Affinage

ETS2

Protein C-ets-2 · UniProt P15036

Length
469 aa
Mass
53.0 kDa
Annotated
2026-04-28
100 papers in source corpus 37 papers cited in narrative 37 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

ETS2 is a sequence-specific transcription factor that integrates Ras/ERK/MAPK signaling with chromatin remodeling to control inflammatory, developmental, and cell-cycle gene programs. ERK1/2 phosphorylates ETS2 at a conserved N-terminal threonine (T72) within the Pointed domain, which promotes recruitment of CBP/p300 coactivators for transactivation and, context-dependently, BRG1/SWI-SNF for transcriptional repression; an autoinhibitory C-terminal domain additionally modulates DNA-binding affinity (PMID:9710599, PMID:15572696, PMID:12637547, PMID:1409581). ETS2 directly activates invasion-associated proteases (MMP-9, MMP-3, uPA), inflammatory mediators (TNF, IL-6, miR-155, chemokines), survival genes (Bcl-xL), and developmental regulators (CDX2 in trophoblast stem cells, hypertrophic genes with NFAT in cardiomyocytes), and its phosphorylation-site knock-in (T72A) mice develop normally but show impaired mammary tumor progression and attenuated macrophage inflammatory responses (PMID:9573048, PMID:14612405, PMID:24362029, PMID:33821668, PMID:27659014). ETS2 is the causal gene at the chr21q22 inflammatory disease risk locus, where its overexpression in human macrophages is sufficient to reproduce the inflammatory transcriptional signature of associated diseases (PMID:38839969).

Mechanistic history

Synthesis pass · year-by-year structured walk · 17 steps
  1. 1988 High

    Establishing that ETS2 is an unstable nuclear phosphoprotein whose abundance is post-translationally controlled answered how ETS2 levels can be acutely regulated without transcriptional changes.

    Evidence Pulse-chase metabolic labeling and PKC activator treatment in cultured cells

    PMID:3062367

    Open questions at the time
    • Identity of the E3 ligase/degradation pathway unknown
    • Phosphorylation sites mediating stabilization uncharacterized
  2. 1990 High

    Demonstrating that ETS2 is a sequence-specific transcriptional activator binding GGAA-containing Ets-binding sites, with rapid induction in macrophages and a role in Xenopus meiotic maturation, established ETS2 as a signal-responsive transcription factor functioning in both immune and developmental contexts.

    Evidence Gel-shift assays and reporter transactivation (HTLV-1 LTR); antisense oligonucleotide injection in Xenopus oocytes; Northern blots in macrophages stimulated with CSF, LPS, and PKC activators

    PMID:2186967 PMID:2209540 PMID:2255913

    Open questions at the time
    • Upstream kinase cascade not yet defined
    • Endogenous mammalian target genes unknown
  3. 1992 High

    Identification of a C-terminal autoinhibitory domain that reduces DNA-binding 20–50-fold, and demonstration that the ETS2 DNA-binding domain acts as a dominant-negative blocking Ras-responsive transcription and CSF-1-dependent colony formation, placed ETS2 downstream of Ras in mitogenic signaling and revealed an intrinsic regulatory mechanism.

    Evidence Deletion mutagenesis with gel-shift assays; dominant-negative ETS2 in NIH 3T3 colony formation with epistasis rescue by c-Myc

    PMID:1409581 PMID:1448070

    Open questions at the time
    • Identity of the kinase phosphorylating ETS2 in response to Ras not yet determined
    • Structural basis of autoinhibition unclear
  4. 1996 High

    Mapping the Ras-responsive phosphorylation to threonine-72 and showing this residue is required for transcriptional superactivation identified the key post-translational switch coupling MAPK signaling to ETS2 output; concurrently, ETS2 was shown to drive macrophage differentiation and directly activate junB.

    Evidence Phosphoamino acid analysis, T72A mutagenesis, reporter assays in NIH 3T3/RAW264; stable ETS2 expression in M1D+ myeloblasts with differentiation markers

    PMID:8552081 PMID:8943340

    Open questions at the time
    • Direct kinase performing T72 phosphorylation not yet demonstrated
    • Coactivator mechanism downstream of pT72 unknown
  5. 1998 High

    ERK1/2 were identified as the direct T72 kinases, and phosphorylation was linked to activation of invasion-associated protease genes (uPA, MMP-9) through composite Ets-AP-1 sites; ETS2 knockout revealed embryonic lethality from trophoblast failure with defective MMP expression, establishing essential developmental and protease-regulatory roles.

    Evidence In vitro kinase assays with recombinant ERK1/2 and ETS2, phospho-T72 antibody, MEK inhibitor PD98059; Ets2 gene-targeted knockout mice rescued by tetraploid aggregation; promoter mutagenesis of uPA/MMP-9 reporters

    PMID:9573048 PMID:9639404 PMID:9710599

    Open questions at the time
    • How ETS2 recruits coactivators upon phosphorylation not resolved
    • Role of ETS2 in adult tissues beyond placenta unclear
  6. 1999 High

    Discovery that phosphorylated ETS2 physically recruits CBP/p300 coactivators through two independent binding regions established the coactivator-recruitment mechanism by which MAPK-phosphorylated ETS2 enhances transcription.

    Evidence Co-immunoprecipitation, GST-pulldown with purified proteins, domain-mapping deletions, stromelysin reporter assays

    PMID:10358095

    Open questions at the time
    • Whether phosphorylation is strictly required for CBP/p300 interaction not fully demonstrated here
  7. 2001 High

    ETS2 was shown to synergize with PU.1 to activate Bcl-xL transcription and promote macrophage survival, and CDK10 was identified as a Pointed-domain-specific interactor that inhibits ETS2 transactivation, revealing both a pro-survival target gene and a negative regulatory partner.

    Evidence Reporter assays and domain deletions for ETS2-PU.1 synergy on Bcl-xL promoter; CSF-1 withdrawal survival assays; yeast two-hybrid and co-IP for CDK10-ETS2 interaction

    PMID:11278399 PMID:11313931

    Open questions at the time
    • Physiological conditions under which CDK10 inhibits ETS2 unclear
    • Kinase activity of CDK10 toward ETS2 not tested
  8. 2003 High

    The Pointed domain was found to recruit the BRG1/SWI-SNF complex in a phosphorylation-dependent manner for transcriptional repression (e.g., BRCA1), and ETS2 overexpression was shown to induce p53-dependent apoptosis, revealing dual activator-repressor functionality and a link to the p53 pathway.

    Evidence Affinity purification of Pointed-domain interactors, co-IP/pulldown for BRG1, BRCA1 reporter repression; ETS2 transgenic mice crossed with p53-null mice for genetic rescue of thymic apoptosis

    PMID:12554679 PMID:12637547

    Open questions at the time
    • How ETS2 switches between CBP/p300 activation and BRG1-mediated repression at specific loci unclear
    • Mechanism by which ETS2 induces p53 not established
  9. 2003 High

    Demonstration that ETS2 T72A knock-in mice develop normally but show restricted mammary tumor growth with decreased stromal MMP expression established that MAPK-mediated ETS2 phosphorylation is dispensable for development but critical for tumor microenvironment function.

    Evidence T72A knock-in mice in multiple mammary tumor models (PyMT, Neu); macrophage MMP-9/MMP-3 analysis from tumor stroma

    PMID:14612405

    Open questions at the time
    • Whether T72A affects all ETS2-dependent inflammatory programs not tested
    • Cell-autonomous versus stromal contributions not fully separated
  10. 2004 High

    Unbiased affinity chromatography confirmed that phospho-T72 preferentially recruits CBP/p300 in HeLa nuclear extracts, and the T72A knock-in was shown to reduce inflammatory macrophage gene expression and extend lifespan in a chronic inflammation model, unifying the phosphorylation-coactivator mechanism with in vivo inflammatory outcomes.

    Evidence Phospho-ETS2 affinity chromatography of HeLa nuclear extracts; Ets2A72 × Hcph me-v double mutant mice with macrophage gene expression and survival analysis

    PMID:15240733 PMID:15572696

    Open questions at the time
    • Genome-wide identification of phospho-ETS2-dependent target genes not performed
    • PTEN-mediated suppression of ETS2 phosphorylation not tested in vivo
  11. 2007 Medium

    Conditional ETS2 knockout in trophoblast stem cells revealed that ETS2 maintains TS cell self-renewal through direct regulation of CDX2, a master trophoblast transcription factor, extending its developmental role beyond placental tissue structure to stem cell identity.

    Evidence Conditional Ets2 knockout in TS cells, gene expression and chromatin analysis for CDX2 as direct target

    PMID:17977525

    Open questions at the time
    • Full set of ETS2-regulated stem cell genes not defined
    • Mechanism of ETS2 regulation of CDX2 (enhancer architecture) not detailed
  12. 2012 High

    ETS2 was found to mediate gain-of-function mutant p53 binding to ETS-binding sites genome-wide, activating TDP2 to confer etoposide resistance; separately, co-expression of ETS2 with MESP1 was sufficient to reprogram fibroblasts into cardiac progenitors, revealing a new oncogenic partnership and a cardiogenic function.

    Evidence ChIP-seq for mutant p53, co-IP with ETS2, TDP2 knockdown sensitization; lentiviral ETS2+MESP1 expression with cardiac marker and functional readouts in human fibroblasts

    PMID:22508727 PMID:22826236

    Open questions at the time
    • Whether ETS2-mutant p53 axis operates across all p53 mutation types unknown
    • In vivo cardiac reprogramming with ETS2+MESP1 not tested
  13. 2013 High

    ETS2 was shown to directly activate miR-155 transcription in LPS-stimulated macrophages and to interact with the MLL histone methyltransferase complex to activate MMP1/MMP3 through H3K4me3 deposition, linking ETS2 to both microRNA regulation and epigenetic gene activation at invasion-related loci.

    Evidence ChIP for ETS2 at miR-155 promoter with Ets2-deficient mice; co-IP of ETS2-MLL complex, ChIP for H3K4me3 at MMP promoters upon HGF treatment

    PMID:23934123 PMID:24362029

    Open questions at the time
    • Global landscape of ETS2-MLL co-regulated genes undefined
    • Whether ETS2-MLL interaction is phosphorylation-dependent not tested
  14. 2017 High

    ZMYND11 was identified as a co-repressor that attenuates ETS2 transcriptional output relative to ETS1, with ZMYND11 expression levels determining whether ETS2 acts as oncogene or tumor suppressor; separately, ETS2 was found to drive snoRNA expression and metastatic phenotype in p53-mutant osteosarcomas.

    Evidence ChIP-seq cistrome comparison of ETS1/ETS2, ZMYND11 interaction mapping and transcriptional assays; RNA-seq of p53-mutant osteosarcomas with conditional ETS2 deletion

    PMID:28119415 PMID:29021240

    Open questions at the time
    • Structural basis of ZMYND11-ETS2 selectivity over ETS1 unknown
    • Mechanism connecting snoRNAs to metastasis not established
  15. 2019 High

    ETS2 was shown to function as an anti-inflammatory regulator by directly repressing the IL-6 promoter and inhibiting MAPK/NF-κB signaling in macrophages, with Ets2-deficient mice showing exacerbated sepsis, demonstrating context-dependent activator versus repressor roles in inflammation.

    Evidence ChIP for ETS2 at IL-6 promoter, conditional ETS2 KO mice in CLP sepsis model, signaling pathway phosphorylation analysis

    PMID:31785145

    Open questions at the time
    • How ETS2 switches from inflammatory gene activator to repressor at specific promoters not mechanistically resolved
    • Discrepancy with pro-inflammatory ETS2 functions at other loci needs reconciliation
  16. 2021 High

    In cardiomyocytes, ERK1/2-phosphorylated ETS2 was shown to form a complex with NFAT to co-activate hypertrophic genes including Rcan1.4 and miR-223, and cardiomyocyte-specific ETS2 knockout protected from pressure overload-induced hypertrophy, establishing ETS2 as an integrator of ERK and calcineurin/NFAT signaling in cardiac disease.

    Evidence Cardiomyocyte-specific Ets2 conditional KO mice with pressure overload, co-IP of ETS2-NFAT, ChIP at Rcan1.4 and miR-223 promoters

    PMID:33821668

    Open questions at the time
    • Full cardiac ETS2 targetome not defined
    • Whether pT72 is specifically required in cardiac hypertrophy not tested with knock-in
  17. 2024 High

    ETS2 was identified as the causal gene at the chr21q22 inflammatory disease risk locus; overexpression in primary human macrophages recapitulated the inflammatory transcriptional signature, establishing ETS2 as a master regulator of human inflammatory macrophage identity.

    Evidence Functional genomics in primary human macrophages, ETS2 overexpression with genome-wide gene expression profiling, pharmacological validation

    PMID:38839969

    Open questions at the time
    • Therapeutic targeting strategies for ETS2 in inflammatory bowel disease not yet clinically validated
    • Whether ZMYND11 modulates disease-associated ETS2 activity not tested

Open questions

Synthesis pass · forward-looking unresolved questions
  • The mechanism by which ETS2 switches between transcriptional activation (via CBP/p300) and repression (via BRG1/SWI-SNF or ZMYND11) at specific genomic loci, and how this switching is dysregulated in disease, remains unresolved.
  • No structural model of the ETS2 Pointed domain in complex with its diverse co-regulators
  • Genome-wide maps of ETS2 activator vs. repressor modes not available
  • Pharmacological approaches to selectively modulate ETS2 activity lacking

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140110 transcription regulator activity 13 GO:0003677 DNA binding 5
Localization
GO:0005634 nucleus 2
Pathway
R-HSA-74160 Gene expression (Transcription) 9 R-HSA-168256 Immune System 6 R-HSA-1266738 Developmental Biology 4 R-HSA-5357801 Programmed Cell Death 3 R-HSA-1640170 Cell Cycle 1
Partners
BRG1CBPCDK10EP300NFATPU.1TP53ZMYND11
Complex memberships
MLL histone methyltransferase complexSWI/SNF (BRG1/BAF57/INI1)

Evidence

Reading pass · 37 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1996 Ras signaling induces phosphorylation of a conserved threonine residue (T72 in ETS2, T38 in ETS1) that is required for Ras-mediated transcriptional superactivation of Ets-responsive reporters containing Ets-AP-1 binding sites. Phosphoamino acid analysis of radiolabeled ETS2, site-directed mutagenesis (T72A), transient transfection reporter assays in NIH 3T3 and RAW264 cells Molecular and cellular biology High 8552081
1988 ETS2 protein is a short-lived (half-life ~20 min) nuclear phosphoprotein; activation of protein kinase C (PKC) by TPA or diacylglycerol stabilizes ETS2 protein (half-life >2 h) through a post-translational mechanism without significantly increasing mRNA levels. Pulse-chase metabolic labeling, cycloheximide chase, PKC inhibitor H7 treatment, subcellular fractionation Molecular and cellular biology High 3062367
1990 ETS2 (and ETS1) function as sequence-specific transcriptional activators by binding to GGAA-containing Ets-binding sites in the HTLV-1 LTR enhancer region; nuclear localization is required for transactivation activity. Transient co-transfection CAT reporter assays, gel-shift DNA-binding assay, competition experiments with oligonucleotides, nuclear localization mutant analysis The EMBO journal High 2209540
1990 ETS2 expression is required for hormone-induced meiotic maturation (germinal vesicle breakdown) in Xenopus oocytes, as antisense oligonucleotide-mediated degradation of ets-2 mRNA blocks this process. Antisense oligonucleotide injection into Xenopus oocytes, hormone-induced maturation assay Science Medium 2255913
1990 ETS2 expression is rapidly and transiently induced in macrophages in response to CSF (cMGF), LPS, and PKC activators; PKC down-regulation blunts cMGF-induced ETS2 expression, implicating PKC in the signaling pathway. Northern blot, protein analysis, PKC inhibition/down-regulation experiments in chicken bone marrow macrophages, human monocytes, and mouse peritoneal macrophages Genes & development Medium 2186967
1990 ETS2 phosphorylation is induced within 5 min by T-cell antigen receptor-CD3 complex activation in Jurkat cells, mediated through calcium (mimicked by Ca2+ ionophores), detected as a mobility shift from 54 to 56 kDa. 32P metabolic labeling, SDS-PAGE mobility shift, antibody stimulation of TCR-CD3, Ca2+ ionophore treatment Molecular and cellular biology Medium 2137553
1992 The carboxyl-terminal domain of ETS2 (and ETS1) acts as an inhibitory domain that reduces DNA binding affinity; deletion of as few as 16 C-terminal amino acids increases DNA binding 20–50-fold, and this domain acts directly on DNA binding rather than through homodimerization. Gel-shift binding assay, deletion mutagenesis, in vitro cotranslation experiments Proceedings of the National Academy of Sciences of the United States of America High 1409581
1992 The ETS2 DNA-binding domain acts as a dominant-negative to suppress Ras-responsive enhancer activity and inhibit CSF-1-dependent colony formation; ectopic ETS2 rescues the c-myc response that is impaired when Ets-LacZ is expressed, placing ETS2 upstream of c-Myc in the CSF-1/Ras mitogenic signaling cascade. Stable expression of Ets-LacZ fusion in NIH 3T3 cells, colony formation assays, Northern blot analysis of c-ets-2, c-jun, c-fos, c-myc; rescue by c-myc overexpression Molecular and cellular biology High 1448070
1998 MAP kinases p42/p44 (ERK1/2) directly phosphorylate ETS2 at T72 in response to CSF-1/c-fms signaling, leading to persistent ETS2 phosphorylation and activation of the uPA gene target; the RAF/MAP kinase pathway is specifically required for both ETS2 expression and post-translational activation. Phospho-specific antibody (anti-pT72), in vitro kinase assay with recombinant ETS2, MEK inhibitor PD98059, immune depletion of MAP kinases, conditional Raf expression Molecular and cellular biology High 9710599
1998 ETS2 (and ETS1) transactivate the uPA and MMP-9 promoters in response to EGF through composite Ets-AP-1 binding sites; mutation of the conserved threonine (T75 of chicken ETS2, equivalent to T72) abolishes this EGF-dependent cooperation, linking EGF→Ras/ERK→ETS2 to invasion-associated protease expression. Reporter transfection assays, site-directed mutagenesis of Ets and AP-1 binding sites and T75 phosphorylation site, ETS2 expression vectors International journal of cancer High 9639404
1998 Targeted deletion of the ETS2 DNA-binding domain causes embryonic lethality due to defective trophoblast/extraembryonic tissue function, with failure of ectoplacental cone proliferation and deficient MMP-9 expression; rescued Ets2-deficient fibroblasts fail to induce MMP-13 and MMP-3 in response to FGF, and ectopic ETS2 restores this MMP expression. Gene targeting/knockout mice, tetraploid aggregation rescue, Northern blot for MMPs, ectopic ETS2 re-expression in knockout fibroblasts Genes & development High 9573048
1999 ETS2 physically interacts with the coactivators p300 and CBP in vivo; two independent regions of p300/CBP (aa 328–596 and aa 1678–2370) directly bind the ETS2 transactivation domain in vitro and in vivo, enabling coactivator recruitment to the stromelysin promoter. Co-immunoprecipitation from cells, GST-pulldown with purified proteins, reporter transactivation assays, domain-mapping deletion analysis The Journal of biological chemistry High 10358095
2001 CDK10, a CDC2-related kinase, physically interacts with the N-terminus (Pointed domain) of ETS2 and inhibits ETS2 transactivation activity; the interaction is ETS2-specific (CDK10 does not bind ETS1 in yeast two-hybrid) and requires an intact Pointed domain. Yeast two-hybrid, in vitro binding (GST-pulldown), co-immunoprecipitation from mammalian cells, transactivation reporter assays Oncogene Medium 11313931
2003 ETS2 interacts with components of the mammalian SWI/SNF chromatin remodeling complex (BRG-1, BAF57/p50, INI1) through its Pointed domain to form a repressor complex; BRG-1 directly binds the ETS2 Pointed domain in a phosphorylation-dependent manner, and the ETS2/BRG-1 complex represses the BRCA1 promoter. Biochemical affinity purification of Pointed-domain-interacting proteins, co-immunoprecipitation, in vitro pulldown, reporter repression assays, conditional ETS2 overexpression in MCF-7 The Journal of biological chemistry High 12637547
2004 ERK1/2-mediated phosphorylation of ETS2 (and ETS1) at the conserved N-terminal threonine (T72) enhances transactivation by promoting preferential recruitment of the coactivators CBP and p300; this interaction requires both the phosphoacceptor site and the Pointed domain, and was identified by unbiased affinity chromatography of HeLa nuclear extracts. Affinity chromatography of HeLa nuclear extracts using phospho- vs. mock-ETS2 as ligand, direct binding with purified proteins, co-immunoprecipitation from cells, MEK1-stimulated reporter assays, CBP co-expression experiments Molecular and cellular biology High 15572696
2003 ETS2 overexpression induces apoptosis through the p53 pathway; genetic rescue by p53 knockout (crossing ETS2 transgenic mice with p53-/- mice) abolishes the thymic apoptosis phenotype, placing ETS2 upstream of p53-dependent apoptosis. ETS2 transgenic mice, p53-/- crossing/genetic rescue, p53 and downstream factor expression analysis, HeLa transfection with p53 and ETS2 Human molecular genetics High 12554679
2001 ETS2 and PU.1 synergistically transactivate the Bcl-xL promoter in macrophages; this synergy depends on the transactivation domains of both proteins and is specific (ETS1 does not substitute for ETS2), and overexpression of both factors increases macrophage survival upon CSF-1 withdrawal. Reporter transactivation assays, domain deletion analysis, retroviral overexpression in bone marrow-derived macrophages, CSF-1 withdrawal survival assays, Bax-induced apoptosis assays The Journal of biological chemistry High 11278399
2002 PTEN suppresses insulin-stimulated ETS2 phosphorylation (at the T72 MAP kinase site) through inhibition of ERK/MAP kinase signaling independently of PI3K/Akt, and this functional suppression is dependent on PTEN phosphatase activity; phosphatase-dead PTEN fails to block ETS2 phosphorylation or uPA RRE activation. Phospho-specific ETS2 antibody (anti-pT72), MEK inhibitor vs PI3K inhibitor treatment, PTEN overexpression, uPA RRE reporter assays Human molecular genetics High 12095911
2003 MAP kinase phosphorylation of ETS2 at T72 is required for mammary tumor progression; knock-in mice with T72A mutation (Ets2A72) develop normally but show restricted mammary tumor growth, with decreased stromal MMP-9 and MMP-3 expression in macrophages, identifying ETS2 pT72 as acting in tumor stroma. Gene-targeted knock-in mice (T72A point mutation), mammary tumor models (polyoma middle T, Neu, Neu+VEGF), tumor transplantation into fat pads, macrophage MMP expression analysis Molecular and cellular biology High 14612405
2004 Constitutive phosphorylation of ETS2 at T72 is required for persistent inflammatory macrophage responses in the motheaten viable model; Ets2A72 allele (T72A knock-in) reduces inflammatory gene expression (TNF-α, CCL3, MMP-9, integrin αM, Bcl-X), increases macrophage apoptosis, and extends lifespan of me-v mice. Genetic double-mutant mice (Ets2A72 × Hcph me-v), alveolar macrophage gene expression analysis, LPS stimulation of bone marrow-derived macrophages, macrophage apoptosis assays Journal of immunology High 15240733
2005 ETS2 directly activates Bcl-xL transcription in osteoclasts; TNF stimulates ETS2 expression in osteoclasts, which in turn upregulates Bcl-xL, protecting osteoclasts from bisphosphonate-induced apoptosis; dominant-negative ETS2 blocks this TNF-protective effect. Retrovirus-mediated ETS2 overexpression in osteoclasts, dominant-negative ETS2 construct, in vitro osteoclast survival assay, Bcl-xL mRNA measurement, TNF-Tg mouse model Arthritis and rheumatism Medium 16142752
2007 ETS2 is required for trophoblast stem (TS) cell self-renewal; conditional inactivation of ETS2 reduces TS cell growth and promotes differentiation; a direct target in TS cells is CDX2, a master regulator of TS cell state, identified by chromatin analysis. Conditional Ets2 knockout via targeted allele, gene expression analysis, identification of CDX2 as direct ETS2 target Developmental biology Medium 17977525
2012 Mutant p53 (gain-of-function) interacts with ETS2 to regulate gene expression through ETS-binding sites in promoters; ETS2 mediates mutant p53 binding to EBS motifs and together they activate TDP2 transcription, contributing to etoposide resistance. ChIP-seq (genome-wide mutant p53 binding), reporter assays with EBS motifs, co-immunoprecipitation, TDP2 knockdown sensitization assays, gene expression analysis Genes & development High 22508727
2012 Co-expression of ETS2 and MESP1 transcription factors reprograms human dermal fibroblasts into cardiac progenitors expressing KDR+ cardiac mesoderm marker, core cardiac transcription factors, Ca2+ transients, and sarcomeres; neither factor alone is sufficient. Lentivirus-mediated forced expression, marker expression analysis (KDR, cardiac TFs), Ca2+ imaging, sarcomere detection, embryonic stem cell cardiopoiesis assays Proceedings of the National Academy of Sciences of the United States of America Medium 22826236
2013 ETS2 directly binds to the promoters of miR-155 in macrophages in response to LPS; ETS2-deficient mice show decreased miR-155 induction by LPS; IL-10 inhibits ETS2 induction, reducing its activity on the miR-155 promoter. Promoter truncation/mutational analysis, ChIP assay, ETS2-deficient mice, LPS stimulation, IL-10 treatment The Journal of biological chemistry High 24362029
2013 ETS2 suppresses MET phosphorylation and MET-dependent cell invasion in lung cancer cells; ETS2 knockdown augments HGF-induced MET phosphorylation and invasion, placing ETS2 as a negative regulator of the HGF/MET pathway. RNAi knockdown, MET phosphorylation Western blot, invasion assays, MET knockdown epistasis experiment, microarray pathway analysis Clinical cancer research Medium 23659968
2013 HGF-MET signaling leads to accumulation of ETS2, which interacts with the MLL histone methyltransferase complex to transactivate MMP1 and MMP3 promoters; ChIP assays show increased occupancy of the MLL-ETS2 complex and increased H3K4 trimethylation at these promoters upon HGF-MET activation. Co-immunoprecipitation of MLL-ETS2 complex, ChIP assay for complex occupancy and H3K4me3, HGF treatment of hepatocellular carcinoma cell lines, MLL knockout mouse phenotypic analysis The Journal of clinical investigation High 23934123
2014 ETS2 in macrophages regulates the expression of miR-21, miR-29a, miR-142-3p, and miR-223 downstream of CSF1 signaling; CSF1-ETS2-induced microRNAs promote M2 reprogramming, angiogenesis, and metastatic tumor growth by targeting anti-angiogenic genes. Loss-of-function (conditional Dicer deletion in macrophages), miRNA expression profiling, ETS2 knockdown/overexpression, angiogenesis and tumor growth assays, target gene validation Oncogene Medium 25241894
2016 ETS2 directly binds regulatory sequences of Ccl3, Ccl4, Cxcl4, Cxcl5, and Cxcl10 in pancreatic fibroblasts to control chemokine production and immune cell recruitment; conditional ablation of ETS2 in pancreatic fibroblasts decreased acinar-to-ductal metaplasia and altered immune infiltration. ChIP assay for ETS2 occupancy at chemokine promoters, conditional Ets2 ablation in fibroblasts, mouse ADM model (Kras G12D), flow cytometry of immune cell populations Neoplasia High 27659014
2017 ETS2 transcription factor-binding sites are enriched in the regulatory elements of snoRNA genes upregulated in p53 mutant osteosarcomas; homozygous deletion of ETS2 in p53 mutant mice strongly downregulates snoRNAs and reverses the prometastatic phenotype without affecting tumor development. RNA-seq of mouse osteosarcomas, regulatory element analysis, conditional ETS2 deletion in p53 mutant mice, phenotypic and transcriptomic analysis Genes & development High 29021240
2017 ETS2 interaction with the co-repressor ZMYND11 (BS69) attenuates ETS2's transcriptional activation compared to ETS1, causing ETS2 to act as a weaker activator or repressor at shared target genes; this interaction is mediated by the ETS2 N-terminus and ZMYND11 expression levels determine oncogenic vs. tumor-suppressive roles of ETS2. ETS1/ETS2 cistrome comparison (ChIP-seq), ETS1 deletion lines, transcriptional activity assays, co-repressor interaction mapping, patient tumor expression correlation Nucleic acids research High 28119415
2021 ETS2 is phosphorylated and activated by ERK1/2 in response to hypertrophic stimuli in cardiomyocytes; conditional cardiomyocyte-specific ETS2 knockout protects mice from pressure overload-induced cardiac hypertrophy; ETS2 forms a complex with NFAT to stimulate transcription of hypertrophic genes including Rcan1.4 and miR-223, linking Erk1/2 and calcineurin/NFAT signaling pathways. Cardiomyocyte-specific Ets2 conditional knockout mice, calcineurin transgenic mouse model with ETS2 silencing, ChIP for ETS2 and NFAT at target promoters, co-immunoprecipitation of ETS2-NFAT complex, miR-223 functional studies Circulation High 33821668
2024 ETS2 is the causal gene at the chr21q22 inflammatory disease risk locus; overexpressing ETS2 in resting macrophages reproduces the inflammatory state of chr21q22-associated diseases, including upregulation of TNF and IL-23; functional genomics in primary human macrophages identified ETS2 as a central regulator of human inflammatory macrophage gene expression. Functional genomics in primary human macrophages, ETS2 overexpression, gene expression profiling, cellular signature database screening, pharmacological validation in vitro and ex vivo Nature High 38839969
1995 ETS2 transactivates the CDC2 promoter through Ets-binding sites in its 5' flanking region; constitutive ETS2 expression in fibroblasts increases CDC2 expression, histone H1 kinase activity, and cyclin A levels, demonstrating a direct role for ETS2 in regulating G2/M cell cycle entry. Promoter-reporter transactivation assays, site-directed mutagenesis of EBS in cdc2 promoter, stable ETS2 expression in BALB/c3T3 cells, kinase activity assays Experimental cell research Medium 7867724
1996 Constitutive expression of ETS2 in M1D+ myeloblast leukemia cells is sufficient to drive macrophage differentiation; ETS2 directly activates the junB promoter through Ets-binding sites, and dominant-negative ETS2 reduces junB transcription. Stable ETS2 expression in M1D+ cells, differentiation marker analysis (lysozyme, TNF-α), transient reporter assays with junB promoter, dominant-negative ETS2 transfection Molecular and cellular biology Medium 8943340
2003 ETS2 transactivates the beta-APP gene promoter via specific Ets-binding sites and cooperates with AP1; ETS2 transgenic mouse brains and fibroblasts overexpressing ETS2 show elevated beta-APP, increased presenilin-1, and increased beta-amyloid production. Reporter transactivation assays, EBS mutagenesis, ETS2 transgenic mouse brain analysis, Western blot for APP/presenilin-1/beta-amyloid Biochimica et biophysica acta Medium 12890557
2019 ETS2 suppresses inflammatory cytokine production (IL-6, TNF-α, IFN-β) in macrophages by inhibiting ERK1/2, JNK, p38, and p65 MAPK/NF-κB signaling pathways, and also directly binds to and represses the IL-6 promoter; Ets2-deficient mice show exacerbated inflammation and increased susceptibility to CLP-induced sepsis. ETS2 knockdown and knockout macrophages, Ets2 conditional KO mice, CLP sepsis model, ChIP for ETS2 at IL-6 promoter, cytokine measurements, signaling pathway phosphorylation analysis Aging High 31785145

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1996 Ras-mediated phosphorylation of a conserved threonine residue enhances the transactivation activities of c-Ets1 and c-Ets2. Molecular and cellular biology 329 8552081
1988 Mammalian ets-1 and ets-2 genes encode highly conserved proteins. Proceedings of the National Academy of Sciences of the United States of America 303 2847145
1998 Defective trophoblast function in mice with a targeted mutation of Ets2. Genes & development 255 9573048
2010 EGFR promotes lung tumorigenesis by activating miR-7 through a Ras/ERK/Myc pathway that targets the Ets2 transcriptional repressor ERF. Cancer research 239 20978205
1990 The product of the c-ets-1 proto-oncogene and the related Ets2 protein act as transcriptional activators of the long terminal repeat of human T cell leukemia virus HTLV-1. The EMBO journal 236 2209540
2007 Curcumin, a dietary component, has anticancer, chemosensitization, and radiosensitization effects by down-regulating the MDM2 oncogene through the PI3K/mTOR/ETS2 pathway. Cancer research 232 17332326
1998 The Ets-1 and Ets-2 transcription factors activate the promoters for invasion-associated urokinase and collagenase genes in response to epidermal growth factor. International journal of cancer 194 9639404
1994 Differential expression of ets-1 and ets-2 proto-oncogenes during murine embryogenesis. Oncogene 191 8183549
2012 Mutant p53 cooperates with ETS2 to promote etoposide resistance. Genes & development 173 22508727
2004 Ras/mitogen-activated protein kinase signaling activates Ets-1 and Ets-2 by CBP/p300 recruitment. Molecular and cellular biology 169 15572696
1996 Down's syndrome-like skeletal abnormalities in Ets2 transgenic mice. Nature 164 8596630
2012 Transcription factors ETS2 and MESP1 transdifferentiate human dermal fibroblasts into cardiac progenitors. Proceedings of the National Academy of Sciences of the United States of America 161 22826236
1992 Mitogenic signaling by colony-stimulating factor 1 and ras is suppressed by the ets-2 DNA-binding domain and restored by myc overexpression. Molecular and cellular biology 153 1448070
2009 Ets1 and Ets2 are required for endothelial cell survival during embryonic angiogenesis. Blood 152 19411629
1992 An inhibitory carboxyl-terminal domain in Ets-1 and Ets-2 mediates differential binding of ETS family factors to promoter sequences of the mb-1 gene. Proceedings of the National Academy of Sciences of the United States of America 146 1409581
2010 Ets-1 and Ets-2 regulate the expression of microRNA-126 in endothelial cells. Arteriosclerosis, thrombosis, and vascular biology 130 20671229
2013 ETS2 mediated tumor suppressive function and MET oncogene inhibition in human non-small cell lung cancer. Clinical cancer research : an official journal of the American Association for Cancer Research 127 23659968
1999 p300/cAMP-responsive element-binding protein interactions with ets-1 and ets-2 in the transcriptional activation of the human stromelysin promoter. The Journal of biological chemistry 123 10358095
2024 A disease-associated gene desert directs macrophage inflammation through ETS2. Nature 106 38839969
2009 ETS2 and ERG promote megakaryopoiesis and synergize with alterations in GATA-1 to immortalize hematopoietic progenitor cells. Blood 97 19168790
2001 Cdk10, a Cdc2-related kinase, associates with the Ets2 transcription factor and modulates its transactivation activity. Oncogene 93 11313931
2013 The role of Ets2 transcription factor in the induction of microRNA-155 (miR-155) by lipopolysaccharide and its targeting by interleukin-10. The Journal of biological chemistry 91 24362029
1999 Regulation of the human interleukin-5 promoter by Ets transcription factors. Ets1 and Ets2, but not Elf-1, cooperate with GATA3 and HTLV-I Tax1. The Journal of biological chemistry 89 10212281
1998 Persistent activation of mitogen-activated protein kinases p42 and p44 and ets-2 phosphorylation in response to colony-stimulating factor 1/c-fms signaling. Molecular and cellular biology 88 9710599
1993 Transactivation of GATA-1 promoter with ETS1, ETS2 and ERGB/Hu-FLI-1 proteins: stabilization of the ETS1 protein binding on GATA-1 promoter sequences by monoclonal antibody. Oncogene 87 8510925
2011 Analysis of gene networks in white adipose tissue development reveals a role for ETS2 in adipogenesis. Development (Cambridge, England) 85 21989915
1988 A short-lived nuclear phosphoprotein encoded by the human ets-2 proto-oncogene is stabilized by activation of protein kinase C. Molecular and cellular biology 84 3062367
2003 ETS2 overexpression in transgenic models and in Down syndrome predisposes to apoptosis via the p53 pathway. Human molecular genetics 80 12554679
2005 ets-2 promotes the activation of a mitochondrial death pathway in Down's syndrome neurons. The Journal of neuroscience : the official journal of the Society for Neuroscience 77 15745955
2003 Ets-1 and Ets-2 transcription factors are essential for normal coronary and myocardial development in chicken embryos. Circulation research 76 12637368
1990 Molecular and functional characterization of the promoter of ETS2, the human c-ets-2 gene. Proceedings of the National Academy of Sciences of the United States of America 74 2405393
2013 Ets-2 regulates cell apoptosis via the Akt pathway, through the regulation of urothelial cancer associated 1, a long non-coding RNA, in bladder cancer cells. PloS one 70 24069250
2003 Ets-2 and components of mammalian SWI/SNF form a repressor complex that negatively regulates the BRCA1 promoter. The Journal of biological chemistry 70 12637547
2021 Cooperative Binding of ETS2 and NFAT Links Erk1/2 and Calcineurin Signaling in the Pathogenesis of Cardiac Hypertrophy. Circulation 67 33821668
2007 Ets2 is required for trophoblast stem cell self-renewal. Developmental biology 65 17977525
2002 PTEN blocks insulin-mediated ETS-2 phosphorylation through MAP kinase, independently of the phosphoinositide 3-kinase pathway. Human molecular genetics 63 12095911
2014 CSF1-ETS2-induced microRNA in myeloid cells promote metastatic tumor growth. Oncogene 61 25241894
1987 Genetic mapping of Prm-1, Igl-1, Smst, Mtv-6, Sod-1, and Ets-2 and localization of the Down syndrome region on mouse chromosome 16. Cytogenetics and cell genetics 61 2882955
2005 Tumor necrosis factor prevents alendronate-induced osteoclast apoptosis in vivo by stimulating Bcl-xL expression through Ets-2. Arthritis and rheumatism 57 16142752
1990 Rapid and transient expression of Ets2 in mature macrophages following stimulation with cMGF, LPS, and PKC activators. Genes & development 57 2186967
1988 The Drosophila ets-2 gene: molecular structure, chromosomal localization, and developmental expression. Developmental biology 57 2834248
2017 Integrative genome analysis of somatic p53 mutant osteosarcomas identifies Ets2-dependent regulation of small nucleolar RNAs by mutant p53 protein. Genes & development 56 29021240
1998 Ets-2 transdominant mutant abolishes anchorage-independent growth and macrophage colony-stimulating factor-stimulated invasion by BT20 breast carcinoma cells. Cancer research 56 9500466
2007 Ets-2 and p160 proteins collaborate to regulate c-Myc in endocrine resistant breast cancer. Oncogene 55 18059336
2003 Selective inhibition of transcription of the Ets2 gene in prostate cancer cells by a triplex-forming oligonucleotide. Nucleic acids research 54 12560478
2017 ATG7 Overexpression Is Crucial for Tumorigenic Growth of Bladder Cancer In Vitro and In Vivo by Targeting the ETS2/miRNA196b/FOXO1/p27 Axis. Molecular therapy. Nucleic acids 53 28624205
2013 HGF-MET signals via the MLL-ETS2 complex in hepatocellular carcinoma. The Journal of clinical investigation 53 23934123
2003 Ets2-dependent stromal regulation of mouse mammary tumors. Molecular and cellular biology 52 14612405
1997 Identification of differentially expressed prostate genes: increased expression of transcription factor ETS-2 in prostate cancer. The Prostate 52 9122038
2012 Transcriptional regulation of miR-196b by ETS2 in gastric cancer cells. Carcinogenesis 50 22298639
2001 Induction of ETS-1 and ETS-2 transcription factors is required for thyroid cell transformation. Cancer research 50 11280797
2001 Bcl-XL expression correlates with primary macrophage differentiation, activation of functional competence, and survival and results from synergistic transcriptional activation by Ets2 and PU.1. The Journal of biological chemistry 48 11278399
1999 A single targeted Ets2 allele restricts development of mammary tumors in transgenic mice. Cancer research 48 10485465
1998 Elevated expression of Ets2 or distinct portions of Ets2 can reverse Ras-mediated cellular transformation. The Journal of biological chemistry 48 9668063
1990 Phosphorylation of the ETS-2 protein: regulation by the T-cell antigen receptor-CD3 complex. Molecular and cellular biology 48 2137553
2003 Overexpression of the chromosome 21 transcription factor Ets2 induces neuronal apoptosis. Neurobiology of disease 47 14678752
2004 Activated Ets2 is required for persistent inflammatory responses in the motheaten viable model. Journal of immunology (Baltimore, Md. : 1950) 46 15240733
2018 Aberrant expression of ETS1 and ETS2 proteins in cancer. Cancer reports and reviews 44 29974077
2008 Feedback regulation of DUSP6 transcription responding to MAPK1 via ETS2 in human cells. Biochemical and biophysical research communications 44 18848526
1990 Requirement of ets-2 expression for Xenopus oocyte maturation. Science (New York, N.Y.) 43 2255913
2001 Ets-2 is induced by oxidative stress and sensitizes cells to H(2)O(2)-induced apoptosis: implications for Down's syndrome. Biochemical and biophysical research communications 40 11573964
1994 Ets-2 and c-Myb act independently in regulating expression of the hematopoietic stem cell antigen CD34. The Journal of biological chemistry 40 7523384
2007 The role of the proto-oncogene ETS2 in acute megakaryocytic leukemia biology and therapy. Leukemia 38 18094719
1996 Constitutive c-ets2 expression in M1D+ myeloblast leukemic cells induces their differentiation to macrophages. Molecular and cellular biology 37 8943340
2009 Activation of Ets-2 by oxidative stress induces Bcl-xL expression and accounts for glial survival in amyotrophic lateral sclerosis. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 36 19179380
2002 The role of the Ets2 transcription factor in the proliferation, maturation, and survival of mouse thymocytes. Journal of immunology (Baltimore, Md. : 1950) 36 12391198
2019 Ets2 suppresses inflammatory cytokines through MAPK/NF-κB signaling and directly binds to the IL-6 promoter in macrophages. Aging 34 31785145
2007 Detailed technical analysis of urine RNA-based tumor diagnostics reveals ETS2/urokinase plasminogen activator to be a novel marker for bladder cancer. Clinical chemistry 34 17921261
2020 RNA-binding protein CELF1 enhances cell migration, invasion, and chemoresistance by targeting ETS2 in colorectal cancer. Clinical science (London, England : 1979) 33 32677671
2020 Exosomal miR-663b targets Ets2-repressor factor to promote proliferation and the epithelial-mesenchymal transition of bladder cancer cells. Cell biology international 32 31872468
2016 Stromal ETS2 Regulates Chemokine Production and Immune Cell Recruitment during Acinar-to-Ductal Metaplasia. Neoplasia (New York, N.Y.) 32 27659014
2009 Analysis of the fibroblastic growth factor receptor-RAS/RAF/MEK/ERK-ETS2/brachyury signalling pathway in chordomas. Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc 32 19407855
1995 ets-2 regulates cdc2 kinase activity in mammalian cells: coordinated expression of cdc2 and cyclin A. Experimental cell research 31 7867724
2013 The Rho-GEF Trio regulates a novel pro-inflammatory pathway through the transcription factor Ets2. Biology open 30 23789107
2003 The chromosome 21 transcription factor ETS2 transactivates the beta-APP promoter: implications for Down syndrome. Biochimica et biophysica acta 30 12890557
2002 Expression of ets-1 and ets-2 in colonic neoplasms. Anticancer research 30 12168840
2015 VEGFA Expression Is Inhibited by Arsenic Trioxide in HUVECs through the Upregulation of Ets-2 and miRNA-126. PloS one 29 26274316
1990 The human ETS-2 gene promoter: molecular dissection and nuclease hypersensitivity. Oncogene 29 2216458
2013 Transcription factor Ets1, but not the closely related factor Ets2, inhibits antibody-secreting cell differentiation. Molecular and cellular biology 28 24277931
2011 Ets2 regulates colonic stem cells and sensitivity to tumorigenesis. Stem cells (Dayton, Ohio) 28 21425406
2006 The transcriptional ETS2 repressor factor associates with active and inactive Erks through distinct FXF motifs. The Journal of biological chemistry 28 16799155
2003 A central role for Ets-2 in the transcriptional regulation and cyclic adenosine 5'-monophosphate responsiveness of the human chorionic gonadotropin-beta subunit gene. Molecular endocrinology (Baltimore, Md.) 28 12511603
1999 Evidence against the current hypothesis of "gene dosage effects" of trisomy 21: ets-2, encoded on chromosome 21" is not overexpressed in hearts of patients with Down Syndrome. Biochemical and biophysical research communications 28 9918849
2019 MicroRNA-146b Overexpression Promotes Human Bladder Cancer Invasion via Enhancing ETS2-Mediated mmp2 mRNA Transcription. Molecular therapy. Nucleic acids 27 31071529
2019 Kcnq1ot1/miR-381-3p/ETS2 Axis Regulates Inflammation in Mouse Models of Acute Respiratory Distress Syndrome. Molecular therapy. Nucleic acids 27 31841990
2009 Ets2 transcription factor, telomerase activity and breast cancer. Clinical and experimental pharmacology & physiology 26 19566835
2017 Interaction with ZMYND11 mediates opposing roles of Ras-responsive transcription factors ETS1 and ETS2. Nucleic acids research 25 28119415
2011 RuvBl2 cooperates with Ets2 to transcriptionally regulate hTERT in colon cancer. FEBS letters 25 21763315
2005 Ets2 transcription factor in normal and neoplastic human breast tissue. European journal of cancer (Oxford, England : 1990) 25 16380248
2016 Mutant p53 and ETS2, a Tale of Reciprocity. Frontiers in oncology 24 26925389
2009 Complex contributions of Ets2 to craniofacial and thymus phenotypes of trisomic "Down syndrome" mice. American journal of medical genetics. Part A 24 19764029
2009 Ets-2 and p53 mediate cAMP-induced MMP-2 expression, activity and trophoblast invasion. Reproductive biology and endocrinology : RB&E 23 19939245
2004 Regulation of interferon-tau (IFN-tau) gene promoters by growth factors that target the Ets-2 composite enhancer: a possible model for maternal control of IFN-tau production by the conceptus during early pregnancy. Endocrinology 23 15217985
1998 Selective inhibition of prolactin gene transcription by the ETS-2 repressor factor. The Journal of biological chemistry 23 9822660
2010 New insights for Ets2 function in trophoblast using lentivirus-mediated gene knockdown in trophoblast stem cells. Placenta 22 20569982
2023 ETS2 promotes cardiomyocyte apoptosis and autophagy in heart failure by regulating lncRNA TUG1/miR-129-5p/ATG7 axis. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 21 37171262
2014 Elf5 and Ets2 maintain the mouse extraembryonic ectoderm in a dosage dependent synergistic manner. Developmental biology 21 25446535
2016 The C-ETS2-TFEB Axis Promotes Neuron Survival under Oxidative Stress by Regulating Lysosome Activity. Oxidative medicine and cellular longevity 20 27195074
2014 MicroRNA 17-92 cluster mediates ETS1 and ETS2-dependent RAS-oncogenic transformation. PloS one 20 24968297
1999 Expression of the transcription factor ETS2 in brain of patients with Down syndrome--evidence against the overexpression-gene dosage hypothesis. Journal of neural transmission. Supplementum 20 10666682