Affinage

IER3

Radiation-inducible immediate-early gene IEX-1 · UniProt P46695

Length
156 aa
Mass
16.9 kDa
Annotated
2026-04-28
100 papers in source corpus 33 papers cited in narrative 29 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

IER3 is a stress-inducible immediate-early gene that functions as a context-dependent regulator of cell survival, apoptosis, and DNA damage responses by modulating multiple signaling cascades. Its principal biochemical activity is inhibition of B56-containing PP2A holoenzymes: IER3 binds B56 subunits and phosphorylated ERK, enabling ERK-mediated transphosphorylation of B56 that dissociates B56 from PP2A catalytic subunits, thereby sustaining both ERK and Akt phosphorylation (PMID:16456541, PMID:17200115, PMID:25250570). IER3 also directly binds RelA/p65 to attenuate NF-κB transactivation of anti-apoptotic targets (PMID:18191642), targets the mitochondrial ATPase inhibitor IF1 for degradation to suppress ROS production (PMID:19096392), and forms a complex with phospho-ERK and DNA-PKcs to promote NHEJ repair in hematopoietic stem cells (PMID:24184684). IER3 protein stability is controlled by MDM2-mediated ubiquitination at K60, scaffolded by FHL2, and its pro- versus anti-apoptotic output is determined by distinct structural domains including a nuclear localization sequence required for pro-apoptotic function and glycosylation/phosphorylation sites required for anti-apoptotic function (PMID:26973248, PMID:16567805).

Mechanistic history

Synthesis pass · year-by-year structured walk · 14 steps
  1. 1998 High

    IER3 was established as an NF-κB- and p53-responsive immediate-early gene with anti-apoptotic function, answering whether NF-κB transcriptional targets directly mediate cell survival after TNF/Fas signaling.

    Evidence Antisense knockdown sensitized cells to TNF-induced killing; EMSA and reporter assays confirmed direct p53 and NF-κB binding to the IER3 promoter in multiple cell lines

    PMID:9627114 PMID:9703517 PMID:9781666

    Open questions at the time
    • Downstream effector mechanism of IER3-mediated survival was unknown
    • Relative contributions of p53 vs NF-κB to physiological IER3 induction were not delineated
  2. 2002 High

    IER3 was identified as a direct ERK2 substrate whose phosphorylation is required for anti-apoptotic activity, and reciprocally, IER3 potentiates ERK activation — establishing a positive feedback loop between IER3 and MAPK signaling.

    Evidence In vitro kinase assay with ERK2, in vivo phosphorylation, ERK-docking-site and phosphoacceptor mutants with cell death assays

    PMID:12356731

    Open questions at the time
    • The direct molecular target through which IER3 potentiates ERK was not identified
    • Whether ERK phosphorylation of IER3 controls its stability or localization was unknown
  3. 2002 High

    Transgenic mouse models demonstrated that IER3 overexpression in T cells impairs Fas- and TCR-induced apoptosis in vivo, leading to autoimmunity and lymphomagenesis — establishing IER3's in vivo relevance to immune homeostasis.

    Evidence Eμ-IER3 transgenic mice with T cell apoptosis assays, immune response phenotyping, and lymphoma analysis

    PMID:11782530 PMID:14534530

    Open questions at the time
    • Molecular target in the Fas/TCR death pathway inhibited by IER3 was not identified
    • Whether IER3 effects were cell-autonomous in vivo was not fully resolved
  4. 2005 High

    IER3 was shown to undergo nucleocytoplasmic shuttling and to co-localize with PML nuclear bodies, with its NLS required selectively for pro-apoptotic function — resolving how a single protein can exert opposing effects on cell fate depending on subcellular compartment.

    Evidence GFP-IER3 confocal microscopy, leptomycin B treatment, co-IP with PML, NLS deletion mutant apoptosis assays

    PMID:15855159

    Open questions at the time
    • The nuclear target(s) mediating IER3's pro-apoptotic function were not identified
    • Functional significance of PML body association was not mechanistically dissected
  5. 2006 High

    The mechanism of ERK potentiation was solved: IER3 inhibits B56-containing PP2A holoenzymes by bridging phospho-ERK to B56 subunits, enabling ERK-mediated transphosphorylation and dissociation of B56 from the PP2A catalytic subunit — identifying IER3 as a PP2A inhibitor.

    Evidence Reciprocal co-IP, in vitro phosphatase assay reconstitution, RNAi of B56 subunits, domain mutagenesis

    PMID:16456541

    Open questions at the time
    • Whether IER3 inhibits PP2A complexes containing other B-family subunits was not tested
    • Structural basis of the IER3–B56 interaction was unknown
  6. 2006 High

    Systematic structure-function analysis mapped anti-apoptotic activity to glycosylation/phosphorylation sites and the C-terminus, and pro-apoptotic activity to the NLS, with both requiring a transmembrane-like hydrophobic region — establishing that dual functionality is encoded in separable protein domains.

    Evidence Site-directed mutagenesis of hydrophobic residues, glycosylation sites, phosphorylation sites, NLS; apoptosis and ROS assays

    PMID:16567805

    Open questions at the time
    • Whether post-translational modifications control domain switching in physiological settings was not shown
    • The transmembrane-like region's membrane insertion and topology were not resolved structurally
  7. 2007 High

    IER3-mediated PP2A inhibition was extended to the Akt pathway: IER3 sustains Akt phosphorylation at Thr308 and Ser473 via B56-PP2A inhibition in an ERK-dependent manner, linking IER3 to two major survival kinase cascades simultaneously.

    Evidence Overexpression and RNAi of IER3 and B56 subunits, ERK dominant-negative mutants, phospho-Akt immunoblot, ERK-binding-deficient IER3 mutant

    PMID:17200115

    Open questions at the time
    • Whether Akt sustaining is the primary mechanism of IER3's anti-apoptotic activity versus other targets was not determined
  8. 2007 High

    The negative-feedback role of IER3 on NF-κB was mechanistically defined: IER3 directly binds the RelA/p65 transactivation domain, represses NF-κB target genes (Bcl-2, Bcl-xL, cIAP1/2), and associates with their promoters — explaining how an NF-κB-induced gene can attenuate its own inducer.

    Evidence GST pulldown, endogenous co-IP, GAL4/luciferase reporter, ChIP on anti-apoptotic gene promoters

    PMID:18191642

    Open questions at the time
    • Whether IER3–p65 interaction competes with coactivators or recruits corepressors was not resolved
    • Chromatin-level mechanism of repression was not defined
  9. 2008 High

    IER3 was found to target the mitochondrial F1Fo-ATPase inhibitor IF1 for degradation, accelerating ATP hydrolysis and reducing mitochondrial ROS — providing a direct metabolic mechanism for IER3's effects on ROS and explaining the ROS phenotype of IER3-knockout mice.

    Evidence Co-IP mapping to IF1 C-terminus, IF1 siRNA phenocopy, IER3 KO mice with stabilized IF1, ATP hydrolysis and ROS assays

    PMID:19096392

    Open questions at the time
    • The degradation pathway (proteasomal vs lysosomal) through which IER3 eliminates IF1 was not defined
    • Whether IF1 degradation fully accounts for IER3's metabolic effects was untested
  10. 2010 High

    IER3 was shown to interact with MCL-1 and to be required for ATM-dependent nuclear translocation of MCL-1 after DNA damage, linking IER3 to the DNA damage checkpoint: loss of IER3 prevents MCL-1 nuclear accumulation, impairs Chk1 activation and G2 arrest, and causes genomic instability.

    Evidence IER3 knockdown/knockout, ATM inhibition, γ-irradiation, nuclear fractionation, Chk1 phosphorylation assay

    PMID:20467439

    Open questions at the time
    • How IER3 mediates MCL-1 nuclear import (carrier vs retention mechanism) was not determined
    • Whether IER3–MCL-1 interaction is direct or requires additional factors in vivo was uncertain
  11. 2012 High

    IER3 deficiency was shown to promote Th17 differentiation at the expense of Th1 survival through increased mitochondrial ROS, establishing IER3 as a metabolic regulator of T helper cell fate decisions.

    Evidence IER3 KO mice in collagen-induced arthritis model, mitochondrial ROS measurement, antioxidant rescue of Th17 skewing

    PMID:22798682

    Open questions at the time
    • Whether ROS-mediated Th17 skewing is solely via BATF or involves additional transcription factors was not fully resolved
    • Cell-intrinsic vs cell-extrinsic contributions in vivo were not separated
  12. 2013 High

    IER3 was identified as a scaffold for a phospho-ERK/DNA-PKcs complex that promotes NHEJ repair in hematopoietic stem cells downstream of TPO, establishing a direct role in DNA repair beyond checkpoint activation.

    Evidence Co-IP of ternary IER3/pERK/DNA-PKcs complex, IER3 knockdown and overexpression, NHEJ repair assay in mouse and human HSPCs

    PMID:24184684

    Open questions at the time
    • Whether IER3 activates DNA-PKcs kinase activity directly or facilitates its recruitment to DSBs was not resolved
    • Contribution of IER3-dependent NHEJ to HSC genomic integrity during aging was not tested
  13. 2014 High

    IER3 was shown to be essential for KrasG12D-driven pancreatic tumorigenesis through PP2A-dependent ERK sustaining, as IER3-deficient mice exhibited delayed PanIN and PDAC formation — providing in vivo genetic evidence that IER3's PP2A-inhibitory function is oncogenically required.

    Evidence IER3/KrasG12D compound mutant mice, PP2A phosphatase assay, pERK immunohistochemistry

    PMID:25250570

    Open questions at the time
    • Whether therapeutic PP2A reactivation can substitute for IER3 loss in established tumors was not tested
    • Contribution of IER3's non-PP2A functions to pancreatic tumorigenesis was not assessed
  14. 2016 High

    MDM2 was identified as the E3 ubiquitin ligase for IER3, with FHL2 acting as a scaffold and K60 as the critical ubiquitination site — defining the proteolytic control mechanism for IER3 protein levels.

    Evidence Ubiquitination assay, K60 point mutant, co-IP of MDM2–FHL2–IER3 ternary complex, FHL2/MDM2 siRNA

    PMID:26973248

    Open questions at the time
    • Whether other E3 ligases contribute to IER3 turnover in specific contexts was not examined
    • How IER3 ubiquitination is regulated by upstream signals beyond MDM2/FHL2 was not defined

Open questions

Synthesis pass · forward-looking unresolved questions
  • The structural basis of IER3's interactions with its multiple partners (B56, ERK, RelA, IF1, MCL-1, DNA-PKcs) remains undetermined, as does how IER3 integrates competing pro-survival and pro-apoptotic outputs in a single cell under physiological conditions.
  • No crystal or cryo-EM structure of IER3 or any IER3-containing complex exists
  • How post-translational modifications dynamically partition IER3 among its functional complexes is unknown
  • Whether IER3's transmembrane-like domain inserts into membranes or serves as a protein-protein interaction surface is unresolved

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0098772 molecular function regulator activity 5 GO:0060090 molecular adaptor activity 4
Localization
GO:0005634 nucleus 3 GO:0005739 mitochondrion 2 GO:0005829 cytosol 2
Pathway
R-HSA-162582 Signal Transduction 6 R-HSA-5357801 Programmed Cell Death 5 R-HSA-168256 Immune System 2 R-HSA-73894 DNA Repair 2 R-HSA-392499 Metabolism of proteins 1
Partners
MAPK1MCL1MDM2PPP2R5APPP2R5BPPP2R5CPRKDCRELA
Complex memberships
IER3–MDM2–FHL2IER3–pERK–B56-PP2AIER3–pERK–DNA-PKcs

Evidence

Reading pass · 29 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1998 IEX-1 (IER3) is transcriptionally induced by TNF in an NF-κB-dependent manner and protects cells from Fas- or TNF-induced apoptosis; overexpression of antisense IEX-1 sensitized cells to TNF-induced killing, establishing IEX-1 as a downstream NF-κB target mediating cell survival. Antisense overexpression, transfection of IEX-1 expression vector, cell viability assays in TNF/Fas-stimulated cells Science Medium 9703517
1998 The IEX-1 (p22/PRG1) promoter contains functional binding sites for p53 and NF-κB; gel shift/supershift assays confirmed direct binding of both transcription factors, and reporter assays demonstrated p53-dependent and TNF/NF-κB-dependent transactivation of the IEX-1 promoter. EMSA/supershift assay, CAT reporter gene assay, stable transfection with temperature-sensitive p53 FEBS letters High 11844788 12360408 9627114 9781666
2002 IEX-1 is a direct substrate of ERK2; it is phosphorylated in vivo upon ERK activation, interacts specifically with phosphorylated ERKs (but not JNK or p38), and upon ERK-mediated phosphorylation acquires anti-apoptotic activity. Independently, IEX-1 potentiates ERK activation, with ERK-docking-site mutants abolishing this potentiation while phosphorylation-site mutants abolish survival signaling. Phosphorylation screening with active ERK2, in vivo phosphorylation assay, IEX-1 domain mutants (ERK phosphoacceptor and docking site mutations), cell death assays The EMBO journal High 12356731
2006 B56-containing PP2A holoenzymes dephosphorylate ERK; IEX-1 binds directly to B56 subunits and to phosphorylated ERK, enabling ERK to transphosphorylate B56 at a conserved Ser/Pro site, which triggers dissociation of B56 from the PP2A catalytic subunit, thereby inhibiting ERK dephosphorylation and sustaining ERK activity. RNAi of B56 subunits, overexpression, co-immunoprecipitation, in vitro phosphatase assay, ERK phosphorylation assays, domain mutants The EMBO journal High 16456541
2007 IEX-1 inhibits B56-PP2A-mediated dephosphorylation of Akt on both Thr308 and Ser473, thereby sustaining Akt activity in an ERK-dependent manner; an IEX-1 mutant deficient in ERK binding had no effect on Akt, and B56β/γ mutants that cannot be phosphorylated by the ERK·IEX-1 complex showed enhanced ability to dephosphorylate Akt. Overexpression and RNAi of IEX-1 and B56 subunits, ERK dominant-negative mutants, phospho-Akt immunoblot, ERK-binding-deficient IEX-1 mutant The Journal of biological chemistry High 17200115
2001 IEX-1 overexpression in HeLa cells accelerates cell cycle progression and increases susceptibility to apoptosis induced by death-receptor ligands or etoposide; NF-κB-dependent induction of IEX-1 does not mediate NF-κB's anti-apoptotic effect but instead modulates cell cycle. Inducible IEX-1 expression vector, antisense hammerhead ribozyme knockdown, apoptosis and cell cycle assays Oncogene Medium 11244505
2002 Transgenic expression of IEX-1 specifically in T cells impairs Fas- and TCR/CD3-induced apoptosis, extends the effector phase of immune responses, and leads to lupus-like autoimmunity and T-cell lymphomas in aging mice, demonstrating a T-cell-specific anti-apoptotic role in vivo. Eμ-IEX-1 transgenic mice, T cell apoptosis assays (Fas/TCR ligation), immune response phenotyping, lymphoma analysis Proceedings of the National Academy of Sciences High 11782530 14534530
2003 IEX-1 attenuation of NF-κB activation involves inhibition of the 26S proteasome and altered IκBα turnover; IEX-1 overexpression decreases nuclear p65 accumulation and NF-κB reporter activity, while IEX-1 disruption by ribozymes increases NF-κB activity and decreases apoptotic sensitivity. Stable inducible IEX-1 overexpression, anti-IEX-1 hammerhead ribozyme knockdown, gel-shift and luciferase reporter assays, fluorometric proteasome assay, immunofluorescence for nuclear p65 Oncogene Medium 12761504
2007 IEX-1 directly binds the C-terminal transactivation domain of RelA/p65 (shown by GST pulldown and confirmed by endogenous co-immunoprecipitation), inhibits RelA/p65-dependent transactivation, reduces expression of anti-apoptotic NF-κB targets (Bcl-2, Bcl-xL, cIAP1, cIAP2), and associates with their promoters (ChIP assay). GST pulldown, co-immunoprecipitation, GAL4/luciferase reporter assay, chromatin immunoprecipitation (ChIP), deletion constructs of IEX-1 Biochimica et biophysica acta High 18191642
2008 IEX-1 targets the mitochondrial F1Fo-ATPase inhibitor (IF1) for degradation via interaction with the C-terminus of IF1, leading to acceleration of ATP hydrolysis, reduction of mitochondrial ROS production, and a metabolic shift from oxidative phosphorylation to glycolysis; IEX-1 knockout mice show stabilized IF1 and reduced mitochondrial ATPase activity in vivo. Co-immunoprecipitation, C-terminal truncation studies, siRNA knockdown of IF1, IEX-1 knockout mice, ATP hydrolysis assay, ROS measurement, metabolic assays Cell death and differentiation High 19096392
2005 IEX-1 localizes to distinct subnuclear structures in a nuclear-localization-sequence-dependent manner, partially co-localizes with PML nuclear bodies, physically interacts with PML (shown by co-immunoprecipitation), and is subject to nucleocytoplasmic shuttling via CRM1; loss of the NLS impairs pro-apoptotic but not anti-apoptotic function. Confocal microscopy of GFP-IEX-1 fusion protein, double immunofluorescence, leptomycin B treatment, co-immunoprecipitation with PML isoforms, NLS deletion mutant apoptosis assay The Journal of biological chemistry High 15855159
2006 IEX-1 anti- and pro-apoptotic activities map to distinct protein domains: a transmembrane-like hydrophobic region is critical for both functions; N-linked glycosylation sites, phosphorylation sites, and the C-terminus are required for anti-apoptotic but not pro-apoptotic activity; the nuclear localization sequence is required for pro-apoptotic but not anti-apoptotic activity; anti-apoptotic mutants all fail to suppress acute mitochondrial ROS production. Site-directed mutagenesis of hydrophobic residues, glycosylation/phosphorylation sites, NLS; apoptosis assays; intracellular ROS measurement The Journal of biological chemistry High 16567805
2009 IEX-1 interacts with the anti-apoptotic protein MCL-1 (identified by yeast two-hybrid and confirmed by endogenous co-immunoprecipitation); IEX-1-induced caspase-dependent apoptosis requires BIM but not NOXA or PUMA, and is modulated by MCL-1 expression levels. Yeast two-hybrid screen, co-immunoprecipitation in human cells, BIM/NOXA/PUMA knockout cells, caspase assay, mitochondrial membrane potential assay Biochemical and biophysical research communications Medium 19285955
2010 IEX-1 (IER3) interacts with MCL-1 and is required for ATM-dependent nuclear translocation of MCL-1 in response to DNA damage; IEX-1 is rapidly induced by γ-irradiation in an ATM-dependent manner; loss of IEX-1 prevents Mcl-1 nuclear accumulation, impairs Chk1 activation and G2 checkpoint arrest, and leads to genomic instability; proteasomal degradation of IEX-1 reverses Mcl-1 to the cytosol. IEX-1 knockdown/knockout, ATM inhibition, γ-irradiation, nuclear fractionation, co-immunoprecipitation, Chk1 phosphorylation assay, genomic instability assay Cell death and differentiation High 20467439
2013 TPO specifically activates ERK and NF-κB pathways in hematopoietic stem and progenitor cells; both pathways cooperate to induce IEX-1 upon DNA damage; IEX-1 forms a complex with phospho-ERK and the catalytic subunit of DNA-PK, which is necessary and sufficient for TPO-increased DNA-PK activation and NHEJ repair in mouse and human HSPCs. Signaling pathway inhibitors, IEX-1 knockdown and overexpression, co-immunoprecipitation of IEX-1/pERK/DNA-PKcs complex, NHEJ repair assay, DNA-PK phosphorylation assay Blood High 24184684
2012 IEX-1 deficiency promotes Th17 differentiation and impairs Th1 cell survival through increased mitochondrial ROS production following T cell activation; mitochondrial ROS augment B cell-activating transcription factor expression contributing to IL-17 production; ROS scavengers or mitochondria-specific antioxidants inhibit Th17 induction in IEX-1 KO mice. IEX-1 knockout mice, collagen-induced arthritis model, mitochondrial ROS measurement, N-acetylcysteine/mitoquinone treatment, flow cytometry for Th17/Th1, IL-17 ELISA Journal of immunology High 22798682
2013 IEX-1 modulates Nrf2 activity through the PI3K/Akt-Fyn pathway in colonic epithelial cells; IER3 deficiency (KO mice or shRNA knockdown) increases Nrf2 nuclear accumulation and target gene expression; IER3 deficiency reduces ROS and decreases apoptotic sensitivity; PI3K inhibition or Akt/Fyn knockdown abrogates IER3-deficiency-induced Nrf2 activation. Ier3 knockout mice, shRNA knockdown, IER3 overexpression, Nrf2 nuclear fractionation, Nrf2 target gene qPCR, PI3K inhibitor, siRNA knockdown of Akt and Fyn, ROS measurement, clonogenicity assay The Journal of biological chemistry High 24311782
2014 IER3 sustains ERK1/2 phosphorylation in pancreatic cancer cells by inhibiting PP2A phosphatase activity; IER3 expression is required for KrasG12D-driven PanIN and PDAC development in vivo, and IER3-deficient KrasG12D mice show delayed PanIN and PDAC formation. IER3 overexpression and knockdown in human pancreatic cancer cells, PP2A phosphatase activity assay, IER3/KrasG12D double mutant mice, immunohistochemistry for pERK1/2 and IER3 The Journal of clinical investigation High 25250570
2016 MDM2 is the E3 ubiquitin ligase responsible for IER3 ubiquitination and proteasomal degradation; polyubiquitination at lysine 60 of IER3 is essential; FHL2 acts as a scaffold protein that binds both IER3 and MDM2, facilitating efficient MDM2-mediated IER3 degradation. Co-immunoprecipitation of MDM2-IER3-FHL2 ternary complex, ubiquitination assay, K60 point mutant of IER3, FHL2/MDM2 siRNA knockdown, proteasome inhibitor, cell cycle assay Oncogene High 26973248
2003 In vascular smooth muscle cells, IEX-1 expression induced by NF-κB (abolished by IκBα overexpression) inhibits cell cycle progression by reducing p27kip1 degradation and Rb hyperphosphorylation; adenoviral IEX-1 overexpression in vivo reduces neointima formation after carotid artery injury. Northern and Western blot, adenoviral gene transfer, 3H-thymidine incorporation, p27kip1 immunoblot, Rb phosphorylation assay, in vivo carotid injury model, histomorphometry Circulation research High 14592999
2002 In cardiomyocytes, IEX-1 is induced by biomechanical strain in an NF-κB-dependent manner (abolished by IκBα overexpression), and adenoviral overexpression of IEX-1 abolishes cardiomyocyte hypertrophy induced by mechanical strain, phenylephrine, or endothelin-1 without affecting cell viability. In vivo pressure overload model, in vitro mechanical stimulation, adenoviral IEX-1 overexpression, IκBα overexpression, Northern/Western blot, hypertrophy readouts Circulation research Medium 11934837
2006 HSV-1 ICP27 stabilizes ARE-containing IEX-1 mRNA by activating the p38/MK2 MAPK pathway; ICP27 mutants deficient in p38 activation fail to stabilize IEX-1 mRNA, and the p38 inhibitor SB203580 abrogates IEX-1 mRNA stabilization, whereas the virion host shutoff protein (vhs) plays little role. Panel of ICP27 mutant HSV-1 isolates, actinomycin D mRNA stability assay, p38 inhibitor SB203580, Northern blot/real-time PCR Journal of virology Medium 16973576
2015 TAp73β transcriptionally activates IER3 in cervical cancer cells (whereas p53 and TAp63 do not); IER3 silencing suppresses TAp73β-induced apoptosis but not p53-induced apoptosis; etoposide upregulates TAp73β and IER3 through c-Abl kinase, and etoposide chemosensitivity is largely determined by the TAp73β-IER3 axis. Luciferase reporter assay, IER3 siRNA knockdown, p53/TAp63/TAp73β expression vectors, c-Abl inhibition, apoptosis assay Scientific reports Medium 25666857
2016 IEX-1 deficiency induces browning of white adipose tissue and promotes alternative activation of adipose macrophages, leading to increased thermogenic gene expression (e.g., UCP1), enhanced thermogenesis, and resistance to high-fat diet-induced obesity; IEX-1 is a negative regulator of WAT browning. IEX-1 knockout mice, high-fat diet feeding, gene expression profiling of thermogenic genes, energy expenditure measurement, macrophage polarization assay Scientific reports Medium 27063893
2016 MCPIP1 RNase interacts with IER3 mRNA via a stem-loop structure in the IER3 3'UTR and degrades it; deletion of the stem-loop abolishes MCPIP1-mediated destabilization; IF-combined smRNA FISH confirms co-localization of MCPIP1 protein with IER3 mRNA in cells; RNA immunoprecipitation confirms MCPIP1-IER3 mRNA interaction in vivo. Dual luciferase assay with IER3 3'UTR constructs, deletion mutagenesis of stem-loop, immunofluorescence-combined single-molecule RNA FISH, RNA immunoprecipitation Biology open Medium 27256408
2014 IL-1β-induced IER3 expression is mediated through ERK1/2 and transcription factor Elk-1; Elk-1 is phosphorylated by ERK and binds ETS5/6 sequences in the IER3 promoter; mutation of ETS5/6 abolishes IL-1β-induced and constitutively active Elk-1-driven IER3 promoter activity. Promoter-luciferase reporter assay, EMSA, site-directed mutagenesis of ETS binding sites, constitutively active Elk-1 (Elk-VP16), Elk-1 phosphorylation immunoblot Cytokine Medium 25066273
2008 IEX-1 overexpression in HeLa cells induces astrocytic differentiation phenotype in U87-MG glioma cells (increased S-100 and GFAP); IEX-1 acts downstream of PKA in cAMP-induced astrocytic differentiation, as antisense IEX-1 abolishes dbcAMP-induced morphological changes, while IEX-1-induced differentiation is not blocked by PKA inhibitor H89. IEX-1 transfection, antisense RNA disruption, dbcAMP stimulation, PKA inhibitor H89, GFAP/S-100 immunoblot, morphological analysis Journal of cellular biochemistry Low 16960879
2016 EGR2 is a transcription factor downstream of gonadotropins that directly transactivates IER3 in granulosa cells; EGR2 binds EGR-binding elements in the IER3 promoter (confirmed by EMSA, ChIP, luciferase assay); EGR2-promoted cell survival requires IER3 as a mediator, and EGR2 also regulates MCL-1 expression. Luciferase reporter assay, EMSA, ChIP, EGR2 overexpression and knockdown, IER3 knockdown, cell survival assay Biochemical and biophysical research communications Medium 27890615
2021 TRAIL physically interacts with IER3 (shown by co-immunoprecipitation and immunofluorescence co-localization) in hepatocellular carcinoma cells; TRAIL and IER3 cooperate to inhibit Wnt/β-catenin signaling, thereby inducing apoptosis and reducing proliferation and migration both in vitro and in vivo. Co-immunoprecipitation, immunofluorescence, Wnt/β-catenin pathway reporter/immunoblot, apoptosis/proliferation/migration assays, xenograft model Cancer cell international Low 33472635

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2008 PRG-1 and 21U-RNAs interact to form the piRNA complex required for fertility in C. elegans. Molecular cell 458 18571452
1998 IEX-1L, an apoptosis inhibitor involved in NF-kappaB-mediated cell survival. Science (New York, N.Y.) 385 9703517
2008 A C. elegans Piwi, PRG-1, regulates 21U-RNAs during spermatogenesis. Current biology : CB 222 18501605
2006 B56-containing PP2A dephosphorylate ERK and their activity is controlled by the early gene IEX-1 and ERK. The EMBO journal 185 16456541
2010 Role of the immediate early response 3 (IER3) gene in cellular stress response, inflammation and tumorigenesis. European journal of cell biology 157 21112119
2009 Synaptic PRG-1 modulates excitatory transmission via lipid phosphate-mediated signaling. Cell 122 19766573
2003 Roles of the stress-induced gene IEX-1 in regulation of cell death and oncogenesis. Apoptosis : an international journal on programmed cell death 110 12510147
2003 A new phospholipid phosphatase, PRG-1, is involved in axon growth and regenerative sprouting. Nature neuroscience 110 12730698
2002 IEX-1: a new ERK substrate involved in both ERK survival activity and ERK activation. The EMBO journal 98 12356731
1988 Structure elucidation of two differentiation inducing factors (DIF-2 and DIF-3) from the cellular slime mould Dictyostelium discoideum. The Biochemical journal 91 3355503
2002 Impaired apoptosis, extended duration of immune responses, and a lupus-like autoimmune disease in IEX-1-transgenic mice. Proceedings of the National Academy of Sciences of the United States of America 86 11782530
2007 Inhibition of B56-containing protein phosphatase 2As by the early response gene IEX-1 leads to control of Akt activity. The Journal of biological chemistry 78 17200115
2018 LncRNA GAS5 confers the radio sensitivity of cervical cancer cells via regulating miR-106b/IER3 axis. International journal of biological macromolecules 77 30579899
2001 Expression of the NF-kappa B target gene IEX-1 (p22/PRG1) does not prevent cell death but instead triggers apoptosis in Hela cells. Oncogene 77 11244505
2012 Enhanced Th17 differentiation and aggravated arthritis in IEX-1-deficient mice by mitochondrial reactive oxygen species-mediated signaling. Journal of immunology (Baltimore, Md. : 1950) 68 22798682
2010 ATM-dependent expression of IEX-1 controls nuclear accumulation of Mcl-1 and the DNA damage response. Cell death and differentiation 64 20467439
2001 IEX-1, an immediate early gene, increases the rate of apoptosis in keratinocytes. Oncogene 63 11753682
1998 The promoter of human p22/PACAP response gene 1 (PRG1) contains functional binding sites for the p53 tumor suppressor and for NFkappaB. FEBS letters 61 9781666
2008 IEX-1 targets mitochondrial F1Fo-ATPase inhibitor for degradation. Cell death and differentiation 59 19096392
2013 Thrombopoietin promotes NHEJ DNA repair in hematopoietic stem cells through specific activation of Erk and NF-κB pathways and their target, IEX-1. Blood 55 24184684
1997 Identification of PRG1, a novel progestin-responsive gene with sequence homology to 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase. Molecular endocrinology (Baltimore, Md.) 53 9092801
2002 Identification of IEX-1 as a biomechanically controlled nuclear factor-kappaB target gene that inhibits cardiomyocyte hypertrophy. Circulation research 52 11934837
2013 Modulation of nuclear factor E2-related factor-2 (Nrf2) activation by the stress response gene immediate early response-3 (IER3) in colonic epithelial cells: a novel mechanism of cellular adaption to inflammatory stress. The Journal of biological chemistry 50 24311782
2006 Distinct domains for anti- and pro-apoptotic activities of IEX-1. The Journal of biological chemistry 49 16567805
2019 LncRNA H19 over-expression inhibited Th17 cell differentiation to relieve endometriosis through miR-342-3p/IER3 pathway. Cell & bioscience 47 31636893
2002 Divergent regulation of the growth-promoting gene IEX-1 by the p53 tumor suppressor and Sp1. The Journal of biological chemistry 46 11844788
2016 Molecular cause and functional impact of altered synaptic lipid signaling due to a prg-1 gene SNP. EMBO molecular medicine 45 26671989
2007 The apoptosis-inducing effect of gastrin on colorectal cancer cells relates to an increased IEX-1 expression mediating NF-kappa B inhibition. Oncogene 44 17704804
2002 Synergistic and opposing regulation of the stress-responsive gene IEX-1 by p53, c-Myc, and multiple NF-kappaB/rel complexes. Oncogene 44 12360408
2016 PRG-1 Regulates Synaptic Plasticity via Intracellular PP2A/β1-Integrin Signaling. Developmental cell 43 27453502
2014 IER3 supports KRASG12D-dependent pancreatic cancer development by sustaining ERK1/2 phosphorylation. The Journal of clinical investigation 43 25250570
2000 Respiratory syncytial virus infection induces expression of the anti-apoptosis gene IEX-1L in human respiratory epithelial cells. The Journal of infectious diseases 43 10720500
1996 PRG1: a novel early-response gene transcriptionally induced by pituitary adenylate cyclase activating polypeptide in a pancreatic carcinoma cell line. Cancer research 43 8653710
1998 A novel immediate early response gene, IEX-1, is induced by ultraviolet radiation in human keratinocytes. Biochemical and biophysical research communications 42 9878538
2001 Expression of an immediate early gene, IEX-1, in human tissues. Histochemistry and cell biology 41 11455449
2005 p73beta-Mediated apoptosis requires p57kip2 induction and IEX-1 inhibition. Cancer research 40 15781630
2003 The stress-inducible immediate-early responsive gene IEX-1 is activated in cells infected with herpes simplex virus 1, but several viral mechanisms, including 3' degradation of its RNA, preclude expression of the gene. Journal of virology 40 12743274
1998 The proliferation-associated early response gene p22/PRG1 is a novel p53 target gene. Oncogene 38 9627114
2003 The early response gene IEX-1 attenuates NF-kappaB activation in 293 cells, a possible counter-regulatory process leading to enhanced cell death. Oncogene 37 12761504
2009 Rearrangements and amplification of IER3 (IEX-1) represent a novel and recurrent molecular abnormality in myelodysplastic syndromes. Cancer research 36 19773435
1998 Regulation of a novel immediate early response gene, IEX-1, in keratinocytes by 1alpha,25-dihydroxyvitamin D3. Biochemical and biophysical research communications 36 9791001
2015 IER3 is a crucial mediator of TAp73β-induced apoptosis in cervical cancer and confers etoposide sensitivity. Scientific reports 33 25666857
2003 Biomechanically induced gene iex-1 inhibits vascular smooth muscle cell proliferation and neointima formation. Circulation research 33 14592999
2001 Functional disruption of IEX-1 expression by concatemeric hammerhead ribozymes alters growth properties of 293 cells. FEBS letters 33 11311240
2014 MiR-30a upregulates BCL2A1, IER3 and cyclin D2 expression by targeting FOXL2. Oncology letters 32 25621074
2007 IEX-1 directly interferes with RelA/p65 dependent transactivation and regulation of apoptosis. Biochimica et biophysica acta 32 18191642
1999 Human PACAP response gene 1 (p22/PRG1): proliferation-associated expression in pancreatic carcinoma cells. Pancreas 32 10231843
1999 The putative apoptosis inhibitor IEX-1L is a mutant nonspliced variant of p22(PRG1/IEX-1) and is not expressed in vivo. Biochemical and biophysical research communications 32 10448082
1998 Genomic organization, promoter cloning, and chromosomal localization of the Dif-2 gene. Biochemical and biophysical research communications 32 9588170
2016 Scaffold protein FHL2 facilitates MDM2-mediated degradation of IER3 to regulate proliferation of cervical cancer cells. Oncogene 30 26973248
2020 Identification of the ABCC4, IER3, and CBFA2T2 candidate genes for resistance to paratuberculosis from sequence-based GWAS in Holstein and Normande dairy cattle. Genetics, selection, evolution : GSE 29 32183688
2014 The role of Iex-1 in the pathogenesis of venous neointimal hyperplasia associated with hemodialysis arteriovenous fistula. PloS one 29 25036043
2010 Identification and characterization of PRG-1 as a neuronal calmodulin-binding protein. The Biochemical journal 29 20653564
2008 ZnT-1, ZnT-3, CaMK II, PRG-1 expressions in hippocampus following neonatal seizure-induced cognitive deficit in rats. Toxicology letters 29 19059322
1994 Mutations in PRG1, a yeast proteasome-related gene, cause defects in nuclear division and are suppressed by deletion of a mitotic cyclin gene. Proceedings of the National Academy of Sciences of the United States of America 29 8134345
2006 Herpes simplex virus ICP27 is required for virus-induced stabilization of the ARE-containing IEX-1 mRNA encoded by the human IER3 gene. Journal of virology 28 16973576
2003 Development of T-cell lymphomas in Emu-IEX-1 mice. Oncogene 28 14534530
2010 Ablation of gly96/immediate early gene-X1 (gly96/iex-1) aggravates DSS-induced colitis in mice: role for gly96/iex-1 in the regulation of NF-kappaB. Inflammatory bowel diseases 27 19714745
2021 PRG-1 relieves pain and depressive-like behaviors in rats of bone cancer pain by regulation of dendritic spine in hippocampus. International journal of biological sciences 26 34671215
2012 Resistance of Sézary cells to TNF-α-induced apoptosis is mediated in part by a loss of TNFR1 and a high level of the IER3 expression. Experimental dermatology 25 22417305
2005 Elevated blood pressure and cardiac hypertrophy after ablation of the gly96/IEX-1 gene. Journal of applied physiology (Bethesda, Md. : 1985) 25 16166241
2011 Clinical significance of IEX-1 expression in ovarian carcinoma. Ultrastructural pathology 23 22085302
2002 Characterization of a novel hexameric repeat DNA sequence in the promoter of the immediate early gene, IEX-1, that mediates 1alpha,25-dihydroxyvitamin D(3)-associated IEX-1 gene repression. Oncogene 22 12032839
2017 Altered synaptic phospholipid signaling in PRG-1 deficient mice induces exploratory behavior and motor hyperactivity resembling psychiatric disorders. Behavioural brain research 21 28843862
2016 Dual PI3K/ERK inhibition induces necroptotic cell death of Hodgkin Lymphoma cells through IER3 downregulation. Scientific reports 19 27767172
2016 IEX-1 deficiency induces browning of white adipose tissue and resists diet-induced obesity. Scientific reports 18 27063893
2013 Stress-induced hematopoietic failure in the absence of immediate early response gene X-1 (IEX-1, IER3). Haematologica 18 24056813
2009 IEX-1-induced cell death requires BIM and is modulated by MCL-1. Biochemical and biophysical research communications 18 19285955
2003 A novel vitamin D-regulated immediate-early gene, IEX-1, alters cellular growth and apoptosis. Recent results in cancer research. Fortschritte der Krebsforschung. Progres dans les recherches sur le cancer 17 12899517
2021 TRAIL promotes hepatocellular carcinoma apoptosis and inhibits proliferation and migration via interacting with IER3. Cancer cell international 16 33472635
2017 Dysregulated IER3 Expression is Associated with Enhanced Apoptosis in Titin-Based Dilated Cardiomyopathy. International journal of molecular sciences 16 28353642
2012 IEX-1 deficiency protects against colonic cancer. Molecular cancer research : MCR 16 22550081
2014 Mitochondrial anti-oxidant protects IEX-1 deficient mice from organ damage during endotoxemia. International immunopharmacology 15 25466275
2005 Immediate early gene X1 (IEX-1) is organized in subnuclear structures and partially co-localizes with promyelocytic leukemia protein in HeLa cells. The Journal of biological chemistry 15 15855159
2011 IEX-1 suppresses apoptotic damage in human intestinal epithelial Caco-2 cells induced by co-culturing with macrophage-like THP-1 cells. Bioscience reports 14 21250941
1991 A possible role for DIF-2 in the formation of stalk cells during Dictyostelium development. Developmental biology 14 1850369
2008 Prg1 is regulated by the basic helix-loop-helix transcription factor Math2. Journal of neurochemistry 13 18643870
2005 Herpes simplex virus infection stabilizes cellular IEX-1 mRNA. Journal of virology 13 15767410
2004 Immediate early gene X-1 (IEX-1), a hydroxytamoxifen regulated gene with increased stimulation in MCF-7 derived resistant breast cancer cells. The Journal of steroid biochemistry and molecular biology 13 15120418
2016 IF-combined smRNA FISH reveals interaction of MCPIP1 protein with IER3 mRNA. Biology open 12 27256408
2018 Additive antitumor effect of arsenic trioxide combined with intravesical bacillus Calmette-Guerin immunotherapy against bladder cancer through blockade of the IER3/Nrf2 pathway. Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie 11 30257321
2017 Serum Levels of TIMP-3, LIPC, IER3, and SLC16A8 in CFH-Negative AMD Cases. Journal of cellular biochemistry 11 27966779
2016 EGR2 is a gonadotropin-induced survival factor that controls the expression of IER3 in ovarian granulosa cells. Biochemical and biophysical research communications 11 27890615
2016 Activation of ERK/IER3/PP2A-B56γ-positive feedback loop in lung adenocarcinoma by allelic deletion of B56γ gene. Oncology reports 10 26986830
2007 Immediate early gene IEX-1 induces astrocytic differentiation of U87-MG human glioma cells. Journal of cellular biochemistry 10 16960879
2024 Comprehensive analysis of bulk, single-cell RNA sequencing, and spatial transcriptomics revealed IER3 for predicting malignant progression and immunotherapy efficacy in glioma. Cancer cell international 9 39354533
2015 IER3 Promotes Expansion of Adipose Progenitor Cells in Response to Changes in Distinct Microenvironmental Effectors. Stem cells (Dayton, Ohio) 9 25827082
2008 Overexpression of immediate early gene X-1 (IEX-1) enhances gamma-radiation-induced apoptosis of human glioma cell line, U87-MG. Neuropathology : official journal of the Japanese Society of Neuropathology 9 18564103
2004 The expression of immediate early gene X-1 (IEX-1) is differentially induced by retinoic acids in NB4 and KG1 cells: possible implication in the distinct phenotype of retinoic acid-responsive and -resistant leukemic cells. Leukemia 9 15306824
2025 IER3: exploring its dual function as an oncogene and tumor suppressor. Cancer gene therapy 8 40090972
2017 Immediate Early Response Gene X-1 (IEX-1) Mediates Ischemic Preconditioning-Induced Cardioprotection in Rats. Oxidative medicine and cellular longevity 7 29213350
2022 PRG-1 prevents neonatal stimuli-induced persistent hyperalgesia and memory dysfunction via NSF/Glu/GluR2 signaling. iScience 6 36093041
2017 Molecular characterization of the bovine IER3 gene: Down-regulation of IL-8 by blocking NF-κB activity mediated by IER3 overexpression in MDBK cells infected with bovine viral diarrhea virus-1. Molecular immunology 6 29101849
2016 Expression and Functions of Immediate Early Response Gene X-1 (IEX-1) in Rheumatoid Arthritis Synovial Fibroblasts. PloS one 5 27736946
2015 NT-3 protein levels are enhanced in the hippocampus of PRG1-deficient mice but remain unchanged in PRG1/LPA2 double mutants. Neuroscience letters 5 26687273
2014 Transcription factor Elk-1 participates in the interleukin-1β-dependent regulation of expression of immediate early response gene 3 (IER3). Cytokine 5 25066273
2015 Expression of IER3 in primary hepatocarcinoma: correlation with clinicopathological parameters. Asian Pacific journal of cancer prevention : APJCP 4 25684507
2014 The influences of PRG-1 on the expression of small RNAs and mRNAs. BMC genomics 4 24884413
2025 Exercise-Mediated Mechanical Stress Promotes Osteogenic Differentiation of BMSCs Through Upregulation of Lactylation via the IER3/LDHB Axis. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 3 40244862
2024 Unveiling the glycolysis in sepsis: Integrated bioinformatics and machine learning analysis identifies crucial roles for IER3, DSC2, and PPARG in disease pathogenesis. Medicine 3 39331858