signaling. Chromatin immunoprecipitation (ChIP), EMSA, promoter-deletion reporter assays, lentiviral overexpression Biochemical and biophysical research communications High 20696134
2011 ATF3 directly binds to an ATF/CRE site (−759 to −738) in the mouse PDX-1 promoter and represses PDX-1 expression in pancreatic β-cells; mutation of this site abolishes ATF3-mediated repression. EMSA, ChIP, promoter-deletion reporter assays, site-directed mutagenesis, siRNA knockdown Biochemical and biophysical research communications High 21821004
2012 MicroRNA-494 binds to the 3′ UTR of ATF3 mRNA and decreases ATF3 expression; overexpression of miR-494 in mice attenuates ATF3 levels after renal ischemia/reperfusion and exacerbates NF-κB-mediated inflammatory injury. 3′ UTR luciferase reporter assay, miRNA overexpression in vivo, NF-κB pathway analysis Journal of the American Society of Nephrology Medium 23160513
2013 RyR3 silencing reduces mitochondrial Ca2+ and ATF3 expression; overexpression of ATF3 blocks the RyR3-silencing-mediated upregulation of adiponectin expression, placing ATF3 downstream of RyR3 signaling as a repressor of adiponectin. siRNA knockdown, ATF3 overexpression rescue, adiponectin promoter activity assay Endocrinology Medium 23389954
2014 ATF3 directly binds to an ATF/CRE site (−2037 to −1530) in the PPARγ2 promoter and represses PPARγ expression, inhibiting adipocyte differentiation. Mutation of this CRE site abolishes ATF3-mediated transrepression. EMSA, ChIP, 5′-deletion promoter reporter assays, site-directed mutagenesis Biochemical and biophysical research communications High 25445599
2014 ATF3 physically interacts with PPARγ (demonstrated by co-IP and GST pulldown), prevents PPARγ binding to PPRE on the aP2 promoter, and suppresses p300-mediated transcriptional co-activation of PPARγ target genes. Co-immunoprecipitation, GST pulldown, ChIP, promoter reporter assays Biochemical and biophysical research communications High 25446101
2014 ATF3 directly binds to the MCP-1 promoter at ATF/CRE sites and inhibits MCP-1 transcription in renal epithelial cells after ischemia/reperfusion injury. Exosomal ATF3 RNA also suppresses MCP-1 expression in recipient cells. ChIP assay, ATF3-knockout mice, in vitro exosome transfer assay Journal of cellular physiology High 24420912
2015 ATF3 directly binds to the Tip60 MYST histone acetyltransferase at a region adjacent to its catalytic domain, promoting Tip60 acetyltransferase activity. ATF3 also increases Tip60 protein stability by promoting USP7-mediated deubiquitination of Tip60. Knockdown of ATF3 decreases Tip60 expression and suppresses ATM signaling, causing DNA lesion accumulation and increased cell sensitivity to irradiation. Co-immunoprecipitation, acetyltransferase activity assay, ubiquitination assay, siRNA knockdown, DNA damage assays Nature communications High 25865756
2015 ATF3 accumulates in the nucleus of activated macrophages and is recruited to the Ptgs2 (Cox-2) promoter region, functioning as a transcriptional repressor to terminate Cox-2 expression and limit prostaglandin production during acute inflammation. Atf3-/- macrophages show significantly higher Ptgs2 expression. ChIP analysis, Atf3 knockout mice, peritoneal macrophage isolation, peritonitis and wound models Prostaglandins & other lipid mediators High 25619459
2015 ATF3 acts as a transcriptional repressor of IFN-β by directly binding to a specific regulatory site distal to the Ifnb1 promoter in macrophages. ATF3 is itself an IFN-inducible gene, constituting a negative feedback loop for IFN signaling. ChIP for direct binding to Ifnb1 regulatory site, ATF3-deficient macrophages, viral infection models Journal of immunology High 26416280
2016 ATF3 mediates dichotomous UV responses: it binds Tip60 upon UV irradiation to increase Tip60 stability and promote apoptosis in p53-defective cells. In p53 wild-type cells, ATF3 activates p53 and promotes p53-mediated DNA repair by altering histone modifications that facilitate recruitment of DDB2 to damaged DNA sites. Co-immunoprecipitation (ATF3-Tip60 binding after UV), knockdown experiments, histone modification analysis, DNA repair assays The Journal of biological chemistry High 26994140
2016 In chondrocytes, ATF3 deficiency decreases cytokine-induced IL-6 transcription by attenuating NF-κB signaling through reduced phosphorylation of IκB and p65. ATF3 expression is induced by inflammatory cytokines via NF-κB, establishing a feed-forward loop of inflammatory cytokines/NF-κB/ATF3 in chondrocytes. Conditional Atf3 knockout mice (chondrocyte-specific), NF-κB phosphorylation assays, surgically-induced OA model, human chondrocyte knockdown The Journal of pathology High 27159257
2016 In osteoclast precursors, ATF3 regulates cyclin D1 mRNA expression through modulating AP-1-dependent transcription; introduction of cyclin D1 rescues impaired osteoclastogenesis in ATF3-deleted bone marrow macrophages. RANKL-induced transient proliferation of osteoclast precursors requires ATF3. Osteoclast precursor-specific ATF3 KO mice, in vitro osteoclastogenesis, cyclin D1 rescue experiment, RANKL-induced bone resorption model Scientific reports Medium 27480204
2017 In Drosophila midgut, ATF3 restricts JNK activity by transcriptionally regulating the JNK antagonist Raw. Enterocyte-specific ATF3 inactivation increases JNK activity and sensitivity to infection; this phenotype is rescued by Raw overexpression or JNK suppression, placing ATF3 upstream of Raw in the JNK pathway. Drosophila genetic epistasis (ATF3 inactivation rescued by Raw OE or JNK suppression), in vivo infection models Nature communications High 28272390
2017 ATF3 directly binds to the NFATc1 gene promoter (671–775 bp upstream of TSS) and modulates its activity, altering expression of Wnt6 and Fzd9 (NFATc1 targets), thereby promoting podocyte apoptosis and injury. Promoter reporter assay, ChIP, ATF3 overexpression and siRNA knockdown, apoptosis assays Journal of molecular medicine Medium 29038896
2018 Itaconate and its derivative DI induce ATF3, which acts as a key mediator of IκBζ inhibition, selectively suppressing secondary (but not primary) inflammatory gene transcription in macrophages. This regulatory pathway is conserved across species and cell types. Itaconate/DI treatment, Nrf2-independent ATF3 induction analysis, IκBζ protein level assay, genetic knockdown Nature High 29670287
2018 ATF3 directly binds the PINK1 promoter (within the first 150 bp upstream of the TSS); ATF3 overexpression inhibits PINK1 promoter activity, causes accumulation of depolarized mitochondria, increased mitochondrial ROS, and loss of cell viability. Conditional deletion of ATF3 in type II lung epithelial cells protects mice from bleomycin-induced lung fibrosis. Promoter reporter assay with defined ATF3 binding site, ATF3 overexpression, ATF3 conditional KO mice, mitochondrial function assays Aging cell High 29363258
2018 TRPV1-mediated Ca2+ influx activates calcineurin, which in turn activates ATF3 transcription; ATF3 then activates p53 expression. This TRPV1-calcineurin-ATF3-p53 cascade mediates the pro-apoptotic effect of TRPV1 activation in melanoma cells. Ca2+ channel manipulation, calcineurin inhibition, ATF3 overexpression/knockdown, p53 reporter and expression assays The Journal of investigative dermatology Medium 29580868
2019 ATF3 promotes erastin-induced ferroptosis by binding to the SLC7A11 promoter and repressing SLC7A11 (xCT) expression in a p53-independent manner, thereby depleting intracellular GSH and promoting lipid peroxidation. ChIP showing ATF3 binding to SLC7A11 promoter, ATF3 overexpression/knockdown, GSH assay, lipid peroxidation assay, erastin ferroptosis model Cell death and differentiation High 31273299
2019 ATF3 and JDP2 regulate SDF-1 transcription and secretion in cancer-associated fibroblasts; double deficiency of ATF3 and JDP2 results in elevated SDF-1 secretion, increased tumor vascular perfusion, and enhanced tumor growth that is reversed by SDF-1 depletion. ATF3/JDP2 double knockout mice, tumor transplantation models, SDF-1 depletion rescue experiment Oncogene Medium 30670778
2020 ATF3 transcriptionally upregulates PD-L1 expression; tumor ATF3 deletion reduces PD-L1 levels and improves the efficacy of ADORA1 antagonist treatment in xenograft models. ATF3 deletion in tumor cells, PD-L1 expression analysis, T cell co-culture assays, in vivo xenograft models Cancer cell Medium 32183950
2020 ATF3 binds ATF/CRE sites in the ATF3-responsive region of AdipoR1 and represses its promoter; deficiency of ATF3 in podocytes reduces podocyte apoptosis (separate study: ATF3 increases apoptosis via NFATc1). In renal I/R, ATF3-KO mice show higher induction of adhesion molecules including ICAM, VCAM, and MCP-1, confirming ATF3 represses these pro-inflammatory genes. ATF3 knockout mice, gene expression analysis, ChIP Journal of cellular physiology High 24420912
2021 ATF3 is rapidly induced by serine deprivation via an ATF4-dependent mechanism; ATF3 then binds to ATF4 and increases the stability of ATF4 (a master regulator of the serine synthesis pathway, SSP). ATF3 also binds the enhancers/promoters of PHGDH, PSAT1, and PSPH, and recruits p300 to promote expression of these SSP genes, driving intracellular serine biosynthesis. ATF4/ATF3 co-immunoprecipitation, ChIP showing ATF3 binding to SSP gene enhancers/promoters, ATF3 loss-of-function, serine biosynthesis metabolic assays, in vivo dietary serine restriction model Cell reports High 34551291
2021 ATF3 directly activates transcription of the lysosomal trafficking gene Rab7b during paligenosis (injury-induced cell plasticity); Atf3-/- mice fail to induce RAB7-positive autophagic and lysosomal vesicles and show increased cell death at paligenosis Stage 1. Atf3 knockout mice, in vivo gastric and pancreatic injury models, lysosomal/autophagy vesicle assays, reporter analysis EMBO reports Medium 34309175
2021 ATF3 coordinates serine and nucleotide metabolism in AML by directly activating transcription of genes encoding key enzymes in serine synthesis, one-carbon metabolism, and de novo purine and pyrimidine synthesis. ATF3 inhibition reduces serine-derived carbon incorporation into purines; exogenous nucleotide supplementation rescues anti-leukemia effects of ATF3 inhibition. ATF3 knockdown in mouse and human AML models, heavy isotope metabolic tracing, total steady-state polar metabolite analysis, nucleotide supplementation rescue Molecular cell High 34081901
2021 ATF3 drives cellular senescence by reconstructing chromatin accessibility through AP-1 family binding at intergenic enhancer elements; low DNA methylation improves ATF3 binding affinity and increases chromatin accessibility at these sites. ATAC-seq, RNA-seq, HUVEC senescence model, ATF3 functional validation in senescence Aging cell Medium 33539668
2021 In the heart, ATF3 transcriptionally activates FANCD2 by binding to its transcription start site (demonstrated by ChIP-seq and dual luciferase assay); FANCD2 overexpression exerts anti-ferroptosis and cardioprotective effects. ATF3 knockout aggravates myocardial I/R injury and increases ferroptosis markers. ATF3 knockout and overexpression mice/cells, ChIP-seq, dual luciferase activity assay, ferroptosis assays in I/R model Free radical biology & medicine Medium 35843476
2021 ATF3 promotes decidualization in endometrial stromal cells by upregulating FOXO1 via suppression of miR-135b expression. ATF3 also inhibits proliferation of human endometrial stromal cells through CDKN1A. ATF3 knockdown and overexpression in hESCs, miR-135b manipulation, FOXO1 and CDKN1A expression analysis, decidualization marker assays Cell death & disease Medium 33846304
2021 Hepatocyte ATF3 enhances HDL uptake by inducing scavenger receptor SR-BI, and represses CYP8B1 (cholesterol 12α-hydroxylase) through interaction with p53 and hepatocyte nuclear factor 4α (HNF4α), respectively, thereby reducing atherosclerosis. Hepatocyte-specific ATF3 overexpression and ablation in atherosclerosis mouse models, mechanistic co-immunoprecipitation/promoter studies with p53 and HNF4α Nature metabolism High 33462514
2021 ATF3 promotes brucine-induced glioma cell ferroptosis by upregulating NOX4 and SOD1 (generating H2O2) and downregulating catalase and xCT (preventing H2O2 degradation), leading to iron accumulation and lipid peroxidation. ATF3 is induced and translocates to the nucleus via ER stress activation. ATF3 siRNA knockdown, H2O2 accumulation assays, iron measurement, lipid peroxidation, ER stress inhibitors, in vivo glioma model Acta pharmacologica Sinica Medium 34112960
2022 ATF3 directly binds to the FANCD2/RIPK3 promoter regions; in hepatic steatosis ATF3 induces RIPK3 expression, switching hepatocellular death from apoptosis to necroptosis. ATF3-deficient or overexpressing mice show decreased or increased RIPK3 and necroptosis, respectively. ATF3 hepatocyte-specific KO and overexpression mice, RIPK3 expression analysis, live-cell imaging of cell death mode, NASH mouse model Nature communications High 36690638
2022 In cytotoxic T lymphocytes, tumor-derived factors induce ATF3 transcription factor which suppresses CH25H (cholesterol 25-hydroxylase) expression, thereby depleting 25-hydroxycholesterol (25HC). This ATF3-CH25H axis stimulates effector trogocytosis, antigen loss, and CTL fratricide. Restoring CH25H expression reverses ATF3-mediated trogocytosis and improves CAR-T cell efficacy. ATF3 induction/deletion in CTLs, CH25H expression analysis, trogocytosis assays, lipid profiling, in vivo tumor models, armored CAR constructs Cell metabolism High 36070682
2022 ATF3 suppresses Slc7a11 (xCT) expression and promotes ferroptosis in sorafenib-induced cardiotoxicity; overexpression of Slc7a11 protects cells from this ferroptosis, establishing ATF3/Slc7a11 as a key axis in sorafenib-induced cardiotoxicity. ATF3 overexpression, Slc7a11 overexpression/knockdown, ferroptosis markers (MDA, GPX4), in vivo sorafenib cardiotoxicity model Frontiers in pharmacology Medium 36210815
2022 ATF3 acts as a transcriptional repressor of ILF3; ATF3 binds the ILF3 promoter (validated by luciferase reporter and ChIP assays) and promotes M2 macrophage polarization via the ILF3/NEAT1 axis (ILF3 stabilizes NEAT1 through direct interaction). ATF3 overexpression suppresses the ILF3/NEAT1 axis and reduces M1-like macrophage polarization in sepsis. ChIP, luciferase reporter assays, RIP and RNA pulldown for ILF3-NEAT1 interaction, ATF3 overexpression in LPS-stimulated macrophages and CLP sepsis model Molecular medicine Medium 38395749
2022 In cardiac fibroblasts, KDM5B (a histone H3K4me2/3 demethylase) binds the Atf3 promoter and inhibits ATF3 expression by demethylating H3K4me2/3; this reduction in ATF3 leads to enhanced TGF-β signaling and profibrotic gene expression. KDM5B deficiency restores ATF3 expression and reduces cardiac fibrosis. KDM5B knockout mice, ChIP showing KDM5B binding to Atf3 promoter and H3K4me2/3 demethylation, cardiac fibrosis models (MI and pressure overload) Experimental & molecular medicine High 36481938
2022 In liver fibrosis, ATF3 promotes transcription of lnc-SCARNA10, which recruits SMAD3 to fibrogenic gene promoters; lnc-SCARNA10 in turn promotes ATF3 expression via TGF-β/SMAD3, creating a TGF-β/ATF3/lnc-SCARNA10 feed-forward axis in hepatic stellate cell activation. ATF3 knockdown in vivo and in vitro, ChIP, luciferase reporter assay, SMAD3 recruitment analysis, mouse fibrosis model Cell death & disease Medium 33311456
2022 MCPIP1 promotes monocyte-to-macrophage maturation via an ATF3-AP1S2 axis; in Mcpip1-deficient macrophages, ATF3 and AP1S2 are upregulated, and silencing of either Atf3 or Ap1s2 suppresses the M1-like macrophage polarization. ATF3 acts upstream of AP1S2 in this maturation axis. ScRNA-seq, CUT&Tag assay, luciferase assay, RNA-seq, Mcpip1 conditional KO mice, colitis model with AP1S2 in vivo blockage Gut High 37015751
2022 In proteasome-dysfunctional adipocytes, ATF3 is a key effector of inflammation and blocks adipogenesis; simultaneous silencing of Psmb4 and Atf3 lowers inflammation and restores adipogenesis, placing ATF3 downstream of proteasome dysfunction in the integrated stress response. siRNA co-knockdown of Psmb4 and Atf3, adipogenesis assays, inflammation marker measurement Molecular metabolism Medium 35636710
2023 ATF3 directly binds to the P4HA1 promoter and negatively regulates its transcription in glioblastoma (HIF1α activates P4HA1). P4HA1 elevates succinate, which succinylates PGK1 at K191/K192, inhibiting its proteasomal degradation and enhancing aerobic glycolysis. ATF3 overexpression reduces succinate and lactate, inhibiting immune evasion and tumor growth. ChIP assays, LC-MS/MS for succinylation sites, in vitro succinate production assay, Seahorse metabolic assay, in vivo intracranial mouse model Neuro-oncology High 38441561
2023 ATF3 directly activates H2B gene transcription in skeletal muscle satellite cells; reduced H2B accelerates nucleosome displacement and gene transcription required for satellite cell activation. ATF3-dependent H2B expression also prevents genome instability and replicative senescence in satellite cells. Atf3 short-term and long-term conditional deletion in satellite cells, ChIP for ATF3 binding to H2B gene promoters, H2B knockdown/overexpression, nucleosome displacement assays Nature communications High 37591871
2023 In endometriosis stromal cells, the P38/JNK pathway activated by IL-33/ST2 suppresses ATF3, which relieves ATF3-mediated repression of SLC7A11, thereby increasing SLC7A11 expression and inhibiting ferroptosis. IL-33 stimulation, P38/JNK inhibition, ATF3 knockdown, SLC7A11 expression analysis, ferroptosis assays, endometriosis mouse model Cell death & disease Medium 37816731
2023 Atf3 defines a subpopulation of pulmonary capillary endothelial cells; endothelial cell-specific Atf3 deletion results in defective alveolar regeneration after influenza infection, with increased apoptosis and decreased proliferation in the endothelium, and an emphysema-like phenotype. Atf3 endothelial-specific conditional KO mice, influenza lung injury model, single-cell transcriptomics, histological and morphological analysis eLife High 37233732
2024 ATF3 bidirectionally activates senescence-associated endogenous retroviruses (SA-ERVs) to generate double-stranded RNAs, which activate the RIG-I/MDA5-MAVS signaling pathway and trigger a type I interferon response in senescent fibroblasts. ATF3 overexpression/depletion in senescent fibroblasts, dsRNA detection, RIG-I/MDA5-MAVS pathway analysis, IFN-I response measurement, aged human tissue analysis Nature aging High 39543280
2024 In vascular smooth muscle cells, ATF3 suppresses PDGFRB expression (mediating cell proliferation in response to TNF-α at early AAA stage) and upregulates BCL2 (suppressing mitochondria-dependent apoptosis at advanced AAA stage). NFκB1 and P300/BAF/H3K27ac complex recruitment to the ATF3 promoter via enhancer activation drives ATF3 transcription. VSMC-specific ATF3 knockdown/overexpression via AAV, ChIP for NFκB1 and H3K27ac at ATF3 promoter, Ang II-induced AAA mouse model, in vitro proliferation/apoptosis assays Circulation research High 38686580
2024 ATF3 upregulates transferrin receptor 1 (TFR1) expression while inhibiting SLC7A11-mediated cystine import in senescent osteocytes, leading to iron overload and lipid peroxidation (ferroptosis) and contributing to cortical bone loss during aging. ATF3 inhibition in aged mice alleviates osteocyte ferroptosis and cortical bone loss. Single-cell transcriptome analysis, ATF3 overexpression/inhibition in osteocytes, aged mouse model, ferroptosis markers, TFR1 and SLC7A11 expression analysis Cell proliferation Medium 38764128
2022 ATF3 directly binds to the promoter of FANCD2 transcription start site and the LRG1 promoter (in gastric cancer), activating their transcription. In gastric cancer, ATF3-driven LRG1 promotes VEGFA expression via the SRC/STAT3/VEGFA pathway to enhance angiogenesis. ChIP assay, dual-luciferase reporter assay, LRG1 and VEGFA expression analysis, angiogenesis assays in vitro/in vivo Gastric cancer Medium 35094168
2021 Topoisomerase I activity produces DNA breaks at the ATF3 gene locus immediately after nerve injury in sensory neurons, and these breaks contribute to ATF3 induction. ATF3 induction promotes neurite outgrowth and axonal regeneration; camptothecin (topoisomerase inhibitor) increases ATF3 expression and enhances axonal regeneration after sciatic nerve crush. ATF3 reporter systems, topoisomerase inhibitor treatment, DNA break detection at ATF3 locus, in vitro neurite outgrowth assay, in vivo sciatic nerve crush model Cell reports Medium 34496254
2022 PXR stabilizes ATF3 protein by blocking ATF3 ubiquitination; PXR-ATF3 interaction requires K42 of ATF3 (K42R mutant loses PXR binding and abolishes PXR-mediated ubiquitination reduction). PXR disrupts ATF3-MDM2 interaction and promotes MDM2 auto-ubiquitination, shortening MDM2 half-life and thereby preventing MDM2-mediated ATF3 degradation. Co-IP, ubiquitination assays, site-directed mutagenesis (ATF3 K42R, PXR T432A), MDM2 interaction analysis, protein half-life assays Frontiers in oncology High 35372071
2020 ATF3-deficient Cockayne Syndrome cells show persistent ATF3 protein retention at chromatin (defective degradation of chromatin-bound ATF3) caused by CSA/CSB dysfunction, leading to permanent transcriptional arrest of ATF3-responsive genes. This defective ATF3 removal can be used as a diagnostic marker for CS. Immunofluorescence for ATF3 protein stability, ChIP-seq of Pol II and ATF3 promoter occupancy, RNA-seq, quantitative RT-PCR in 64 patient cell lines Scientific reports Medium 31980658
2024 SIRT1 (activated by AROS via ROS-dependent AROS upregulation) promotes ATF3 nuclear translocation and expressional upregulation during ferroptosis by consuming NAD+; ATF3 then suppresses SLC7A11 and GPX4 expression, promoting ferroptosis. Maintaining intracellular NAD+ levels suppresses ATF3 activation. SIRT1 activator/inhibitor, siRNA knockdown of SIRT1 and ATF3, NAD+ supplementation/depletion, SLC7A11/GPX4 expression analysis, glioma cell ferroptosis assays Redox biology Medium 38181705

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2019 ATF3 promotes erastin-induced ferroptosis by suppressing system Xc. Cell death and differentiation 681 31273299
2018 Electrophilic properties of itaconate and derivatives regulate the IκBζ-ATF3 inflammatory axis. Nature 572 29670287
1999 ATF3 and stress responses. Gene expression 572 10440233
2009 ATF3 transcription factor and its emerging roles in immunity and cancer. Journal of molecular medicine (Berlin, Germany) 298 19705082
2021 Induction of ferroptosis by ATF3 elevation alleviates cisplatin resistance in gastric cancer by restraining Nrf2/Keap1/xCT signaling. Cellular & molecular biology letters 237 34098867
1996 ATF3 gene. Genomic organization, promoter, and regulation. The Journal of biological chemistry 211 8576171
1994 ATF3 and ATF3 delta Zip. Transcriptional repression versus activation by alternatively spliced isoforms. The Journal of biological chemistry 208 7515060
2023 ATF3/SPI1/SLC31A1 Signaling Promotes Cuproptosis Induced by Advanced Glycosylation End Products in Diabetic Myocardial Injury. International journal of molecular sciences 195 36675183
2020 ADORA1 Inhibition Promotes Tumor Immune Evasion by Regulating the ATF3-PD-L1 Axis. Cancer cell 168 32183950
2021 ATF3 contributes to brucine-triggered glioma cell ferroptosis via promotion of hydrogen peroxide and iron. Acta pharmacologica Sinica 117 34112960
2012 MicroRNA-494 reduces ATF3 expression and promotes AKI. Journal of the American Society of Nephrology : JASN 114 23160513
2018 ATF3 represses PINK1 gene transcription in lung epithelial cells to control mitochondrial homeostasis. Aging cell 109 29363258
2015 ATF3 Is a Key Regulator of Macrophage IFN Responses. Journal of immunology (Baltimore, Md. : 1950) 103 26416280
2022 ATF3 -activated accelerating effect of LINC00941/lncIAPF on fibroblast-to-myofibroblast differentiation by blocking autophagy depending on ELAVL1/HuR in pulmonary fibrosis. Autophagy 89 35427207
2021 ATF3 promotes the serine synthesis pathway and tumor growth under dietary serine restriction. Cell reports 85 34551291
2003 ATF3 enhances c-Jun-mediated neurite sprouting. Brain research. Molecular brain research 85 14667575
2024 The Dual Roles of Activating Transcription Factor 3 (ATF3) in Inflammation, Apoptosis, Ferroptosis, and Pathogen Infection Responses. International journal of molecular sciences 83 38255898
2021 Hepatocyte ATF3 protects against atherosclerosis by regulating HDL and bile acid metabolism. Nature metabolism 77 33462514
2017 ATF3 promotes migration and M1/M2 polarization of macrophages by activating tenascin‑C via Wnt/β‑catenin pathway. Molecular medicine reports 77 28714032
2008 Expression of ATF3 and axonal outgrowth are impaired after delayed nerve repair. BMC neuroscience 75 18801180
2014 Exosomal ATF3 RNA attenuates pro-inflammatory gene MCP-1 transcription in renal ischemia-reperfusion. Journal of cellular physiology 71 24420912
2022 ATF3 and CH25H regulate effector trogocytosis and anti-tumor activities of endogenous and immunotherapeutic cytotoxic T lymphocytes. Cell metabolism 70 36070682
2020 Transcriptional factor ATF3 promotes liver fibrosis via activating hepatic stellate cells. Cell death & disease 68 33311456
2021 Exercise-induced angiogenesis is dependent on metabolically primed ATF3/4+ endothelial cells. Cell metabolism 67 34358431
2022 A novel function of ATF3 in suppression of ferroptosis in mouse heart suffered ischemia/reperfusion. Free radical biology & medicine 64 35843476
2022 MCPIP1 restrains mucosal inflammation by orchestrating the intestinal monocyte to macrophage maturation via an ATF3-AP1S2 axis. Gut 64 37015751
2021 ATF3 drives senescence by reconstructing accessible chromatin profiles. Aging cell 64 33539668
2022 ATF3 promotes ferroptosis in sorafenib-induced cardiotoxicity by suppressing Slc7a11 expression. Frontiers in pharmacology 63 36210815
2018 ATF3 inhibits the tumorigenesis and progression of hepatocellular carcinoma cells via upregulation of CYR61 expression. Journal of experimental & clinical cancer research : CR 62 30376856
2015 Atf3 negatively regulates Ptgs2/Cox2 expression during acute inflammation. Prostaglandins & other lipid mediators 56 25619459
2021 ATF3 coordinates serine and nucleotide metabolism to drive cell cycle progression in acute myeloid leukemia. Molecular cell 55 34081901
2019 Adipocyte browning and resistance to obesity in mice is induced by expression of ATF3. Communications biology 55 31667363
2023 The transcription factor ATF3 switches cell death from apoptosis to necroptosis in hepatic steatosis in male mice. Nature communications 54 36690638
2024 SIRT1 activated by AROS sensitizes glioma cells to ferroptosis via induction of NAD+ depletion-dependent activation of ATF3. Redox biology 50 38181705
2023 Inhibition of TCA cycle improves the anti-PD-1 immunotherapy efficacy in melanoma cells via ATF3-mediated PD-L1 expression and glycolysis. Journal for immunotherapy of cancer 50 37678921
2016 ATF3 expression in cardiomyocytes preserves homeostasis in the heart and controls peripheral glucose tolerance. Cardiovascular research 50 28082453
2016 ATF3 deficiency in chondrocytes alleviates osteoarthritis development. The Journal of pathology 47 27159257
2024 HIF1α/ATF3 partake in PGK1 K191/K192 succinylation by modulating P4HA1/succinate signaling in glioblastoma. Neuro-oncology 46 38441561
2018 Downregulated TRPV1 Expression Contributes to Melanoma Growth via the Calcineurin-ATF3-p53 Pathway. The Journal of investigative dermatology 46 29580868
2018 Transcription factor ATF3 mediates the radioresistance of breast cancer. Journal of cellular and molecular medicine 46 30117642
2023 Macrophages originated IL-33/ST2 inhibits ferroptosis in endometriosis via the ATF3/SLC7A11 axis. Cell death & disease 45 37816731
2017 ATF3 acts as a rheostat to control JNK signalling during intestinal regeneration. Nature communications 42 28272390
2023 Saikosaponin A triggers cell ferroptosis in hepatocellular carcinoma by inducing endoplasmic reticulum stress-stimulated ATF3 expression. Biochemical and biophysical research communications 39 37393639
2015 The stress-responsive gene ATF3 regulates the histone acetyltransferase Tip60. Nature communications 39 25865756
2008 ATF3 and Fra1 have opposite functions in JNK- and ERK-dependent DNA damage responses. DNA repair 38 18249159
2021 ATF3 deficiency impairs the proliferative-secretory phase transition and decidualization in RIF patients. Cell death & disease 36 33846304
2022 LRG1 mediated by ATF3 promotes growth and angiogenesis of gastric cancer by regulating the SRC/STAT3/VEGFA pathway. Gastric cancer : official journal of the International Gastric Cancer Association and the Japanese Gastric Cancer Association 35 35094168
2017 Atf3 deficiency promotes genome instability and spontaneous tumorigenesis in mice. Oncogene 35 28869597
2022 Loss of KDM5B ameliorates pathological cardiac fibrosis and dysfunction by epigenetically enhancing ATF3 expression. Experimental & molecular medicine 34 36481938
2021 ATF3 induces RAB7 to govern autodegradation in paligenosis, a conserved cell plasticity program. EMBO reports 34 34309175
2024 Apigenin-7-glucoside-loaded nanoparticle alleviates intestinal ischemia-reperfusion by ATF3/SLC7A11-mediated ferroptosis. Journal of controlled release : official journal of the Controlled Release Society 33 38145659
2024 Spatiotemporal ATF3 Expression Determines VSMC Fate in Abdominal Aortic Aneurysm. Circulation research 33 38686580
2023 Atf3 defines a population of pulmonary endothelial cells essential for lung regeneration. eLife 32 37233732
2016 ATF3 controls proliferation of osteoclast precursor and bone remodeling. Scientific reports 31 27480204
2022 Proteasome dysfunction disrupts adipogenesis and induces inflammation via ATF3. Molecular metabolism 30 35636710
2010 A key role for ATF3 in regulating mast cell survival and mediator release. Blood 30 20203264
2024 ATF3-CBS signaling axis coordinates ferroptosis and tumorigenesis in colorectal cancer. Redox biology 29 38490069
2022 UPF1/circRPPH1/ATF3 feedback loop promotes the malignant phenotype and stemness of GSCs. Cell death & disease 29 35871061
2020 ATF3 Coordinates Antitumor Synergy between Epigenetic Drugs and Protein Disulfide Isomerase Inhibitors. Cancer research 28 32561529
2010 ATF3 negatively regulates adiponectin receptor 1 expression. Biochemical and biophysical research communications 28 20696134
2014 ATF3 represses PPARγ expression and inhibits adipocyte differentiation. Biochemical and biophysical research communications 27 25445599
2024 Reactivation of senescence-associated endogenous retroviruses by ATF3 drives interferon signaling in aging. Nature aging 26 39543280
2023 Sophoridine derivative 6j inhibits liver cancer cell proliferation via ATF3 mediated ferroptosis. Cell death discovery 26 37580343
2021 Topoisomerase I inhibition and peripheral nerve injury induce DNA breaks and ATF3-associated axon regeneration in sensory neurons. Cell reports 26 34496254
2017 Inducible ATF3-NFAT axis aggravates podocyte injury. Journal of molecular medicine (Berlin, Germany) 26 29038896
2023 ATF3 induction prevents precocious activation of skeletal muscle stem cell by regulating H2B expression. Nature communications 25 37591871
2019 ATF3 and JDP2 deficiency in cancer associated fibroblasts promotes tumor growth via SDF-1 transcription. Oncogene 25 30670778
2013 ER stress-inducible ATF3 suppresses BMP2-induced ALP expression and activation in MC3T3-E1 cells. Biochemical and biophysical research communications 25 24315873
2022 ATF3 in atherosclerosis: a controversial transcription factor. Journal of molecular medicine (Berlin, Germany) 24 36207452
2018 MicroRNA-488 inhibits tongue squamous carcinoma cell invasion and EMT by directly targeting ATF3. Cellular & molecular biology letters 24 29946339
2022 ATF3 Positively Regulates Antibacterial Immunity by Modulating Macrophage Killing and Migration Functions. Frontiers in immunology 23 35370996
2020 Activation of ATF3/AP-1 signaling pathway is required for P2X3-induced endometriosis pain. Human reproduction (Oxford, England) 22 32303740
2016 The Stress-responsive Gene ATF3 Mediates Dichotomous UV Responses by Regulating the Tip60 and p53 Proteins. The Journal of biological chemistry 22 26994140
2016 Peripheral and central neuronal ATF3 precedes CD4+ T-cell infiltration in EAE. Experimental neurology 21 27343802
2024 Osteocyte ferroptosis induced by ATF3/TFR1 contributes to cortical bone loss during ageing. Cell proliferation 20 38764128
2019 An ATF3-CreERT2 Knock-In Mouse for Axotomy-Induced Genetic Editing: Proof of Principle. eNeuro 20 30993183
2018 NDRG1 Downregulates ATF3 and Inhibits Cisplatin-Induced Cytotoxicity in Lung Cancer A549 Cells. International journal of medical sciences 20 30443171
2018 Atf3 links loss of epithelial polarity to defects in cell differentiation and cytoarchitecture. PLoS genetics 19 29494583
2024 SEH1L siliencing induces ferroptosis and suppresses hepatocellular carcinoma progression via ATF3/HMOX1/GPX4 axis. Apoptosis : an international journal on programmed cell death 18 39095556
2020 Defective transcription of ATF3 responsive genes, a marker for Cockayne Syndrome. Scientific reports 18 31980658
2018 Atf3 induction is a therapeutic target for obesity and metabolic diseases. Biochemical and biophysical research communications 18 30224057
2012 GnRH regulation of Jun and Atf3 requires calcium, calcineurin, and NFAT. Molecular endocrinology (Baltimore, Md.) 18 22446101
2021 The ATF3 inducer protects against diet-induced obesity via suppressing adipocyte adipogenesis and promoting lipolysis and browning. Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie 17 34839254
2020 ATF3 Prevents Stress-Induced Hematopoietic Stem Cell Exhaustion. Frontiers in cell and developmental biology 17 33195236
2023 Knockdown of ATF3 suppresses the progression of ischemic stroke through inhibiting ferroptosis. Frontiers in molecular neuroscience 16 36743288
2021 GCN2 Regulates ATF3-p38 MAPK Signaling Transduction in Pulmonary Veno-Occlusive Disease. Journal of cardiovascular pharmacology and therapeutics 16 33988041
2014 ATF3 inhibits PPARγ-stimulated transactivation in adipocyte cells. Biochemical and biophysical research communications 16 25446101
2013 MPP+-induces PUMA- and p53-dependent, but ATF3-independent cell death. Toxicology letters 16 23500530
2011 ATF3 represses PDX-1 expression in pancreatic β-cells. Biochemical and biophysical research communications 16 21821004
2024 Alternate day fasting aggravates atherosclerosis through the suppression of hepatic ATF3 in Apoe mice. Life metabolism 15 39872376
2021 Induction of heparanase 2 (Hpa2) expression by stress is mediated by ATF3. Matrix biology : journal of the International Society for Matrix Biology 15 34808335
2019 JDP2 and ATF3 deficiencies dampen maladaptive cardiac remodeling and preserve cardiac function. PloS one 15 30818334
2024 FATP2 activates PI3K/Akt/mTOR pathway by inhibiting ATF3 and promotes the occurrence and development of bladder cancer. Cellular signalling 14 38316266
2024 Role of ATF3 triggering M2 macrophage polarization to protect against the inflammatory injury of sepsis through ILF3/NEAT1 axis. Molecular medicine (Cambridge, Mass.) 14 38395749
2024 ATF3 is a neuron-specific biomarker for spinal cord injury and ischaemic stroke. Clinical and translational medicine 14 38649772
2022 Nuclear Receptor PXR Confers Irradiation Resistance by Promoting DNA Damage Response Through Stabilization of ATF3. Frontiers in oncology 14 35372071
2020 ATF3 expression in cardiomyocytes and myofibroblasts following transverse aortic constriction displays distinct phenotypes. International journal of cardiology. Heart & vasculature 14 33437861
2017 RNA-Seq revealed ATF3-regulated inflammation induced by silica. Toxicology 14 29102675
2013 Knockdown of RyR3 enhances adiponectin expression through an atf3-dependent pathway. Endocrinology 14 23389954
2000 Expression of the ATF3 gene on cell lines and surgically excised specimens. Oncology research 14 11341467

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