Affinage

ATF4

Cyclic AMP-dependent transcription factor ATF-4 · UniProt P18848

Length
351 aa
Mass
38.6 kDa
Annotated
2026-06-09
100 papers in source corpus 47 papers cited in narrative 47 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

ATF4 is a stress-induced bZIP transcription factor that serves as the master effector of the integrated stress response (ISR), coupling diverse upstream signals to a transcriptional program governing amino acid metabolism, redox homeostasis, autophagy, and mitochondrial adaptation (PMID:19800252, PMID:33646118). Its expression is controlled chiefly at the level of translation: phosphorylation of eIF2alpha by stress-sensing kinases—GCN2 detecting uncharged tRNA in the amino acid response (PMID:19800252), PERK during ER stress (PMID:19114033), and HRI in erythroid precursors (PMID:22498744)—selectively upregulates ATF4 synthesis, a step requiring the RNA helicase DDX3 acting through the eIF4F complex (PMID:29062139). mTORC1 provides a parallel, ISR-distinct route to ATF4 induction and, upon mitochondrial stress, directly phosphorylates ATF4 in a v-ATPase/lysosome-dependent manner to drive the mitochondrial unfolded protein response (UPRmt) (PMID:33646118, PMID:37679337). Once active, ATF4 heterodimerizes and cooperates with partners including CHOP, FoxO1, KDM4C, Hop2, and CTCF to bind target promoters and CARE/CRE elements (PMID:22298775, PMID:26774480, PMID:31433867, PMID:33154371, PMID:33950334), and directly transactivates genes for cystine uptake and glutathione synthesis (SLC7A11/xCT) (PMID:28553953, PMID:36996941), NADPH-generating pentose-phosphate and serine/glycine/folate enzymes (PMID:35574856), the mTOR repressor REDD1/DDIT4 (PMID:19114033, PMID:34373753), and the NRF2 antioxidant axis via CHAC1 (PMID:37410595), thereby protecting cells from oxidative stress and ferroptosis. ATF4 activity is further tuned post-translationally by PRMT1-mediated arginine-239 methylation that stabilizes the protein (PMID:31787756), PARP-1-mediated PARylation that reduces CRE binding (PMID:28457938), O-GlcNAcylation (PMID:38192280), and PKA-triggered phosphorylation at serine-219 leading to ubiquitin-proteasome degradation (PMID:33198401). Through these outputs ATF4 coordinates adaptation to metabolic, ER, and mitochondrial stress across many tissues, but its sustained activity drives pathology including PERK-ATF4-autophagy-mediated cardiac atrophy (PMID:34168130), skeletal muscle atrophy and aging in cooperation with p53, FOXO1/C/EBPdelta, and Thbs1-TGFbeta-Smad2/3 signaling (PMID:24895282, PMID:37014538, PMID:38678560, PMID:35061305), and ATF4-CHOP-GADD34-dependent protein-synthesis overload in glaucoma (PMID:33154371, PMID:37547290).

Mechanistic history

Synthesis pass · year-by-year structured walk · 13 steps
  1. 2008 High

    Established ATF4 as the necessary and sufficient transcriptional output of the PERK arm of ER stress, linking eIF2alpha phosphorylation to a defined target gene (REDD1).

    Evidence Genetic KO of PERK and ATF4 in MEFs plus ATF4 overexpression with mRNA readout

    PMID:19114033

    Open questions at the time
    • Did not address non-ER stress inputs
    • Direct vs indirect promoter binding at REDD1 not resolved here
  2. 2009 High

    Defined the upstream logic of ATF4 induction in the amino acid response, showing GCN2 sensing of uncharged tRNA feeds eIF2alpha-ATF4 to activate CARE-containing genes.

    Evidence Genetic/biochemical characterization of the AAR pathway with transcriptional reporters

    PMID:19800252

    Open questions at the time
    • Did not enumerate the full ATF4 target set
    • Heterodimer partner identities at CARE elements not defined
  3. 2012 High

    Identified physiological ATF4 partner proteins and kinase inputs, showing FoxO1 binds ATF4 to control glucose homeostasis and HRI drives the erythroid ATF4 program.

    Evidence Co-IP and genetic mouse models (FoxO1/ATF4); HRI KO mice with ROS and differentiation readouts

    PMID:22298775 PMID:22498744

    Open questions at the time
    • Tissue specificity of FoxO1-ATF4 complex not generalized
    • Direct ATF4 target genes in erythroid context not fully mapped
  4. 2013 High

    Revealed a non-transcriptional protein-protein function of ATF4: stabilizing HIF-1alpha to promote VEGF-driven angiogenesis.

    Evidence Co-IP, ATF4 KO mice, ubiquitination and HIF-1alpha stability assays, VEGF rescue

    PMID:23649506

    Open questions at the time
    • Structural basis of ATF4-HIF-1alpha interaction unknown
    • Generality beyond osteoblasts untested
  5. 2016 High

    Connected ATF4 to chromatin-modifying machinery, showing KDM4C cooperates with ATF4 to derepress serine-glycine biosynthesis genes via H3K9me3 removal.

    Evidence Co-IP, ChIP, siRNA knockdown and KDM4C overexpression

    PMID:26774480

    Open questions at the time
    • Whether KDM4C is a general ATF4 cofactor unknown
    • Recruitment order of ATF4 vs KDM4C not resolved
  6. 2017 High

    Showed ATF4 activity and stability are post-translationally controlled (PARP-1 PARylation reducing CRE binding) and that DDX3 governs its stress-induced translation, while xCT/SLC7A11 emerged as a key pro-tumor ATF4 target.

    Evidence ChIP-qPCR, in vitro CRE binding assay, polyribosome profiling/luciferase, xCT inhibition/overexpression rescue

    PMID:28457938 PMID:28553953 PMID:29062139

    Open questions at the time
    • PARylation site on ATF4 not mapped
    • Interplay between translational and PTM control not integrated
  7. 2018 High

    Defined ATF4 as a metabolic master regulator in adaptive immunity and a node co-opted by oncogenes, coordinating amino acid/glutathione metabolism and additive muscle atrophy with p53.

    Evidence Atf4-deficient CD4+ T cells with EAE model; BRAF/GCN2 pharmacology; muscle-specific and double p53/ATF4 KO mice

    PMID:24895282 PMID:29742431 PMID:32283529

    Open questions at the time
    • Direct ATF4 targets in T cells not all validated by ChIP
    • p53-ATF4 convergence point upstream of p21 unresolved
  8. 2019 High

    Established arginine methylation as a stability switch (PRMT1 at R239) and embedded ATF4 in ER-stress ferroptosis defense and skeletal partnerships (Hop2).

    Evidence R239K mutant, PRMT1 KO; siRNA pathway dissection (PERK-ATF4-HSPA5-GPX4); yeast two-hybrid and compound heterozygous mice (Hop2)

    PMID:31433867 PMID:31519193 PMID:31787756

    Open questions at the time
    • Enzyme(s) reversing R239 methylation unknown
    • Whether Hop2-ATF4 acts outside bone untested
  9. 2020 High

    Expanded ATF4 outputs to organelle quality control and direct transcriptional targets, including reticulophagy, UPRmt induction, NRF1 repression, LAMP3, and the HBS1L-MYB enhancer governing globin switching.

    Evidence ATF4 KO with reticulophagy imaging; directional UPRER-to-UPRmt epistasis; ChIP at NRF1, LAMP3, and HBS1L-MYB; CRISPR isogenic erythroid cells

    PMID:32312748 PMID:32551949 PMID:32755585 PMID:33111629 PMID:33177163

    Open questions at the time
    • Direct vs indirect status of some targets varies
    • Determinants of activating vs repressive ATF4 promoter occupancy unclear
  10. 2021 High

    Distinguished mTORC1 from canonical ISR control of ATF4, linked mitochondrial respiration to ATF4 via asparagine, and demonstrated PERK-ATF4-autophagy as a driver of cardiac atrophy and tumor ferroptosis resistance.

    Evidence Comparative transcriptomics in mTORC1- vs ISR-activated cells; metformin/asparagine in tumor models; Thbs1 transgenic/PERK KO hearts; YAP/TAZ-ATF4-SLC7A11 in HCC; DDIT4 m6A/YTHDF2 mechanism

    PMID:33609439 PMID:33646118 PMID:34168130 PMID:34373753 PMID:34664408

    Open questions at the time
    • How mTORC1 selects a subset of ATF4 targets unresolved
    • Crosstalk between transcriptional and translational mTORC1 inputs to ATF4 unclear
  11. 2022 High

    Detailed ATF4's redox/metabolic effector network and additional partners, showing control of NADPH-generating pathways, fructolysis genes, CD36 lipotoxicity, and cooperation with CTCF and FOXO1/C/EBPdelta.

    Evidence Cardiomyocyte-specific ATF4 KO with isotope tracing/metabolomics; ATF4 KD/KO for GLUT5/ALDOB; hepatocyte ATF4 KO for CD36; ChIP-seq/Co-IP with CTCF; promoter assays with C/EBPdelta

    PMID:33950334 PMID:35061305 PMID:35574856 PMID:36245009 PMID:36852918

    Open questions at the time
    • Tissue-specific partner combinations not unified into a single model
    • PRMT5 splicing control of ATF4 mRNA needs orthogonal confirmation
  12. 2023 High

    Resolved direct mTORC1 phosphorylation of ATF4 driving UPRmt selectivity and positioned ATF4 as a therapeutic node in glaucoma, HCC ferroptosis, NRF2 activation, and O-GlcNAc/VDR regulation.

    Evidence v-ATPase/mTORC1 inhibition with phospho-deficient ATF4 mutants; RGC-specific ATF4/CHOP deletion and ISRIB; hepatocyte ATF4 KO with SLC7A11 rescue; ATF4-NRF2-CHAC1 KD/OE; OGT/Thiamet-G ChIP; VDR promoter ChIP

    PMID:36996941 PMID:37173347 PMID:37410595 PMID:37547290 PMID:37679337 PMID:38192280

    Open questions at the time
    • mTORC1 phosphorylation site(s) on ATF4 not fully mapped
    • Several upstream regulators validated in single labs only
  13. 2024 Medium

    Uncovered non-cell-autonomous ATF4 biology and additional atrophy circuitry, showing stress-granule-localized ATF4 transfer between cells via migracytosis and Thbs1-TGFbeta-Smad2/3 induction of ATF4 driving muscle atrophy.

    Evidence G3BP1/2 PROTAC (PT-129) disrupting SG-dependent ATF4 delivery; muscle-specific Smad2/3 and ATF4 KO mice

    PMID:38678560 PMID:39710983

    Open questions at the time
    • Migracytosis-mediated ATF4 transfer awaits independent replication
    • Physiological scope of intercellular ATF4 transfer unknown

Open questions

Synthesis pass · forward-looking unresolved questions
  • How the full repertoire of ATF4 heterodimer partners, post-translational modifications, and upstream kinase/mTORC1 inputs are integrated to select context-specific target gene programs—and to switch between adaptive and pathological outcomes—remains unresolved.
  • No unified model explaining target-gene selectivity across stress inputs
  • Genome-wide partner-dependent ATF4 occupancy maps lacking across tissues
  • Determinants of activating vs repressive ATF4 binding undefined

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140110 transcription regulator activity 8 GO:0003677 DNA binding 5 GO:0140097 catalytic activity, acting on DNA 3
Localization
GO:0005634 nucleus 3 GO:0005654 nucleoplasm 3
Pathway
R-HSA-74160 Gene expression (Transcription) 6 R-HSA-1430728 Metabolism 5 R-HSA-5357801 Programmed Cell Death 4 R-HSA-8953897 Cellular responses to stimuli 4 R-HSA-9612973 Autophagy 4
Partners
CEBPDCHOPCTCFDDX3XFOXO1HIF1AHOP2KDM4C

Evidence

Reading pass · 47 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2009 The amino acid response (AAR) pathway signals through GCN2 kinase detecting uncharged tRNA, leading to eIF2alpha phosphorylation and ATF4 translational upregulation; ATF4 then heterodimerizes with partners to activate specific genes via the CCAAT-enhancer binding protein-activating transcription factor response element (CARE). Genetic and biochemical characterization of AAR pathway; transcriptional reporter assays Trends in endocrinology and metabolism: TEM High 19800252
2008 ATF4 is necessary and sufficient for ER stress-induced REDD1 expression: PERK-deficient MEF cells fail to upregulate REDD1 mRNA upon ER stress, ATF4-deficient MEFs also fail, and exogenous ATF4 expression alone is sufficient to induce REDD1. Genetic KO of PERK and ATF4 in MEF cells; exogenous ATF4 overexpression; mRNA quantification Biochemical and biophysical research communications High 19114033
2021 mTORC1 activates ATF4 through a mechanism distinct from the canonical ISR; mTORC1-ATF4 signaling promotes expression of a subset of ATF4 target genes including those involved in amino acid uptake/synthesis, tRNA charging, and cellular cystine uptake for glutathione synthesis. Comparative transcriptomics in mTORC1-stimulated vs ISR-activated MEFs and human cancer cell lines; ATF4 KO and pharmacological mTORC1 inhibition eLife High 33646118
2021 Asparagine availability communicates active mitochondrial respiration to ATF4 and mTORC1: ETC inhibition depletes asparagine, increases ATF4 levels, and impairs mTORC1 activity; exogenous asparagine restores both ATF4 and mTORC1 activities. ETC inhibition with metformin; exogenous asparagine supplementation; asparaginase treatment; mouse tumor models Cell metabolism High 33609439
2021 Thbs1 binds and activates PERK, inducing its downstream transcription factor ATF4, causing autophagy-mediated cardiac atrophy; PERK gene deletion in Thbs1 transgenic mice blunts ATF4 induction and autophagy, largely rescuing the lethal cardiac atrophy phenotype. AAV9-mediated overexpression of PERK or ATF4 alone is sufficient to promote cardiac atrophy. Transgenic and KO mouse models; AAV9 gene transfer; biochemical analysis of PERK-ATF4-autophagy pathway Nature communications High 34168130
2012 HRI (heme-regulated eIF2alpha kinase) activates the Atf4 signaling pathway in erythroid precursors to reduce oxidative stress and promote erythroid differentiation; Hri-/- erythroblasts show increased ROS and apoptosis upon stress, and the Hri-eIF2αP-Atf4 pathway is required for erythroid differentiation. HRI knockout mice; ex vivo erythroid differentiation; ROS measurement; iron deficiency models Blood High 22498744
2012 FoxO1 physically interacts with ATF4 in osteoblast nuclei and promotes ATF4 transcriptional activity; the FoxO1-ATF4 complex synergistically suppresses osteocalcin activity by upregulating the phosphatase that inactivates osteocalcin, thereby regulating glucose homeostasis. Co-immunoprecipitation; genetic mouse models of FoxO1 and ATF4; transcriptional reporter assays; glucose tolerance tests The Journal of biological chemistry High 22298775
2016 KDM4C physically interacts with ATF4 and cooperates to activate amino acid biosynthesis genes (serine-glycine synthesis pathway); KDM4C activates ATF4 transcription and requires ATF4 to target serine pathway genes, removing repressive H3K9 trimethylation at these loci. Co-immunoprecipitation; ChIP; gene expression analysis; siRNA knockdown; KDM4C overexpression Cell reports High 26774480
2020 ATF4 represses transcription of NRF1 (nuclear respiratory factor 1) by binding to the NRF1 promoter, thereby suppressing NRF1-TFAM signaling, impairing mitochondrial biogenesis and respiratory function in alcohol-induced liver injury. Hepatocyte-specific ATF4 KO mice; ChIP assay showing ATF4 binding to NRF1 promoter; TFAM silencing/overexpression rescue experiments; clinical validation in AH patients Gut High 33177163
2019 DHA (dihydroartemisinin) activates ER stress in glioma cells leading to PERK-upregulated ATF4 expression, which in turn induces HSPA5; HSPA5 then increases GPX4 expression and activity, protecting cells from ferroptosis. siRNA knockdown of PERK, ATF4, or HSPA5 increases DHA-induced ferroptosis. siRNA knockdown; small molecule inhibitors; in vitro and in vivo glioma models; protein expression analysis Journal of experimental & clinical cancer research : CR High 31519193
2017 PARP-1 activation induces PARylation of ATF4, reducing its binding to the CRE sequence; conversely, PARP inhibition increases ATF4 binding to the MKP-1 promoter (confirmed by ChIP-qPCR), inducing MKP-1 expression and inactivating JNK and p38 MAP kinases to reduce mitochondrial ROS. ChIP-qPCR; PARP inhibition/silencing; in vitro CRE binding assay; multiple human cell lines Free radical biology & medicine High 28457938
2019 PRMT1 methylates ATF4 on arginine 239, promoting ATF4 protein stability; a methylation-deficient ATF4 R239K mutant exacerbates ER stress and proapoptotic signaling; PRMT1 inhibition augments ER stress in cardiomyocytes through an ATF4-dependent mechanism. PRMT1 overexpression/inhibition/KO; methylation-deficient ATF4 mutant (R239K); caspase-3 activation and γH2AX measurement Cell death & disease High 31787756
2017 DDX3, an RNA-binding protein, promotes ATF4 mRNA translation downstream of phosphorylated eIF2alpha during ER stress; DDX3 depletion reduces ATF4 protein levels, and DDX3 binds the eIF4F complex which is required for ER stress-induced ATF4 translation. DDX3 depletion; luciferase assays with ATF4 5'UTR; polyribosome profiling; protein interaction assays with eIF4F complex Scientific reports High 29062139
2020 ATF4 is required for ER stress-induced reticulophagy in glioblastoma; ATF4 knockout significantly attenuates loperamide-induced autophagy, autophagic cell death, and reticulophagy mediated through RETREG1/FAM134B and TEX264 receptors. ATF4 KO; electron and fluorescence microscopy; autophagy flux assays; siRNA knockdown of reticulophagy receptors Autophagy Medium 33111629
2023 mTORC1 directly phosphorylates ATF4 in a v-ATPase-dependent manner via lysosomal signaling upon mitochondrial stress; this phosphorylation is required for UPRmt transcriptional activation but not for UPRER; mTORC1-dependent ATF4 phosphorylation maintains mitochondrial redox homeostasis. v-ATPase inhibition; mTORC1 inhibition; phosphorylation-deficient ATF4 mutants; ROS measurement; in vitro kinase assay context Cell discovery High 37679337
2020 Reduction of β-globin is sufficient to induce ATF4 expression in erythroid precursors; ATF4 binds within the HBS1L-MYB intergenic enhancer to regulate MYB expression, and reduced ATF4 upon β-globin knockout decreases MYB and BCL11A levels, leading to γ-globin re-expression. CRISPR-Cas9 genome editing; RNA-seq; ATF4 ChIP at HBS1L-MYB enhancer; isogenic erythroid cell differentiation Cell reports High 32755585
2013 ATF4 interacts with HIF-1alpha in hypoxic osteoblasts and prevents HIF-1alpha binding to prolyl hydroxylases; loss of ATF4 increases HIF-1alpha ubiquitination and reduces its protein stability, thereby decreasing VEGF expression and bone angiogenesis. Co-immunoprecipitation; ATF4 KO mice; ubiquitination assay; HIF-1alpha stability measurement; recombinant VEGF rescue Journal of bone and mineral research High 23649506
2023 ATF4 is an obligatory metabolic activator of NRF2: ATF4 increases NRF2 transcription and induces CHAC1 (glutathione-degrading enzyme), which is critical for maintaining NRF2 activation; NRF2 in turn supports ATF4-induced cells by increasing cystine uptake via xCT and upregulating thioredoxin usage. ATF4 KD/OE; NRF2 measurement; CHAC1 regulation analysis; cystine uptake assays; transcriptional reporter assays Cell reports Medium 37410595
2014 ATF4 and p53 mediate distinct and additive pathways to skeletal muscle atrophy: each is required independently for immobilization-induced atrophy, forced expression of either induces atrophy, and the two pathways converge on p21 as a downstream effector that itself is required for atrophy. Muscle-specific KO mice; forced ATF4 expression in vivo; genome-wide mRNA arrays; double p53/ATF4 knockout American journal of physiology. Endocrinology and metabolism High 24895282
2023 Muscle-specific ATF4 knockout mice are protected from age-related muscle atrophy, weakness, and transcriptional changes of aging (repression of anabolic mRNAs, induction of senescence-associated mRNAs), identifying ATF4 as an essential mediator of skeletal muscle aging. Muscle-specific ATF4 KO mice at 6 and 22 months; transcriptomics; exercise capacity and strength testing; proteomics GeroScience High 37014538
2018 ATF4 regulates a coordinated gene network in CD4+ T cells driving amino acid uptake, mTORC1 activation, protein translation, de novo synthesis of amino acids and glutathione, glycolysis, glutaminolysis, and oxidative phosphorylation; ATF4-deficient mice mount reduced Th1 but elevated Th17 responses. Atf4-deficient CD4+ T cells; gene expression analysis; mTORC1 activity measurement; cytokine production assays; EAE model Cell reports High 29742431
2020 ATF4 is required for ER stress-dependent UPRmt induction in alveolar epithelial cells: ER stress (UPRER) leads to ATF4-dependent UPRmt and mitochondrial dysfunction, but not the reverse; inducible ATF4 expression in mouse alveolar epithelial cells aggravates pulmonary UPRmt and lung injury. ATF4 KD/OE; mitochondrial stress assays; inducible ATF4 transgenic mice; bleomycin lung injury model American journal of respiratory cell and molecular biology High 32551949
2022 ATF4 controls expression of NADPH-generating enzymes in both the pentose phosphate pathway and mitochondrial serine/glycine/folate metabolic pathways; cardiomyocyte-specific ATF4 KO reduces NADPH, lowers reduced glutathione, exacerbates cardiomyopathy under pressure overload; ATF4 overexpression augments metabolic flux in these pathways. Cardiomyocyte-specific ATF4 KO mice; stable isotope tracer experiments; RNA-seq; metabolomics; transverse aortic constriction model Circulation research High 35574856
2020 ATF4 directly regulates LAMP3 (lysosomal-associated membrane protein 3) transcription during the integrated stress response: siRNA knockdown of ATF4 reduces LAMP3 mRNA, exogenous ATF4 upregulates LAMP3, and ChIP assays verified an ATF4-binding site in the LAMP3 promoter confirmed by dual-luciferase assay. siRNA knockdown; ATF4 overexpression; ChIP assay; dual-luciferase promoter assay The Journal of biological chemistry High 32312748
2020 In long-term synaptic plasticity (cLTP), ATF4 (also known as CREB-2, a transcriptional repressor of CREB-mediated gene expression) is phosphorylated at serine-219 by cAMP-dependent protein kinase, then degraded via ubiquitin-proteasome-mediated proteolysis; proteasome inhibitor β-lactone prevents this decrease; β-TrCP may serve as the ubiquitin E3 ligase. Chemically-induced LTP; proteasome inhibitor treatment; phospho-ATF4 immunoblotting; PKA pharmacology International journal of molecular sciences Medium 33198401
2019 Hop2 physically interacts with ATF4 via the Zip domain and enhances ATF4-dependent transcription; Hop2-deficient mice display an osteopenic phenotype similar to Atf4-/- mice with decreased osteocalcin mRNA, and Atf4+/-:Hop2+/- compound heterozygous mice exhibit identical skeletal defects. Yeast two-hybrid; deletional mapping; Hop2-/- mice; compound heterozygous mice; osteoblast differentiation assays Journal of bone and mineral research High 31433867
2018 Oncogenic BRAF ensures ATF4 induction during nutrient stress by activating GCN2 kinase; BRAF utilizes mTOR and eIF4B as downstream regulators of ATF4 translation, a pathway distinct from MEK-ERK that remains transiently active even during BRAF inhibitor treatment. BRAF inhibitors; GCN2 activator/inhibitor; mTOR inhibitors; eIF4B knockdown; ATF4 protein measurement under nutrient stress iScience Medium 32283529
2017 ATF4 transcriptionally targets SLC7A11/xCT (glutamate/cystine antiporter), elevating xCT expression; ATF4-dependent tumor-promoting effects including proliferation and angiogenesis are attenuated by pharmacological or genetic xCT inhibition, and forced xCT expression rescues growth in ATF4 knockdown cells. ATF4 siRNA knockdown; xCT inhibition/overexpression; ferroptosis inducer treatment; in vivo tumor models Oncogene High 28553953
2023 Hepatocyte ATF4 protects against ferroptosis by maintaining SLC7A11/xCT expression for glutathione synthesis; hepatocyte-specific ATF4 deletion increases ferroptosis susceptibility and accelerates HCC development, reversed by ectopic SLC7A11 expression; ATF4 and SLC7A11 are positively correlated in human HCC and NASH. Hepatocyte-specific ATF4 KO mice; SLC7A11 reconstitution in ATF4-deficient livers; RNA-seq; ferroptosis inhibitor experiments; DEN carcinogen model Journal of hepatology High 36996941
2021 YAP/TAZ sustain ATF4 protein stability, nuclear localization, and transcriptional activity in a TEAD-dependent manner; ATF4 cooperates with YAP/TAZ to induce SLC7A11 expression, enabling HCC cells to overcome ferroptosis and develop Sorafenib resistance. shRNA screening; transcriptomic analysis; ATF4 localization and stability assays; SLC7A11 reporter assays; TEAD inhibition EMBO molecular medicine Medium 34664408
2022 PRMT5 controls ATF4 mRNA splicing; PRMT5 inhibition causes intron-retaining ATF4 mRNA that is detained in the nucleus, reducing cytoplasmic ATF4 mRNA and protein, and downregulating ATF4 target genes involved in oxidative stress defense. PRMT5 inhibition; RNA-seq; nuclear/cytoplasmic ATF4 mRNA fractionation; ATF4 target gene expression; ROS measurement Redox biology Medium 35305370
2022 ATF4 interacts with CHOP and this interaction is essential for IOP elevation in glaucoma; ATF4-CHOP-GADD34 pathway promotes aberrant protein synthesis and ER client protein load in trabecular meshwork cells, causing TM dysfunction, IOP elevation, and glaucomatous neurodegeneration. ATF4-CHOP interaction assay; genetic depletion of pathway components; mouse glaucoma models; pharmacological GADD34 inhibition; protein synthesis measurement Nature communications High 33154371
2023 RGC-specific deletion of ATF4 and/or CHOP synergistically promotes retinal ganglion cell and optic nerve survival and preserves visual function; CRISPR-mediated knockdown of the ATF4 downstream effector Gadd45a also delivers neuroprotection in glaucoma models. RGC-specific Cre-mediated ATF4/CHOP deletion; optic nerve crush and ocular hypertension models; CRISPR knockdown; ISRIB pharmacological inhibition; visual function testing Molecular therapy. Nucleic acids High 37547290
2024 ATF4 is preferentially translated within stress granules (SGs) and delivered from fibroblasts to tumor cells via migracytosis; pharmacological disassembly of SGs with PT-129 (a PROTAC targeting G3BP1/2 NTF2L domain) disrupts ATF4 delivery and prevents cancer cell proliferation. PROTAC degrader (PT-129); SG formation/disassembly assays; ATF4 localization and transfer assays; in vitro and in vivo tumor growth assays Journal of the American Chemical Society Medium 39710983
2021 ATF4 transcriptionally upregulates DDIT4 (REDD1) to suppress mTOR, inducing pro-survival autophagy during glutaminolysis inhibition; glutaminolysis inhibition promotes ATF4 mRNA expression by abrogating m6A modification and YTHDF2-mediated RNA decay. RNA-seq; luciferase reporter assays; ChIP; m6A modification analysis; mRNA half-life assays; RNA immunoprecipitation; in vivo CRC model Theranostics High 34373753
2018 EIF1AX-A113splice mutations stabilize the translation preinitiation complex (PIC) and induce ATF4; ATF4 co-opts to suppress EIF2alpha phosphorylation, enabling a general increase in protein synthesis, and ATF4 cooperates with c-MYC to enhance mTOR sensitivity to amino acids. Isogenic cell lines expressing EIF1AX-A113splice; EIF2alpha phosphorylation assays; ATF4 expression measurement; mTOR activity assays; mouse thyroid cancer models Cancer discovery Medium 30305285
2023 VDR (Vitamin D receptor) suppresses ATF4 transcription by binding to the ATF4 promoter region, as confirmed by ChIP-qPCR and dual-luciferase reporter assay; VDR overexpression or agonist (paricalcitol) reduces ATF4-dependent ER stress in ischemia-reperfusion kidney injury. VDR KO/overexpression mice; paricalcitol treatment; ChIP-qPCR; dual-luciferase reporter assay; ATF4 overexpression rescue Cell death discovery Medium 37173347
2024 ATF4 directly binds the SLC7A11 promoter and increases its transcription; DHA inhibits ATF4 expression, thereby reducing SLC7A11, promoting lipid peroxidation and ferroptosis; ATF4 overexpression rescues DHA-induced ferroptosis. ATF4 promoter ChIP; ATF4/SLC7A11 lentiviral overexpression rescue; lipid peroxidation measurement; xenograft model Journal of cellular and molecular medicine Medium 38652216
2022 ATF4-mediated CD36 upregulation contributes to hepatic lipotoxicity: genetic inhibition of ATF4 attenuates palmitate- or ER stress-induced CD36 upregulation; hepatocyte-specific ATF4 KO mice have lower CD36 expression; CD36 knockdown blunts ATF4 activation in a feedforward mechanism. Hepatocyte-specific ATF4 KO mice; siRNA knockdown; ER stress induction; CD36 and ATF4 expression analysis American journal of physiology. Gastrointestinal and liver physiology Medium 36852918
2022 ATF4 directly regulated CTCF expression and interacted with CTCF in 3T3-L1 cells; ATF4 co-localizes with CTCF at promoters of key adipogenic genes including Cebpd and PPARg, cooperating to drive their transactivation and promote adipogenesis. ChIP-seq; RNA-seq; Co-IP of ATF4 and CTCF; ATF4 KD in vivo; CTCF KD/OE Cell biology and toxicology Medium 33950334
2024 Thbs1 activates TGFβ-Smad2/3 signaling in skeletal muscle, which induces ATF4 expression; ATF4 then modulates the autophagy-lysosomal pathway and ubiquitin-proteasome system to facilitate muscle atrophy; myofiber-specific Smad2/3 or ATF4 deletion antagonizes Thbs1-induced muscle atrophy. Skeletal muscle-specific transgenic and KO mice; TGFβ receptor inhibition; Smad2/3 KO; ATF4 KO; ALP and UPS activity assays Cell reports High 38678560
2017 ATF4 knockdown in glioma cells attenuates autophagy induced by FLT3-ITD; FLT3-ITD activity controls cellular ATF4 levels; ATF4 is an essential mediator of FLT3-ITD-induced autophagy-dependent AML cell proliferation. FLT3 inhibitor treatment; ATF4 knockdown; autophagy measurement; xenograft mouse model; conditional shRNA Oncogene Medium 29059168
2021 Brown adipocyte-specific ATF4 activation (genetically via overexpression or physiologically via low-protein diet) improves cold tolerance and systemic metabolism in a Ucp1-independent manner, revealing a diet-dependent thermogenic mechanism in brown adipocytes. BA-specific ATF4 overexpression; Ucp1 KO mice; low-protein diet feeding; cold tolerance tests; proteome analysis Cell reports Medium 34551310
2023 O-GlcNAcylation regulates ATF4 during the mitochondrial integrated stress response: OGT (O-GlcNAc transferase) knockdown increases ATF4 protein and mRNA, while Thiamet-G (OGT activator) elevates ATF4 protein upon mitochondrial stress; ATF4 occupancy at the ATF5 promoter increases in TMG-treated mouse brains. OGT KD; Thiamet-G treatment; ATF4 ChIP at ATF5 promoter; iPSC-derived neurons; AD mouse model Frontiers in aging neuroscience Medium 38192280
2022 ATF4 cooperates with FOXO1 and C/EBPδ to regulate the transcriptional program of skeletal muscle atrophy during fasting; ATF4 enhances promoter activity of target atrophy genes in cooperation with C/EBPδ. FOXO1-transgenic and FOXO1,3a,4-/- mice; C/EBPδ KD/OE; gene expression arrays; promoter activity assays FASEB journal Medium 35061305
2022 ATF4 transcriptionally activates GLUT5 and ALDOB expression in GBM cells in response to glucose deprivation, switching energy supply from glycolysis to fructolysis; disruption of ATF4-dependent fructolysis inhibits GBM growth in vitro and in vivo. ATF4 KD/KO; GLUT5 and ALDOB expression analysis; genetic/pharmacological disruption of fructolysis; xenograft models; patient specimen correlation Nature communications Medium 36245009
2020 ATF4 in Drosophila (ortholog): Notch signaling combined with ETC attenuation activates the PERK-ATF4 pathway, which drives expression of metabolic enzymes, nutrient transporters, and mitochondrial chaperones; this ATF4-mediated Warburg metabolism promotes cell proliferation, pH changes mediate over-proliferation. Drosophila genetic models (COX7a KD, Notch activation); PERK and ATF4 genetic manipulation; metabolic profiling; pH measurement Cell reports Medium 32433968

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2009 ATF4-dependent transcription mediates signaling of amino acid limitation. Trends in endocrinology and metabolism: TEM 507 19800252
2021 YAP/TAZ and ATF4 drive resistance to Sorafenib in hepatocellular carcinoma by preventing ferroptosis. EMBO molecular medicine 414 34664408
2017 ATF4 promotes angiogenesis and neuronal cell death and confers ferroptosis in a xCT-dependent manner. Oncogene 352 28553953
2023 ATF4 suppresses hepatocarcinogenesis by inducing SLC7A11 (xCT) to block stress-related ferroptosis. Journal of hepatology 308 36996941
2006 The PERK/eIF2alpha/ATF4 module of the UPR in hypoxia resistance and tumor growth. Cancer biology & therapy 290 16861899
2019 Dihydroartemisinin-induced unfolded protein response feedback attenuates ferroptosis via PERK/ATF4/HSPA5 pathway in glioma cells. Journal of experimental & clinical cancer research : CR 268 31519193
2021 Asparagine couples mitochondrial respiration to ATF4 activity and tumor growth. Cell metabolism 225 33609439
2021 The mTORC1-mediated activation of ATF4 promotes protein and glutathione synthesis downstream of growth signals. eLife 194 33646118
2019 Artesunate activates the ATF4-CHOP-CHAC1 pathway and affects ferroptosis in Burkitt's Lymphoma. Biochemical and biophysical research communications 173 31537387
2009 Role of ATF4 in regulation of autophagy and resistance to drugs and hypoxia. Cell cycle (Georgetown, Tex.) 166 19887912
2008 ATF4 is necessary and sufficient for ER stress-induced upregulation of REDD1 expression. Biochemical and biophysical research communications 154 19114033
2023 A stay of execution: ATF4 regulation and potential outcomes for the integrated stress response. Frontiers in molecular neuroscience 146 36825279
2009 JNK activity is essential for Atf4 expression and late-stage osteoblast differentiation. Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research 140 19016586
2021 Thbs1 induces lethal cardiac atrophy through PERK-ATF4 regulated autophagy. Nature communications 137 34168130
2010 ATF4 regulates lipid metabolism and thermogenesis. Cell research 137 20066008
2016 KDM4C and ATF4 Cooperate in Transcriptional Control of Amino Acid Metabolism. Cell reports 132 26774480
2012 Heme-regulated eIF2α kinase activated Atf4 signaling pathway in oxidative stress and erythropoiesis. Blood 131 22498744
2020 ATF4 activation promotes hepatic mitochondrial dysfunction by repressing NRF1-TFAM signalling in alcoholic steatohepatitis. Gut 127 33177163
2020 ATF4 links ER stress with reticulophagy in glioblastoma cells. Autophagy 123 33111629
2020 MicroRNA-214-3p enhances erastin-induced ferroptosis by targeting ATF4 in hepatoma cells. Journal of cellular physiology 122 31960438
2012 Targeting the ATF4 pathway in cancer therapy. Expert opinion on therapeutic targets 114 23009153
2023 The integrated stress response effector ATF4 is an obligatory metabolic activator of NRF2. Cell reports 107 37410595
2022 ATF4 Protects the Heart From Failure by Antagonizing Oxidative Stress. Circulation research 102 35574856
2017 Oncogenic FLT3-ITD supports autophagy via ATF4 in acute myeloid leukemia. Oncogene 93 29059168
2014 p53 and ATF4 mediate distinct and additive pathways to skeletal muscle atrophy during limb immobilization. American journal of physiology. Endocrinology and metabolism 91 24895282
2024 ATF4 in cellular stress, ferroptosis, and cancer. Archives of toxicology 90 38383612
2017 PARP inhibition protects mitochondria and reduces ROS production via PARP-1-ATF4-MKP-1-MAPK retrograde pathway. Free radical biology & medicine 90 28457938
2018 ATF4 Regulates CD4+ T Cell Immune Responses through Metabolic Reprogramming. Cell reports 89 29742431
2018 Role of the ISR-ATF4 pathway and its cross talk with Nrf2 in mitochondrial quality control. Journal of clinical biochemistry and nutrition 83 30705506
2018 EIF1AX and RAS Mutations Cooperate to Drive Thyroid Tumorigenesis through ATF4 and c-MYC. Cancer discovery 82 30305285
2021 Targeting ATF4-dependent pro-survival autophagy to synergize glutaminolysis inhibition. Theranostics 79 34373753
2020 ATF4 leads to glaucoma by promoting protein synthesis and ER client protein load. Nature communications 74 33154371
2017 Neurodegeneration: Keeping ATF4 on a Tight Leash. Frontiers in cellular neuroscience 69 29326555
2022 ATF4/CEMIP/PKCα promotes anoikis resistance by enhancing protective autophagy in prostate cancer cells. Cell death & disease 66 35013120
2020 ATF4 Mediates Mitochondrial Unfolded Protein Response in Alveolar Epithelial Cells. American journal of respiratory cell and molecular biology 65 32551949
2012 FoxO1 protein cooperates with ATF4 protein in osteoblasts to control glucose homeostasis. The Journal of biological chemistry 63 22298775
2019 The PERK-EIF2α-ATF4 signaling branch regulates osteoblast differentiation and proliferation by PTH. American journal of physiology. Endocrinology and metabolism 60 30668150
2013 ATF4 promotes bone angiogenesis by increasing VEGF expression and release in the bone environment. Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research 60 23649506
2022 FOXO1 cooperates with C/EBPδ and ATF4 to regulate skeletal muscle atrophy transcriptional program during fasting. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 52 35061305
2019 Regulation of the unfolded protein response through ATF4 and FAM129A in prostate cancer. Oncogene 52 31312022
2022 ATF4 protects against sorafenib-induced cardiotoxicity by suppressing ferroptosis. Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie 49 35724508
2022 Biology of Activating Transcription Factor 4 (ATF4) and Its Role in Skeletal Muscle Atrophy. The Journal of nutrition 47 34958390
2013 An aryl hydrocarbon receptor induces VEGF expression through ATF4 under glucose deprivation in HepG2. BMC molecular biology 45 24330582
2023 Lysosomes mediate the mitochondrial UPR via mTORC1-dependent ATF4 phosphorylation. Cell discovery 44 37679337
2019 HER2 Upregulates ATF4 to Promote Cell Migration via Activation of ZEB1 and Downregulation of E-Cadherin. International journal of molecular sciences 43 31064130
2019 Activation of PERK-eIF2α-ATF4 pathway contributes to diabetic hepatotoxicity: Attenuation of ER stress by Morin. Cellular signalling 42 30877037
2017 Role of ATF4 in skeletal muscle atrophy. Current opinion in clinical nutrition and metabolic care 41 28376050
2023 Advances in the roles of ATF4 in osteoporosis. Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie 40 37948991
2017 ATF4 regulates CCL2 expression to promote endometrial cancer growth by controlling macrophage infiltration. Experimental cell research 39 28843961
2021 Activation of ATF4 triggers trabecular meshwork cell dysfunction and apoptosis in POAG. Aging 36 33714955
2024 GPR68-ATF4 signaling is a novel prosurvival pathway in glioblastoma activated by acidic extracellular microenvironment. Experimental hematology & oncology 35 38291540
2017 DDX3 regulates endoplasmic reticulum stress-induced ATF4 expression. Scientific reports 35 29062139
2023 The transcription regulator ATF4 is a mediator of skeletal muscle aging. GeroScience 34 37014538
2021 Nox4 Promotes RANKL-Induced Autophagy and Osteoclastogenesis via Activating ROS/PERK/eIF-2α/ATF4 Pathway. Frontiers in pharmacology 34 34650437
2020 ATF4 Regulates MYB to Increase γ-Globin in Response to Loss of β-Globin. Cell reports 34 32755585
2017 Up-Regulated ATF4 Expression Increases Cell Sensitivity to Apoptosis in Response to Radiation. Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology 34 28214891
2022 PRMT5 regulates ATF4 transcript splicing and oxidative stress response. Redox biology 33 35305370
2022 ATF4-dependent fructolysis fuels growth of glioblastoma multiforme. Nature communications 33 36245009
2020 ATF4-Induced Warburg Metabolism Drives Over-Proliferation in Drosophila. Cell reports 33 32433968
2017 Emerging Role for the PERK/eIF2α/ATF4 in Human Cutaneous Leishmaniasis. Scientific reports 33 29213084
2024 Thbs1 regulates skeletal muscle mass in a TGFβ-Smad2/3-ATF4-dependent manner. Cell reports 32 38678560
2014 ATF4: a Novel Potential Therapeutic Target for Alzheimer's Disease. Molecular neurobiology 32 25381575
2019 Concomitant Nrf2- and ATF4-activation by Carnosic Acid Cooperatively Induces Expression of Cytoprotective Genes. International journal of molecular sciences 31 30959808
2016 miRNA-1283 Regulates the PERK/ATF4 Pathway in Vascular Injury by Targeting ATF4. PloS one 31 27537404
2016 Crosstalk between ATF4 and MTA1/HDAC1 promotes osteosarcoma progression. Oncotarget 30 26797758
2023 RGC-specific ATF4 and/or CHOP deletion rescues glaucomatous neurodegeneration and visual function. Molecular therapy. Nucleic acids 29 37547290
2023 Tomatidine targets ATF4-dependent signaling and induces ferroptosis to limit pancreatic cancer progression. iScience 29 37554459
2022 Gremlin-1 Promotes Colorectal Cancer Cell Metastasis by Activating ATF6 and Inhibiting ATF4 Pathways. Cells 29 35883579
2021 Long non-coding RNA TINCR suppresses metastatic melanoma dissemination by preventing ATF4 translation. EMBO reports 28 33586907
2021 Brown adipocyte ATF4 activation improves thermoregulation and systemic metabolism. Cell reports 28 34551310
2020 ATF4-modified serum exosomes derived from osteoarthritic mice inhibit osteoarthritis by inducing autophagy. IUBMB life 28 33249722
2019 PRMT1 suppresses ATF4-mediated endoplasmic reticulum response in cardiomyocytes. Cell death & disease 28 31787756
2013 Tetracyclines cause cell stress-dependent ATF4 activation and mTOR inhibition. Experimental cell research 28 24280420
2018 GCN2 reduces inflammation by p-eIF2α/ATF4 pathway after intracerebral hemorrhage in mice. Experimental neurology 26 30529503
2021 Cooperation of ATF4 and CTCF promotes adipogenesis through transcriptional regulation. Cell biology and toxicology 25 33950334
2021 Inhibition of mTORC1 through ATF4-induced REDD1 and Sestrin2 expression by Metformin. BMC cancer 24 34253170
2018 Investigation of Nrf2, AhR and ATF4 Activation in Toxicogenomic Databases. Frontiers in genetics 24 30333853
2024 Dihydroartemisinin induces ferroptosis of hepatocellular carcinoma via inhibiting ATF4-xCT pathway. Journal of cellular and molecular medicine 23 38652216
2023 Vitamin D receptor attenuate ischemia-reperfusion kidney injury via inhibiting ATF4. Cell death discovery 23 37173347
2020 The gene for the lysosomal protein LAMP3 is a direct target of the transcription factor ATF4. The Journal of biological chemistry 23 32312748
2018 P2X4R silence suppresses glioma cell growth through BDNF/TrkB/ATF4 signaling pathway. Journal of cellular biochemistry 22 30362154
2011 Elevated p-CREB-2 (ser 245) expression is potentially associated with carcinogenesis and development of breast carcinoma. Molecular medicine reports 22 22052162
2022 TRIB3 Mediates Fibroblast Activation and Fibrosis though Interaction with ATF4 in IPF. International journal of molecular sciences 21 36555349
2020 Degradation of Transcriptional Repressor ATF4 during Long-Term Synaptic Plasticity. International journal of molecular sciences 21 33198401
2023 Toosendanin induced hepatotoxicity via triggering PERK-eIF2α-ATF4 mediated ferroptosis. Toxicology letters 20 36801351
2020 Aspirin exerts anti-tumor effect through inhibiting Blimp1 and activating ATF4/CHOP pathway in multiple myeloma. Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie 19 32070879
2023 O-GlcNAc regulates the mitochondrial integrated stress response by regulating ATF4. Frontiers in aging neuroscience 18 38192280
2020 Disrupting ATF4 Expression Mechanisms Provides an Effective Strategy for BRAF-Targeted Melanoma Therapy. iScience 18 32283529
2017 Association of ATF4 Expression With Tissue Hypoxia and M2 Macrophage Infiltration in Infantile Hemangioma. The journal of histochemistry and cytochemistry : official journal of the Histochemistry Society 18 28438094
2024 Inhibition of mitophagy via the EIF2S1-ATF4-PRKN pathway contributes to viral encephalitis. Journal of advanced research 17 39103048
2023 ATF4-mediated CD36 upregulation contributes to palmitate-induced lipotoxicity in hepatocytes. American journal of physiology. Gastrointestinal and liver physiology 17 36852918
2020 Hydrogen peroxide induces nucleus pulposus cell apoptosis by ATF4/CHOP signaling pathway. Experimental and therapeutic medicine 17 32855694
1996 CREB-1 and CREB-2 immunoreactivity in the rat brain. Brain research 17 8705300
2024 N6-methyladenosine modification of LATS2 promotes hepatoblastoma progression by inhibiting ferroptosis through the YAP1/ATF4/PSAT1 axis. International journal of biological sciences 16 39247829
2019 Hop2 Interacts with ATF4 to Promote Osteoblast Differentiation. Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research 16 31433867
2023 Shared Gene Targets of the ATF4 and p53 Transcriptional Networks. Molecular and cellular biology 15 37533313
2023 DJ-1 inhibits ferroptosis in cerebral ischemia-reperfusion via ATF4/HSPA5 pathway. Neurochemistry international 15 37820776
2022 Hesperadin suppresses pancreatic cancer through ATF4/GADD45A axis at nanomolar concentrations. Oncogene 15 35551503
2022 ERH Interacts With EIF2α and Regulates the EIF2α/ATF4/CHOP Pathway in Bladder Cancer Cells. Frontiers in oncology 15 35774124
2024 G3BP1/2-Targeting PROTAC Disrupts Stress Granules Dependent ATF4 Migracytosis as Cancer Therapy. Journal of the American Chemical Society 14 39710983

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