Affinage

IER3

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

Length
156 aa
Mass
16.9 kDa
Annotated
2026-06-10
95 papers in source corpus 38 papers cited in narrative 37 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 9/9 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

IER3 (IEX-1) is a stress- and NF-κB-inducible immediate-early protein that couples mitogenic and survival signaling to apoptosis, redox balance, and DNA-damage responses, with a net pro- or anti-apoptotic outcome that is strongly context-dependent (PMID:9703517, PMID:11244505). Its expression is directly driven at the promoter level by NF-κB/Rel complexes, synergized by p53 and antagonized by c-Myc, and is further controlled by VDR/RXRα, Sp1, Elk-1, EGR2, and TAp73β, as well as post-transcriptionally by MCPIP1-mediated degradation of its 3'UTR (PMID:12360408, PMID:12032839, PMID:25066273, PMID:27890615, PMID:25666857, PMID:27256408). A central mechanism is its role in MAPK signaling: IER3 is a direct ERK2 substrate that binds phospho-ERK and the B56 regulatory subunits of PP2A, enabling ERK-mediated phosphorylation of B56 within an IER3–B56–ERK complex, which dissociates B56 from the PP2A catalytic subunit and thereby sustains both ERK and Akt phosphorylation (PMID:12356731, PMID:16456541, PMID:17200115). Through sustained ERK signaling and PP2A inhibition, IER3 enhances KrasG12D-driven pancreatic oncogenesis (PMID:25250570). IER3 directly binds the transactivation domain of RelA/p65 to attenuate NF-κB-dependent transcription of anti-apoptotic genes, constituting a negative-feedback loop (PMID:18191642, PMID:12761504). At mitochondria it targets the F1Fo-ATPase inhibitor IF1 for degradation, promoting ATP hydrolysis and limiting ROS production, and IER3 deficiency shifts cells toward glycolysis and elevated mitochondrial ROS (PMID:19096392, PMID:22798682). In the DNA-damage response, ATM-induced IER3 controls nuclear MCL-1 accumulation and Chk1-dependent G2 checkpoint arrest, and forms a complex with phospho-ERK and DNA-PK to promote NHEJ repair (PMID:20467439, PMID:24184684). IER3 also tunes Nrf2 antioxidant signaling through the PI3K/Akt–Fyn axis (PMID:24311782). In vivo, IER3 limits T-cell apoptosis and constrains Th17 differentiation by suppressing mitochondrial ROS, with transgenic gain-of-function producing lupus-like autoimmunity and knockout exacerbating arthritis (PMID:11782530, PMID:22798682).

Mechanistic history

Synthesis pass · year-by-year structured walk · 15 steps
  1. 1998 Medium

    Established IER3 as an NF-κB-driven anti-apoptotic effector downstream of death-receptor signaling, defining its place in the survival arm of TNF biology.

    Evidence Antisense and overexpression in Jurkat and NF-κB-deficient cells with apoptosis readout

    PMID:9703517

    Open questions at the time
    • The IEX-1L variant used was later shown non-physiological
    • No molecular mechanism for protection defined
    • Context-dependence of pro- vs anti-apoptotic effect not yet appreciated
  2. 1999 Medium

    Corrected the record by showing IEX-1L is a non-spliced mutant transcript not expressed in vivo, clarifying that endogenous spliced IER3 is the functional species.

    Evidence RT-PCR with direct sequencing of nuclear/cytoplasmic RNA fractions from Jurkat cells

    PMID:10448082

    Open questions at the time
    • Single lab
    • Did not address function of correctly spliced IER3
  3. 2001 Medium

    Revealed that IER3 can be pro-apoptotic and pro-proliferative in epithelial cells, exposing the cell-type dependence of its function rather than a single fixed role.

    Evidence Inducible overexpression and antisense ribozyme in HeLa with caspase and cell cycle assays; nuclear localization imaging in keratinocytes

    PMID:11244505 PMID:9791001 PMID:9878538

    Open questions at the time
    • Molecular basis of context switch unknown
    • Nuclear function of IER3 not mechanistically defined
  4. 2002 High

    Identified IER3 as a direct ERK2 substrate whose phosphorylation confers survival and whose ERK association potentiates ERK activation, linking it to MAPK signaling.

    Evidence In vitro kinase assay, in vivo phosphorylation, reciprocal co-IP with phospho-ERK, phosphoacceptor/docking mutants

    PMID:12356731

    Open questions at the time
    • Downstream effector of phospho-IER3 not yet identified
    • How ERK association potentiates ERK was unexplained
  5. 2002 High

    Mapped the transcriptional control of IER3, showing combinatorial regulation by NF-κB/Rel, p53, c-Myc, Sp1, and VDR/RXRα.

    Evidence EMSA, promoter/luciferase reporters, ChIP in living cells across multiple studies

    PMID:11844788 PMID:12032839 PMID:12360408

    Open questions at the time
    • Cell-type specificity of competing inputs not resolved
    • Quantitative contribution of each factor unclear
  6. 2002 High

    Demonstrated in vivo gain-of-function consequences, showing transgenic IER3 impairs T-cell apoptosis and drives lupus-like autoimmunity, establishing physiological relevance.

    Evidence Eμ-IEX-1 transgenic mice with immune challenge, flow cytometry, apoptosis assays

    PMID:11782530

    Open questions at the time
    • Molecular target mediating T-cell survival not defined here
  7. 2003 High

    Defined IER3 as a counter-regulatory negative-feedback brake on NF-κB and as an anti-hypertrophic/anti-proliferative effector of mechanical stress.

    Evidence Bidirectional manipulation with reporter, proteasome, and IκBα epistasis assays in HEK293, cardiomyocytes, and vascular smooth muscle

    PMID:11934837 PMID:12761504 PMID:14592999

    Open questions at the time
    • Mechanism of proteasome inhibition unclear
    • Direct molecular target within NF-κB pathway not yet RelA
  8. 2006 High

    Provided the core biochemical mechanism: IER3 enables ERK to phosphorylate PP2A-B56, dissociating it from the catalytic subunit to sustain ERK activation, and dissected separable structural determinants of its pro- and anti-apoptotic activities.

    Evidence RNAi, B56 co-IP, in-complex in vitro phosphorylation, phospho-site mutagenesis; systematic domain mutagenesis with apoptosis/ROS readouts

    PMID:16456541 PMID:16567805

    Open questions at the time
    • Akt arm not yet connected
    • Structural basis of B56-ERK-IER3 ternary complex unknown
  9. 2007 High

    Extended the PP2A-B56 mechanism to sustained Akt activation and identified direct IER3–RelA/p65 binding that represses anti-apoptotic NF-κB target genes.

    Evidence Dominant-negative/binding-deficient mutants with phospho-Akt blots; GST-pulldown, endogenous co-IP, GAL4 reporter, and ChIP of Bcl-2/Bcl-xL/cIAP promoters

    PMID:17200115 PMID:18191642

    Open questions at the time
    • Selectivity for B56 versus other PP2A B subunits in vivo
    • How nuclear RelA binding integrates with cytoplasmic ERK/Akt role
  10. 2009 High

    Connected IER3 to the mitochondrial apoptotic machinery via direct IF1 degradation (controlling ROS and ATP hydrolysis) and MCL-1 binding with BIM-dependent apoptosis.

    Evidence IF1 binding/degradation with KO mouse metabolic readouts; yeast two-hybrid and co-IP for MCL-1 with BIM/NOXA/PUMA siRNA epistasis

    PMID:19096392 PMID:19285955

    Open questions at the time
    • How IF1 binding leads to its degradation mechanistically unclear
    • MCL-1 interaction surface and stoichiometry undefined
  11. 2010 High

    Placed IER3 in the ATM-dependent DNA-damage response, controlling nuclear MCL-1 trafficking, Chk1 activation, G2 arrest, and genomic stability.

    Evidence γ-irradiation, ATM and proteasome inhibitors, subcellular fractionation, Chk1 phospho and genomic instability assays with IER3 loss-of-function

    PMID:20467439

    Open questions at the time
    • How IER3 mediates MCL-1 nuclear import not defined
    • Link between nuclear MCL-1 and checkpoint mechanistically incomplete
  12. 2013 High

    Showed IER3 directly promotes NHEJ via a phospho-ERK–DNA-PK complex and modulates Nrf2 antioxidant output through the PI3K/Akt-Fyn axis, broadening its DNA-repair and redox roles.

    Evidence TPO pathway analysis with IER3/pERK/DNA-PK co-IP and NHEJ assay in HSPCs; KO colitis model with PI3K/Akt/Fyn pharmacological and siRNA epistasis

    PMID:24184684 PMID:24311782

    Open questions at the time
    • Whether DNA-PK and B56-PP2A mechanisms are coupled unknown
    • Direct vs indirect effect on Fyn localization unresolved
  13. 2014 High

    Demonstrated oncogenic cooperation in vivo, with IER3-sustained ERK signaling accelerating KrasG12D-driven pancreatic carcinogenesis, and mapped additional transcriptional inputs (Elk-1).

    Evidence Compound IER3-deficient × KrasG12D mice with PP2A activity assays and IHC; Elk-1 promoter mutagenesis and ChIP

    PMID:25066273 PMID:25250570

    Open questions at the time
    • Therapeutic targetability of the IER3-PP2A node untested
    • Generalizability beyond pancreatic context
  14. 2016 Medium

    Established how IER3 protein levels are set, identifying MDM2 as the E3 ligase ubiquitinating Lys60 with FHL2 as scaffold, and MCPIP1 as an RNase degrading IER3 mRNA.

    Evidence Co-IP, ubiquitination assay, K60R mutagenesis, MDM2/FHL2 knockdown; luciferase, smFISH, and RIP for MCPIP1-3'UTR interaction

    PMID:26973248 PMID:27256408

    Open questions at the time
    • Signals controlling MDM2/FHL2 recruitment to IER3 unknown
    • Physiological triggers of MCPIP1-mediated turnover undefined
  15. 2025 Medium

    Recent work links IER3 to ferroptosis suppression and senescence control through AKT/GSK3β-NRF2 and PARL-PRDX5 axes, and reinforces context-dependent oncogenic roles via Wnt/β-catenin.

    Evidence Bidirectional manipulation with pathway rescue in NSCLC; KO mouse, IER3-PARL co-IP and PRDX5 fractionation in renal cells; co-IP and reporter assays in HCC and OSCC

    PMID:30472635 PMID:40128149 PMID:41359162 PMID:41581578 PMID:42209919

    Open questions at the time
    • Several mechanisms rest on single-lab co-IP/reporter without mutagenesis
    • Whether ferroptosis and senescence axes converge on the same IER3 redox function unclear

Open questions

Synthesis pass · forward-looking unresolved questions
  • How IER3's many context-specific activities (PP2A inhibition, IF1/MCL-1 binding, DNA-PK complex, RelA repression) are selected and coordinated within a single cell remains unresolved, as does the structural basis for its multiple protein interactions.
  • No structural model of IER3 or its complexes
  • Determinants of the pro- vs anti-apoptotic switch not mechanistically defined
  • Integration of cytoplasmic signaling and nuclear/DNA-repair roles unknown

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0098772 molecular function regulator activity 4 GO:0060089 molecular transducer activity 2 GO:0140110 transcription regulator activity 2
Localization
GO:0005634 nucleus 3 GO:0005739 mitochondrion 2 GO:0005829 cytosol 2 GO:0005730 nucleolus 1
Pathway
R-HSA-162582 Signal Transduction 4 R-HSA-5357801 Programmed Cell Death 4 R-HSA-8953897 Cellular responses to stimuli 3 R-HSA-168256 Immune System 2 R-HSA-73894 DNA Repair 2 R-HSA-392499 Metabolism of proteins 1
Partners
ATPIF1/IF1MAPK1/ERK2MCL1MDM2PARLPPP2R5/B56PRKDC/DNA-PKRELA
Complex memberships
IER3-B56-ERK (PP2A regulatory complex)IER3-pERK-DNA-PK (NHEJ complex)

Evidence

Reading pass · 37 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1998 IEX-1L (IER3) is transcriptionally induced by TNF in an NF-κB-dependent manner and its overexpression protects cells from Fas- or TNF-induced apoptosis; antisense IEX-1L sensitized cells to TNF-induced killing, placing IEX-1L downstream of NF-κB as an anti-apoptotic effector. Antisense transfection, overexpression in Jurkat cells, NF-κB deficient cell lines, apoptosis assays Science Medium 9703517
1999 IEX-1L is a mutant, non-spliced variant of IER3 not expressed in vivo; the only cytoplasmic functional transcript is regularly spliced IER3 mRNA. The apparent anti-apoptotic effects of IEX-1L overexpression represent transdominant negative inhibition of endogenous IER3. RT-PCR with direct DNA sequencing of nuclear and cytoplasmic RNA fractions from PMA-stimulated Jurkat cells; PCR of human genomic DNA Biochemical and Biophysical Research Communications Medium 10448082
2002 IER3 is a direct substrate of ERK2; it is phosphorylated in vivo upon ERK activation, interacts with phosphorylated ERK (but not JNK or p38), and ERK phosphorylation of IER3 confers its pro-survival activity. Separately, IER3–ERK association (independent of IER3 phosphorylation) potentiates ERK activation in response to growth factors. Phosphorylation screening with active ERK2 in vitro, in vivo phosphorylation assay, co-immunoprecipitation with phospho-ERK, IER3 phosphoacceptor and docking-site mutants, apoptosis assays The EMBO journal High 12356731
2002 IER3 transgenic expression in lymphocytes (Eμ-IEX-1 mice) impairs apoptosis of activated T cells triggered by Fas ligation or TCR/CD3 signaling, extends the effector-phase immune response, and leads to accumulation of effector/memory-like T cells and a lupus-like autoimmune disease. Transgenic mouse model (Eμ-IEX-1), in vivo immune challenge, flow cytometry, apoptosis assays PNAS High 11782530
2001 In HeLa cells, IER3 overexpression augments susceptibility to apoptosis induced by death-receptor ligands or etoposide, and accelerates cell cycle progression; antisense ribozyme-mediated knockdown reduces apoptotic sensitivity and slows cell cycle, demonstrating a pro-apoptotic and pro-proliferative role in this context. Inducible overexpression vector, antisense hammerhead ribozyme, caspase activity assays, cell cycle analysis Oncogene Medium 11244505
2001 IER3 protein localizes predominantly to the nucleus of keratinocytes; 1α,25-dihydroxyvitamin D3 translocates IER3 from nucleus to perinuclear region/cytoplasm, correlating with growth arrest. Fluorescent antibody and GFP-fusion protein microscopy in keratinocytes, vitamin D3 treatment Biochemical and Biophysical Research Communications Medium 9791001 9878538
2002 IER3 expression is directly regulated at the promoter level by NF-κB/rel complexes (p65-c-Rel > p65-p50 > p50-p50), synergized by p53 and strongly inhibited by c-Myc; binding of endogenous p53, c-Myc, p50, p65, and c-Rel to the IER3 promoter was confirmed in living cells. EMSA, promoter/luciferase reporter assay, chromatin immunoprecipitation (ChIP) Oncogene High 12360408
2002 p53 and Sp1 have opposite effects on IER3 promoter activity: Sp1 activates a basal element, while p53 represses IER3 promoter activity through a p53 response element in keratinocytes. Systematic promoter truncation/luciferase assay, EMSA Journal of Biological Chemistry Medium 11844788
2002 IER3 overexpression identifies iex-1 as an NF-κB-dependent biomechanical stress-inducible gene in cardiomyocytes; overexpression abolishes cardiomyocyte hypertrophy induced by mechanical strain, phenylephrine, or endothelin-1, while IκBα overexpression blocks strain-mediated iex-1 induction. In vivo pressure-overload mouse model, primary cardiomyocyte mechanical stimulation, adenoviral IER3 gene transfer, IκBα overexpression Circulation Research Medium 11934837
2003 IER3 inhibits NF-κB activation by altering turnover of IκBα and phospho-IκBα and inhibiting 26S proteasome activity; conversely, ribozyme-mediated IER3 disruption increases NF-κB activity and accelerates IκBα degradation. IER3 thus acts as a counter-regulatory negative feedback on NF-κB. Stable inducible overexpression and anti-IER3 ribozyme in HEK-293 cells, gel-shift, luciferase reporter, fluorometric proteasome assay, nuclear p65 accumulation Oncogene Medium 12761504
2006 IER3 binds to B56 regulatory subunits of PP2A and to phospho-ERK independently; upon ERK phosphorylation of IER3, IER3 enhances phosphorylation of B56 at a conserved Ser/Pro site by ERK within the IER3-B56-ERK complex, causing dissociation of B56 from the PP2A catalytic subunit. This inhibits B56-PP2A-mediated ERK dephosphorylation and sustains ERK activation. RNAi of PP2A B subunits, overexpression of individual B subunits, co-immunoprecipitation, in vitro phosphorylation assay, B56 phospho-site mutagenesis The EMBO Journal High 16456541
2006 IER3 has distinct structural determinants for its anti- and pro-apoptotic activities: a transmembrane-like hydrophobic region is critical for both functions; N-linked glycosylation, phosphorylation sites, and C-terminal sequences are required for anti-apoptotic activity but not pro-apoptotic activity; the nuclear localization sequence is important for apoptosis but not for cell survival. Anti-apoptotic mutants uniformly fail to suppress acute intracellular ROS production. Site-directed and truncation mutagenesis, apoptosis assays, ROS measurement Journal of Biological Chemistry High 16567805
2007 IER3 specifically inhibits B56-containing PP2A (not other B-family PP2A) by enabling ERK-mediated phosphorylation of B56, which sustains Akt/PKB phosphorylation on both Thr308 and Ser473. An IER3 mutant deficient in ERK binding fails to activate Akt; B56 mutants that cannot be phosphorylated by ERK show enhanced ability to counteract IER3. Overexpression, RNAi, dominant-negative ERK mutants, phospho-Akt immunoblotting, B56 phospho-site mutagenesis, ERK-binding-deficient IER3 mutant Journal of Biological Chemistry High 17200115
2007 IER3 directly interacts with the C-terminal transactivation domain of RelA/p65 (via IER3's C-terminal region, shown by GST-pulldown and confirmed by co-immunoprecipitation of endogenous proteins), negatively regulates RelA/p65-dependent transactivation, and associates with the promoters of anti-apoptotic NF-κB target genes (Bcl-2, Bcl-xL, cIAP1, cIAP2) to reduce their expression. GST-pulldown, co-immunoprecipitation, GAL4/luciferase transactivation assay, ChIP, deletion constructs Biochimica et Biophysica Acta High 18191642
2008 IER3 targets the mitochondrial F1Fo-ATPase inhibitor protein IF1 for degradation via interaction with the C-terminus of IF1, promoting ATP hydrolysis and reducing ROS production. IER3-knockout mice show stabilized IF1 and reduced mitochondrial F1Fo-ATPase activity in vivo, and IER3-deficient cells exhibit a metabolic switch toward glycolysis. C-terminal truncation of IF1, siRNA knockdown of IF1, co-immunoprecipitation, measurement of ATP hydrolysis and ROS, IER3 knockout mouse model Cell Death and Differentiation High 19096392
2009 IER3 interacts with MCL-1 (identified by yeast two-hybrid and confirmed by endogenous co-immunoprecipitation); IER3-induced apoptosis is specifically dependent on BIM (not NOXA or PUMA) and is modulated by MCL-1 expression levels. Yeast two-hybrid, co-immunoprecipitation, siRNA knockdown of BIM/NOXA/PUMA, overexpression apoptosis assay, mitochondrial membrane potential measurement Biochemical and Biophysical Research Communications Medium 19285955
2010 ATM-dependent induction of IER3 following DNA damage controls nuclear accumulation of MCL-1; IER3 is required for Mcl-1 nuclear translocation, and proteasomal degradation of IER3 triggers Mcl-1 return to the cytoplasm. Loss of IER3 leads to genomic instability, increased sensitivity to genotoxic stress, and impaired Chk1 activation and G2 checkpoint arrest. γ-irradiation, ATM inhibitor, proteasome inhibitor, subcellular fractionation, Chk1 phosphorylation assay, genomic instability assay, IER3 loss-of-function Cell Death and Differentiation High 20467439
2005 IER3 localizes to distinct subnuclear structures in HeLa cells in an NLS-dependent manner; it partially co-localizes with PML nuclear bodies, physically interacts with PML isoforms III and IV, and is shuttled to and from the nucleus via CRM1-dependent nuclear export. Confocal microscopy with GFP-IER3 fusion and endogenous protein, NLS deletion mutant, leptomycin B treatment, PML overexpression, co-immunoprecipitation Journal of Biological Chemistry Medium 15855159
2012 IER3 deficiency promotes Th17 cell differentiation and compromises Th1 cell survival through increased mitochondrial ROS production following T cell activation; scavenging mitochondrial ROS (with NAC or MitoQ) inhibits Th17 induction in IER3-KO cells. IER3-KO mice develop more severe collagen-induced arthritis with higher IL-17. IER3 knockout mouse model, collagen-induced arthritis, mitochondrial ROS measurement, pharmacological ROS scavengers (NAC, MitoQ), flow cytometry, ELISA Journal of Immunology High 22798682
2013 Thrombopoietin (TPO) specifically activates Erk and NF-κB pathways in hematopoietic stem/progenitor cells, which cooperate to induce IER3 upon DNA damage; IER3 forms a complex with phospho-ERK and the catalytic subunit of DNA-PK, which is necessary and sufficient to promote DNA-PK activation and NHEJ double-strand break repair in mouse and human HSPCs. TPO signaling pathway analysis, co-immunoprecipitation of IER3/pERK/DNA-PK complex, NHEJ efficiency assay, IER3 loss-of-function in mouse and human HSPCs Blood High 24184684
2013 IER3 modulates Nrf2 activity via the PI3K/Akt-Fyn pathway: IER3 deficiency increases PI3K/Akt activity, which prevents Fyn-mediated nuclear export and inactivation of Nrf2, resulting in increased nuclear Nrf2 and target gene expression; PI3K inhibitor or knockdown of Akt or Fyn abrogates the IER3-deficiency effect on Nrf2 activity. Ier3(-/-) mouse colitis model, shRNA knockdown in colonocytes, IER3 overexpression, Nrf2 reporter, pharmacological PI3K inhibitor (LY294002), siRNA for Akt and Fyn Journal of Biological Chemistry High 24311782
2014 IER3 sustains ERK1/2 phosphorylation by inhibiting PP2A activity in pancreatic cells; IER3 enhances KrasG12D-dependent oncogenesis, as PanIN and PDAC development are delayed in IER3-deficient KrasG12D mice; IER3 co-localizes with phospho-ERK1/2 in ADM and PanIN lesions. Genetic mouse model (IER3-deficient × KrasG12D), PP2A phosphatase activity assay, immunohistochemistry co-localization, human pancreatic cancer cells Journal of Clinical Investigation High 25250570
2015 TAp73β exclusively transactivates IER3 in cervical cancer cells (p53 and TAp63 do not); IER3 is required for TAp73β-induced apoptosis, and etoposide upregulates TAp73β and IER3 in a c-Abl kinase-dependent manner. IER3 silencing prevents TAp73β-induced cell death. Overexpression of TAp73β/p53/TAp63, IER3 siRNA, c-Abl inhibitor, apoptosis assays Scientific Reports Medium 25666857
2016 MDM2 is the E3 ubiquitin ligase for IER3; MDM2 interacts with IER3, promotes its polyubiquitination at conserved Lys60, and targets it for proteasomal degradation. FHL2 serves as a scaffold bridging MDM2 and IER3 to facilitate this degradation. Co-immunoprecipitation, ubiquitination assay, site-directed mutagenesis (K60R), siRNA knockdown of MDM2 and FHL2 Oncogene High 26973248
2003 In vascular smooth muscle cells, iex-1 expression is induced by mechanical strain via NF-κB activation (abolished by IκB overexpression); overexpression of iex-1 suppresses mitogen-induced proliferation, reduces p27kip1 degradation, inhibits Rb hyperphosphorylation, and reduces cell cycle progression; adenoviral iex-1 gene transfer inhibits neointima formation in vivo. Northern/Western blot, adenoviral gene transfer, [3H]-thymidine incorporation, carotid injury mouse model, IκB overexpression Circulation Research High 14592999
2002 A novel inhibitory hexameric repeat DNA response element between nt -405 and -391 in the IER3 promoter mediates transcriptional repression by 1α,25-dihydroxyvitamin D3 via nuclear VDR/RXRα heterodimers. IER3 promoter truncation/luciferase assay, EMSA with VDR and RXRα, 1α,25(OH)2D3 treatment of HaCaT cells Oncogene Medium 12032839
2016 MCPIP1 (an RNase) interacts directly with IER3 mRNA via a stem-loop in its 3'UTR and degrades it; deletion of the stem-loop abolishes MCPIP1-mediated regulation of IER3; MCPIP1 protein co-localizes with IER3 mRNA in cells and RNA immunoprecipitation confirms in vivo interaction. Dual luciferase assay with IER3 3'UTR, stem-loop deletion mutagenesis, IF-combined single-molecule RNA FISH, RNA immunoprecipitation Biology Open Medium 27256408
2014 Transcription factor Elk-1, acting downstream of ERK1/2, drives IL-1β-induced IER3 expression through ETS5/6 binding sites in the IER3 promoter; mutation of ETS5/6 abolishes IL-1β-driven and constitutively active Elk-1 (Elk-VP16)-driven promoter activation. IER3 promoter mutants, luciferase reporter, ChIP for Elk-1, Elk-1 phosphorylation assay Cytokine Medium 25066273
2016 EGR2, induced by gonadotropins in granulosa cells, directly transactivates IER3 through EGR-binding elements in its promoter; IER3 mediates EGR2-dependent survival of granulosa cells. Luciferase assay, EMSA, ChIP, western blot, EGR2 overexpression and knockdown, IER3 as mediator confirmed by knockdown rescue Biochemical and Biophysical Research Communications Medium 27890615
2017 IER3 mediates ischemic preconditioning (IPC)-induced cardioprotection by promoting phosphorylation and particle translocation of PKCε; IER3 knockdown impairs IPC-induced PKCε activation and reduces cardioprotection; IER3 overexpression reduces hypoxia-reoxygenation-induced mitochondrial ROS and cell apoptosis. In vivo IPC rat model, adenoviral IER3 gene delivery/knockdown, PKCε phosphorylation and translocation assay, ROS measurement, infarct size measurement Oxidative Medicine and Cellular Longevity Medium 29213350
2021 TRAIL interacts with IER3 (shown by co-immunoprecipitation and immunofluorescence), and this interaction inhibits Wnt/β-catenin signaling to promote apoptosis and suppress proliferation/migration of hepatocellular carcinoma cells both in vitro and in vivo. Co-immunoprecipitation, immunofluorescence, Wnt/β-catenin reporter assay, in vitro and xenograft in vivo models Cancer Cell International Medium 33472635
2025 IER3 promotes NSCLC malignancy by suppressing ferroptosis via sustaining AKT phosphorylation, which inactivates GSK3β; this prevents GSK3β-dependent proteasomal degradation of NRF2 and enhances NRF2 nuclear translocation, leading to transactivation of ferroptosis-suppressive gene programs. NRF2 overexpression or AKT/GSK3β activation reverses IER3-knockout-induced ferroptosis. IER3-overexpressing and knockout cell lines, western blot for AKT/GSK3β/NRF2 phosphorylation and localization, ferroptosis assays, ferroptosis inhibitor Fer-1 rescue, NRF2 and AKT/GSK3β rescue overexpression Free Radical Biology and Medicine Medium 41581578
2025 IER3 interacts with PARL (presenilin-associated rhomboid-like protease) and reduces its shear activity; this interaction inhibits cleavage and mitochondrial translocation of cytoplasmic PRDX5, reducing mitochondrial PRDX5 levels and antioxidant capacity, leading to oxidative mitochondrial damage, perinuclear mitochondrial clustering, and stress-induced cellular senescence in renal tubular epithelial cells. IER3 knockout mouse model, RNA-seq, co-immunoprecipitation (IER3-PARL), PRDX5 mitochondrial fractionation, PRDX5 inhibition, cellular senescence assays Cellular and Molecular Life Sciences Medium 41359162
2024 In inflammatory-primed human MSCs, IER3 positively regulates osteogenic differentiation; IER3 knockdown significantly downregulates BST2 expression and ERK1/2 phosphorylation, indicating IER3 promotes osteogenesis through BST2 and ERK1/2 signaling. RNA-sequencing of primed hMSCs, siRNA knockdown, osteogenic differentiation assay, ERK1/2 phosphorylation immunoblot FASEB Journal Low 39373973
2025 IER3 knockdown in hMSCs promotes osteogenic differentiation through activation of the MAPK/ERK signaling pathway; knockdown increases phosphorylated ERK1/2 levels, and MAPK/ERK inhibition reverses the enhanced osteogenesis. shRNA lentiviral knockdown, in vitro osteogenic induction, in vivo subcutaneous implantation, ERK1/2 phosphorylation assay, MAPK inhibitor rescue Biomedicines Medium 40299640
2025 IER3 acts as a transcriptional co-activator for RFX5, forming a complex that upregulates AKR1B10, which subsequently suppresses p53 in HCC cells; co-immunoprecipitation confirmed IER3-RFX5 interaction, and dual-luciferase reporter confirmed AKR1B10 as a transcriptional target of this complex. Co-immunoprecipitation, dual-luciferase reporter, siRNA knockdown, western blot Discover Oncology Low 42209919
2025 IER3 promotes tumor progression and aerobic glycolysis in oral squamous cell carcinoma via activation of Wnt/β-catenin signaling; IER3 knockdown inhibits malignant behavior and suppresses Wnt/β-catenin signaling both in vitro and in vivo. Overexpression and siRNA knockdown, colony formation, flow cytometry, transwell assay, ECAR/OCR measurement, xenograft tumor model, western blot for Wnt/β-catenin components Advanced Biology Low 40128149

Source papers

Stage 0 corpus · 95 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1998 IEX-1L, an apoptosis inhibitor involved in NF-kappaB-mediated cell survival. Science (New York, N.Y.) 385 9703517
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 159 21112119
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
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
2018 LncRNA GAS5 confers the radio sensitivity of cervical cancer cells via regulating miR-106b/IER3 axis. International journal of biological macromolecules 79 30579899
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
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
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 56 24184684
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 51 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
2014 IER3 supports KRASG12D-dependent pancreatic cancer development by sustaining ERK1/2 phosphorylation. The Journal of clinical investigation 45 25250570
2002 Synergistic and opposing regulation of the stress-responsive gene IEX-1 by p53, c-Myc, and multiple NF-kappaB/rel complexes. Oncogene 45 12360408
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
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
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
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 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
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
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 24 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
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
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
2015 IER3 Promotes Expansion of Adipose Progenitor Cells in Response to Changes in Distinct Microenvironmental Effectors. Stem cells (Dayton, Ohio) 10 25827082
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
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
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
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 5 40244862
2016 Expression and Functions of Immediate Early Response Gene X-1 (IEX-1) in Rheumatoid Arthritis Synovial Fibroblasts. PloS one 5 27736946
2014 Transcription factor Elk-1 participates in the interleukin-1β-dependent regulation of expression of immediate early response gene 3 (IER3). Cytokine 5 25066273
2024 Inflammatory priming of human mesenchymal stem cells induces osteogenic differentiation via the early response gene IER3. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 4 39373973
2015 Expression of IER3 in primary hepatocarcinoma: correlation with clinicopathological parameters. Asian Pacific journal of cancer prevention : APJCP 4 25684507
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
2024 Correlation study of NF-κB, IER3, and Recurrence of Ovarian Endometrioid Cysts. Reproductive sciences (Thousand Oaks, Calif.) 3 39377902
2021 HCMV modulates c-Mpl/IEX-1 pathway-mediated megakaryo/thrombopoiesis via PDGFRα and αvβ3 receptors after allo-HSCT. Journal of cellular physiology 3 33611789
2018 Significance of blood and salivary IEX-1 expression in diagnosis of epithelial ovarian carcinoma. The journal of obstetrics and gynaecology research 3 29431239
2013 Construction and expression of an eukaryotic expression vector containing the IER3 gene. Asian Pacific journal of cancer prevention : APJCP 2 23534784
2026 IER3 Promotes Malignant Progression of Colorectal Cancer Through the NF-κB Pathway. International journal of genomics 1 41626627
2025 IER3 Facilitates Tumor Progression and Aberrant Glycolysis via Activating wnt/β-Catenin Pathway in Oral Squamous Cell Carcinoma. Advanced biology 1 40128149
2025 Knockdown of IER3 Promotes Osteogenic Differentiation of Human Mesenchymal Stem Cells. Biomedicines 1 40299640
2025 The biological and immunological significance of the estrogen-related gene IER3 in diabetes. Frontiers in endocrinology 1 40964162
2011 [Methylation status of IEX-1 gene promotor CpG island in malignant hematopoietic cell lines]. Zhongguo shi yan xue ye xue za zhi 1 21518511
2026 IER3 promotes non-small cell lung cancer malignancy by suppressing ferroptosis via the AKT/GSK3β/NRF2 pathway. Free radical biology & medicine 0 41581578
2026 IER3 as an RFX5 transcriptional co-activator promotes hepatocellular carcinoma progression via AKR1B10-mediated p53 transcriptional regulation. Discover oncology 0 42209919
2025 Study on the analgesic mechanism of massage on NPP by LNCRNAH19 regulating miR-342-3p/IER3. Pakistan journal of pharmaceutical sciences 0 41334660
2025 IER3 drives the transition from sepsis-associated AKI to CKD by suppressing the mitochondrial translocation of PRDX5. Cellular and molecular life sciences : CMLS 0 41359162
2011 [IEX-1: an unique protein in regulating apoptosis]. Zhong nan da xue xue bao. Yi xue ban = Journal of Central South University. Medical sciences 0 21464552

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