{"gene":"IER3","run_date":"2026-06-10T01:55:22","timeline":{"discoveries":[{"year":1998,"finding":"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.","method":"Antisense transfection, overexpression in Jurkat cells, NF-κB deficient cell lines, apoptosis assays","journal":"Science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — overexpression and antisense knockdown with functional apoptosis readout, but the IEX-1L variant was later disputed as a non-physiological splice variant (PMID:10448082); the NF-κB-dependent transcription of IER3 itself is independently corroborated","pmids":["9703517"],"is_preprint":false},{"year":1999,"finding":"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.","method":"RT-PCR with direct DNA sequencing of nuclear and cytoplasmic RNA fractions from PMA-stimulated Jurkat cells; PCR of human genomic DNA","journal":"Biochemical and Biophysical Research Communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct sequencing of endogenous transcripts in multiple RNA fractions, single lab","pmids":["10448082"],"is_preprint":false},{"year":2002,"finding":"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.","method":"Phosphorylation screening with active ERK2 in vitro, in vivo phosphorylation assay, co-immunoprecipitation with phospho-ERK, IER3 phosphoacceptor and docking-site mutants, apoptosis assays","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — in vitro kinase assay, in vivo phosphorylation, reciprocal co-IP, structure-function mutagenesis, multiple orthogonal readouts in one study","pmids":["12356731"],"is_preprint":false},{"year":2002,"finding":"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.","method":"Transgenic mouse model (Eμ-IEX-1), in vivo immune challenge, flow cytometry, apoptosis assays","journal":"PNAS","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic gain-of-function in vivo with defined cellular phenotype, replicated across multiple immune readouts","pmids":["11782530"],"is_preprint":false},{"year":2001,"finding":"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.","method":"Inducible overexpression vector, antisense hammerhead ribozyme, caspase activity assays, cell cycle analysis","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — bidirectional genetic manipulation (OE and KD) with specific functional readouts, single lab","pmids":["11244505"],"is_preprint":false},{"year":2001,"finding":"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.","method":"Fluorescent antibody and GFP-fusion protein microscopy in keratinocytes, vitamin D3 treatment","journal":"Biochemical and Biophysical Research Communications","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — direct imaging of endogenous and fusion protein, functional correlation with growth state, replicated across two groups (PMID:9878538, PMID:9791001)","pmids":["9878538","9791001"],"is_preprint":false},{"year":2002,"finding":"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.","method":"EMSA, promoter/luciferase reporter assay, chromatin immunoprecipitation (ChIP)","journal":"Oncogene","confidence":"High","confidence_rationale":"Tier 2 / Strong — EMSA, reporter assay, and ChIP in living cells together constitute multiple orthogonal methods confirming promoter regulation","pmids":["12360408"],"is_preprint":false},{"year":2002,"finding":"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.","method":"Systematic promoter truncation/luciferase assay, EMSA","journal":"Journal of Biological Chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — promoter-reporter and EMSA, single lab","pmids":["11844788"],"is_preprint":false},{"year":2002,"finding":"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.","method":"In vivo pressure-overload mouse model, primary cardiomyocyte mechanical stimulation, adenoviral IER3 gene transfer, IκBα overexpression","journal":"Circulation Research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic epistasis (IκBα blocks iex-1 induction) combined with adenoviral overexpression and hypertrophy readout, single lab","pmids":["11934837"],"is_preprint":false},{"year":2003,"finding":"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.","method":"Stable inducible overexpression and anti-IER3 ribozyme in HEK-293 cells, gel-shift, luciferase reporter, fluorometric proteasome assay, nuclear p65 accumulation","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — bidirectional manipulation with multiple mechanistic assays, single lab","pmids":["12761504"],"is_preprint":false},{"year":2006,"finding":"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.","method":"RNAi of PP2A B subunits, overexpression of individual B subunits, co-immunoprecipitation, in vitro phosphorylation assay, B56 phospho-site mutagenesis","journal":"The EMBO Journal","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — in vitro phosphorylation of B56 in complex, mutagenesis of phospho-acceptor site, co-IP, RNAi, multiple orthogonal methods","pmids":["16456541"],"is_preprint":false},{"year":2006,"finding":"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.","method":"Site-directed and truncation mutagenesis, apoptosis assays, ROS measurement","journal":"Journal of Biological Chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — systematic structure-function mutagenesis across multiple domains with dual functional readouts (pro- and anti-apoptotic) and ROS measurements","pmids":["16567805"],"is_preprint":false},{"year":2007,"finding":"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.","method":"Overexpression, RNAi, dominant-negative ERK mutants, phospho-Akt immunoblotting, B56 phospho-site mutagenesis, ERK-binding-deficient IER3 mutant","journal":"Journal of Biological Chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — epistasis via dominant-negative and binding-deficient mutants, bidirectional manipulation, replicated by prior paper (PMID:16456541) from same lab with orthogonal methods","pmids":["17200115"],"is_preprint":false},{"year":2007,"finding":"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.","method":"GST-pulldown, co-immunoprecipitation, GAL4/luciferase transactivation assay, ChIP, deletion constructs","journal":"Biochimica et Biophysica Acta","confidence":"High","confidence_rationale":"Tier 2 / Strong — GST-pulldown with co-IP of endogenous proteins, ChIP, and functional reporter assay confirming direct interaction and transcriptional consequence","pmids":["18191642"],"is_preprint":false},{"year":2008,"finding":"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.","method":"C-terminal truncation of IF1, siRNA knockdown of IF1, co-immunoprecipitation, measurement of ATP hydrolysis and ROS, IER3 knockout mouse model","journal":"Cell Death and Differentiation","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic loss-of-function in vitro and in vivo, IF1 siRNA phenocopy of IER3, binding domain mapping, multiple metabolic readouts","pmids":["19096392"],"is_preprint":false},{"year":2009,"finding":"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.","method":"Yeast two-hybrid, co-immunoprecipitation, siRNA knockdown of BIM/NOXA/PUMA, overexpression apoptosis assay, mitochondrial membrane potential measurement","journal":"Biochemical and Biophysical Research Communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — yeast two-hybrid confirmed by endogenous co-IP, genetic epistasis with siRNA knockouts, single lab","pmids":["19285955"],"is_preprint":false},{"year":2010,"finding":"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.","method":"γ-irradiation, ATM inhibitor, proteasome inhibitor, subcellular fractionation, Chk1 phosphorylation assay, genomic instability assay, IER3 loss-of-function","journal":"Cell Death and Differentiation","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic loss-of-function, pharmacological inhibition of ATM, subcellular fractionation with multiple mechanistic readouts (Mcl-1 localization, Chk1, genomic instability)","pmids":["20467439"],"is_preprint":false},{"year":2005,"finding":"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.","method":"Confocal microscopy with GFP-IER3 fusion and endogenous protein, NLS deletion mutant, leptomycin B treatment, PML overexpression, co-immunoprecipitation","journal":"Journal of Biological Chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct imaging, pharmacological inhibition of CRM1, co-IP of PML interaction, single lab","pmids":["15855159"],"is_preprint":false},{"year":2012,"finding":"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.","method":"IER3 knockout mouse model, collagen-induced arthritis, mitochondrial ROS measurement, pharmacological ROS scavengers (NAC, MitoQ), flow cytometry, ELISA","journal":"Journal of Immunology","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic KO in vivo, pharmacological rescue of mitochondrial ROS, multiple immune readouts","pmids":["22798682"],"is_preprint":false},{"year":2013,"finding":"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.","method":"TPO signaling pathway analysis, co-immunoprecipitation of IER3/pERK/DNA-PK complex, NHEJ efficiency assay, IER3 loss-of-function in mouse and human HSPCs","journal":"Blood","confidence":"High","confidence_rationale":"Tier 2 / Strong — ternary complex identified by co-IP, genetic loss-of-function, functional NHEJ assay, validated in both mouse and human cells","pmids":["24184684"],"is_preprint":false},{"year":2013,"finding":"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.","method":"Ier3(-/-) mouse colitis model, shRNA knockdown in colonocytes, IER3 overexpression, Nrf2 reporter, pharmacological PI3K inhibitor (LY294002), siRNA for Akt and Fyn","journal":"Journal of Biological Chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic in vivo KO, in vitro bidirectional manipulation, pharmacological and siRNA epistasis defining pathway position","pmids":["24311782"],"is_preprint":false},{"year":2014,"finding":"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.","method":"Genetic mouse model (IER3-deficient × KrasG12D), PP2A phosphatase activity assay, immunohistochemistry co-localization, human pancreatic cancer cells","journal":"Journal of Clinical Investigation","confidence":"High","confidence_rationale":"Tier 2 / Strong — compound genetic mouse model, PP2A activity assay, replicated in human cancer cells, multiple lesion stages examined","pmids":["25250570"],"is_preprint":false},{"year":2015,"finding":"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.","method":"Overexpression of TAp73β/p53/TAp63, IER3 siRNA, c-Abl inhibitor, apoptosis assays","journal":"Scientific Reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — pharmacological epistasis with c-Abl inhibitor, genetic knockdown, comparison of p53 family members, single lab","pmids":["25666857"],"is_preprint":false},{"year":2016,"finding":"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.","method":"Co-immunoprecipitation, ubiquitination assay, site-directed mutagenesis (K60R), siRNA knockdown of MDM2 and FHL2","journal":"Oncogene","confidence":"High","confidence_rationale":"Tier 2 / Strong — co-IP of endogenous and overexpressed proteins, ubiquitination assay, specific Lys60 mutagenesis abolishes degradation, scaffold function of FHL2 confirmed by knockdown","pmids":["26973248"],"is_preprint":false},{"year":2003,"finding":"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.","method":"Northern/Western blot, adenoviral gene transfer, [3H]-thymidine incorporation, carotid injury mouse model, IκB overexpression","journal":"Circulation Research","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vitro and in vivo genetic manipulation, NF-κB epistasis, cell cycle molecular markers, and neointima readout","pmids":["14592999"],"is_preprint":false},{"year":2002,"finding":"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.","method":"IER3 promoter truncation/luciferase assay, EMSA with VDR and RXRα, 1α,25(OH)2D3 treatment of HaCaT cells","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — EMSA and promoter-reporter with identified response element and specific nuclear receptors, single lab","pmids":["12032839"],"is_preprint":false},{"year":2016,"finding":"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.","method":"Dual luciferase assay with IER3 3'UTR, stem-loop deletion mutagenesis, IF-combined single-molecule RNA FISH, RNA immunoprecipitation","journal":"Biology Open","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (luciferase, smFISH, RIP), single lab","pmids":["27256408"],"is_preprint":false},{"year":2014,"finding":"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.","method":"IER3 promoter mutants, luciferase reporter, ChIP for Elk-1, Elk-1 phosphorylation assay","journal":"Cytokine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — promoter mutagenesis, ChIP, and kinase activity assay, single lab","pmids":["25066273"],"is_preprint":false},{"year":2016,"finding":"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.","method":"Luciferase assay, EMSA, ChIP, western blot, EGR2 overexpression and knockdown, IER3 as mediator confirmed by knockdown rescue","journal":"Biochemical and Biophysical Research Communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — EMSA, ChIP, and luciferase confirm direct transcription, single lab","pmids":["27890615"],"is_preprint":false},{"year":2017,"finding":"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.","method":"In vivo IPC rat model, adenoviral IER3 gene delivery/knockdown, PKCε phosphorylation and translocation assay, ROS measurement, infarct size measurement","journal":"Oxidative Medicine and Cellular Longevity","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo and in vitro genetic manipulation, PKCε signaling readout, single lab","pmids":["29213350"],"is_preprint":false},{"year":2021,"finding":"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.","method":"Co-immunoprecipitation, immunofluorescence, Wnt/β-catenin reporter assay, in vitro and xenograft in vivo models","journal":"Cancer Cell International","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — co-IP and immunofluorescence identifying interaction, functional assays in vitro and in vivo, single lab","pmids":["33472635"],"is_preprint":false},{"year":2025,"finding":"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.","method":"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","journal":"Free Radical Biology and Medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — bidirectional genetic manipulation with pathway rescue experiments, multiple mechanistic readouts, single lab","pmids":["41581578"],"is_preprint":false},{"year":2025,"finding":"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.","method":"IER3 knockout mouse model, RNA-seq, co-immunoprecipitation (IER3-PARL), PRDX5 mitochondrial fractionation, PRDX5 inhibition, cellular senescence assays","journal":"Cellular and Molecular Life Sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic KO in vivo, co-IP identifying PARL as binding partner, PRDX5 fractionation, PRDX5 inhibitor epistasis, single lab","pmids":["41359162"],"is_preprint":false},{"year":2024,"finding":"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.","method":"RNA-sequencing of primed hMSCs, siRNA knockdown, osteogenic differentiation assay, ERK1/2 phosphorylation immunoblot","journal":"FASEB Journal","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single knockdown experiment with pathway readout, single lab, no reconstitution or mutagenesis","pmids":["39373973"],"is_preprint":false},{"year":2025,"finding":"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.","method":"shRNA lentiviral knockdown, in vitro osteogenic induction, in vivo subcutaneous implantation, ERK1/2 phosphorylation assay, MAPK inhibitor rescue","journal":"Biomedicines","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic KD in vitro and in vivo, pharmacological epistasis with MAPK inhibitor, single lab","pmids":["40299640"],"is_preprint":false},{"year":2025,"finding":"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.","method":"Co-immunoprecipitation, dual-luciferase reporter, siRNA knockdown, western blot","journal":"Discover Oncology","confidence":"Low","confidence_rationale":"Tier 3 / Weak — co-IP and reporter assay identifying IER3-RFX5-AKR1B10 axis, no mutagenesis or in vivo validation of this mechanism, single lab","pmids":["42209919"],"is_preprint":false},{"year":2025,"finding":"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.","method":"Overexpression and siRNA knockdown, colony formation, flow cytometry, transwell assay, ECAR/OCR measurement, xenograft tumor model, western blot for Wnt/β-catenin components","journal":"Advanced Biology","confidence":"Low","confidence_rationale":"Tier 3 / Weak — pathway activation inferred from downstream markers without direct reconstitution or epistasis of specific Wnt components, single lab","pmids":["40128149"],"is_preprint":false}],"current_model":"IER3 (IEX-1) is a stress- and NF-κB-inducible immediate early response protein that functions as an ERK substrate and dual regulator of ERK and Akt signaling: phosphorylated by ERK, IER3 inhibits B56-containing PP2A holoenzymes (by enabling ERK-mediated phosphorylation of B56 regulatory subunits, causing their dissociation from the catalytic subunit), thereby sustaining phospho-ERK and phospho-Akt levels; IER3 also directly binds RelA/p65 to attenuate NF-κB transactivation, targets the mitochondrial F1Fo-ATPase inhibitor IF1 for degradation to reduce ROS and promote ATP hydrolysis, interacts with MCL-1 to regulate BIM-dependent apoptosis, forms a complex with pERK and DNA-PK to facilitate NHEJ repair, controls nuclear MCL-1 accumulation after ATM-dependent DNA damage, and is itself subject to MDM2/FHL2-mediated ubiquitination and proteasomal degradation; the net outcome of IER3 activity—pro- or anti-apoptotic, oncogenic or tumor-suppressive—is highly context- and cell-type-dependent."},"narrative":{"mechanistic_narrative":"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].","teleology":[{"year":1998,"claim":"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","pmids":["9703517"],"confidence":"Medium","gaps":["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"]},{"year":1999,"claim":"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","pmids":["10448082"],"confidence":"Medium","gaps":["Single lab","Did not address function of correctly spliced IER3"]},{"year":2001,"claim":"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","pmids":["11244505","9878538","9791001"],"confidence":"Medium","gaps":["Molecular basis of context switch unknown","Nuclear function of IER3 not mechanistically defined"]},{"year":2002,"claim":"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","pmids":["12356731"],"confidence":"High","gaps":["Downstream effector of phospho-IER3 not yet identified","How ERK association potentiates ERK was unexplained"]},{"year":2002,"claim":"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","pmids":["12360408","11844788","12032839"],"confidence":"High","gaps":["Cell-type specificity of competing inputs not resolved","Quantitative contribution of each factor unclear"]},{"year":2002,"claim":"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","pmids":["11782530"],"confidence":"High","gaps":["Molecular target mediating T-cell survival not defined here"]},{"year":2003,"claim":"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","pmids":["12761504","11934837","14592999"],"confidence":"High","gaps":["Mechanism of proteasome inhibition unclear","Direct molecular target within NF-κB pathway not yet RelA"]},{"year":2006,"claim":"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","pmids":["16456541","16567805"],"confidence":"High","gaps":["Akt arm not yet connected","Structural basis of B56-ERK-IER3 ternary complex unknown"]},{"year":2007,"claim":"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","pmids":["17200115","18191642"],"confidence":"High","gaps":["Selectivity for B56 versus other PP2A B subunits in vivo","How nuclear RelA binding integrates with cytoplasmic ERK/Akt role"]},{"year":2009,"claim":"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","pmids":["19096392","19285955"],"confidence":"High","gaps":["How IF1 binding leads to its degradation mechanistically unclear","MCL-1 interaction surface and stoichiometry undefined"]},{"year":2010,"claim":"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","pmids":["20467439"],"confidence":"High","gaps":["How IER3 mediates MCL-1 nuclear import not defined","Link between nuclear MCL-1 and checkpoint mechanistically incomplete"]},{"year":2013,"claim":"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","pmids":["24184684","24311782"],"confidence":"High","gaps":["Whether DNA-PK and B56-PP2A mechanisms are coupled unknown","Direct vs indirect effect on Fyn localization unresolved"]},{"year":2014,"claim":"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","pmids":["25250570","25066273"],"confidence":"High","gaps":["Therapeutic targetability of the IER3-PP2A node untested","Generalizability beyond pancreatic context"]},{"year":2016,"claim":"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","pmids":["26973248","27256408"],"confidence":"Medium","gaps":["Signals controlling MDM2/FHL2 recruitment to IER3 unknown","Physiological triggers of MCPIP1-mediated turnover undefined"]},{"year":2025,"claim":"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","pmids":["41581578","41359162","30472635","42209919","40128149"],"confidence":"Medium","gaps":["Several mechanisms rest on single-lab co-IP/reporter without mutagenesis","Whether ferroptosis and senescence axes converge on the same IER3 redox function unclear"]},{"year":null,"claim":"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.","evidence":"","pmids":[],"confidence":"Medium","gaps":["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":{"molecular_activity":[{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[10,12,9,14]},{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[13,35]},{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[2,10]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[5,17,16]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[2,5]},{"term_id":"GO:0005739","term_label":"mitochondrion","supporting_discovery_ids":[14,32]},{"term_id":"GO:0005730","term_label":"nucleolus","supporting_discovery_ids":[17]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[2,10,12,20]},{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[0,4,15,16]},{"term_id":"R-HSA-73894","term_label":"DNA Repair","supporting_discovery_ids":[16,19]},{"term_id":"R-HSA-8953897","term_label":"Cellular responses to stimuli","supporting_discovery_ids":[14,18,31]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[3,18]},{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[23]}],"complexes":["IER3-B56-ERK (PP2A regulatory complex)","IER3-pERK-DNA-PK (NHEJ complex)"],"partners":["MAPK1/ERK2","PPP2R5/B56","RELA","MCL1","ATPIF1/IF1","PRKDC/DNA-PK","MDM2","PARL"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P46695","full_name":"Radiation-inducible immediate-early gene IEX-1","aliases":["Differentiation-dependent gene 2 protein","Protein DIF-2","Immediate early protein GLY96","Immediate early response 3 protein","PACAP-responsive gene 1 protein","Protein PRG1"],"length_aa":156,"mass_kda":16.9,"function":"May play a role in the ERK signaling pathway by inhibiting the dephosphorylation of ERK by phosphatase PP2A-PPP2R5C holoenzyme. Also acts as an ERK downstream effector mediating survival. As a member of the NUPR1/RELB/IER3 survival pathway, may provide pancreatic ductal adenocarcinoma with remarkable resistance to cell stress, such as starvation or gemcitabine treatment","subcellular_location":"Membrane","url":"https://www.uniprot.org/uniprotkb/P46695/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/IER3","classification":"Not Classified","n_dependent_lines":62,"n_total_lines":1208,"dependency_fraction":0.05132450331125828},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/IER3","total_profiled":1310},"omim":[{"mim_id":"614812","title":"NUCLEAR PROTEIN, TRANSCRIPTIONAL REGULATOR, 1; NUPR1","url":"https://www.omim.org/entry/614812"},{"mim_id":"614660","title":"PAT1 HOMOLOG 1, PROCESSING BODY mRNA DECAY FACTOR; PATL1","url":"https://www.omim.org/entry/614660"},{"mim_id":"603075","title":"MACULAR DEGENERATION, AGE-RELATED, 1; ARMD1","url":"https://www.omim.org/entry/603075"},{"mim_id":"602996","title":"IMMEDIATE-EARLY RESPONSE 3; IER3","url":"https://www.omim.org/entry/602996"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in many","driving_tissues":[],"url":"https://www.proteinatlas.org/search/IER3"},"hgnc":{"alias_symbol":["IEX-1","DIF-2","PRG1","IEX-1L"],"prev_symbol":[]},"alphafold":{"accession":"P46695","domains":[],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P46695","model_url":"https://alphafold.ebi.ac.uk/files/AF-P46695-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P46695-F1-predicted_aligned_error_v6.png","plddt_mean":65.25},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=IER3","jax_strain_url":"https://www.jax.org/strain/search?query=IER3"},"sequence":{"accession":"P46695","fasta_url":"https://rest.uniprot.org/uniprotkb/P46695.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P46695/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P46695"}},"corpus_meta":[{"pmid":"9703517","id":"PMC_9703517","title":"IEX-1L, an apoptosis inhibitor involved in NF-kappaB-mediated cell survival.","date":"1998","source":"Science (New York, 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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.","date":"2010","source":"Inflammatory bowel diseases","url":"https://pubmed.ncbi.nlm.nih.gov/19714745","citation_count":27,"is_preprint":false},{"pmid":"22417305","id":"PMC_22417305","title":"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.","date":"2012","source":"Experimental dermatology","url":"https://pubmed.ncbi.nlm.nih.gov/22417305","citation_count":25,"is_preprint":false},{"pmid":"16166241","id":"PMC_16166241","title":"Elevated blood pressure and cardiac hypertrophy after ablation of the gly96/IEX-1 gene.","date":"2005","source":"Journal of applied physiology (Bethesda, Md. : 1985)","url":"https://pubmed.ncbi.nlm.nih.gov/16166241","citation_count":25,"is_preprint":false},{"pmid":"22085302","id":"PMC_22085302","title":"Clinical significance of IEX-1 expression 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acid-responsive and -resistant leukemic cells.","date":"2004","source":"Leukemia","url":"https://pubmed.ncbi.nlm.nih.gov/15306824","citation_count":9,"is_preprint":false},{"pmid":"18564103","id":"PMC_18564103","title":"Overexpression of immediate early gene X-1 (IEX-1) enhances gamma-radiation-induced apoptosis of human glioma cell line, U87-MG.","date":"2008","source":"Neuropathology : official journal of the Japanese Society of Neuropathology","url":"https://pubmed.ncbi.nlm.nih.gov/18564103","citation_count":9,"is_preprint":false},{"pmid":"40090972","id":"PMC_40090972","title":"IER3: exploring its dual function as an oncogene and tumor suppressor.","date":"2025","source":"Cancer gene therapy","url":"https://pubmed.ncbi.nlm.nih.gov/40090972","citation_count":8,"is_preprint":false},{"pmid":"29213350","id":"PMC_29213350","title":"Immediate Early Response Gene X-1 (IEX-1) Mediates Ischemic Preconditioning-Induced Cardioprotection in Rats.","date":"2017","source":"Oxidative medicine and cellular longevity","url":"https://pubmed.ncbi.nlm.nih.gov/29213350","citation_count":7,"is_preprint":false},{"pmid":"29101849","id":"PMC_29101849","title":"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.","date":"2017","source":"Molecular immunology","url":"https://pubmed.ncbi.nlm.nih.gov/29101849","citation_count":6,"is_preprint":false},{"pmid":"40244862","id":"PMC_40244862","title":"Exercise-Mediated Mechanical Stress Promotes Osteogenic Differentiation of BMSCs Through Upregulation of Lactylation via the IER3/LDHB Axis.","date":"2025","source":"FASEB journal : official publication of the Federation of American Societies for Experimental Biology","url":"https://pubmed.ncbi.nlm.nih.gov/40244862","citation_count":5,"is_preprint":false},{"pmid":"27736946","id":"PMC_27736946","title":"Expression and Functions of Immediate Early Response Gene 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IER3.","date":"2024","source":"FASEB journal : official publication of the Federation of American Societies for Experimental Biology","url":"https://pubmed.ncbi.nlm.nih.gov/39373973","citation_count":4,"is_preprint":false},{"pmid":"33611789","id":"PMC_33611789","title":"HCMV modulates c-Mpl/IEX-1 pathway-mediated megakaryo/thrombopoiesis via PDGFRα and αvβ3 receptors after allo-HSCT.","date":"2021","source":"Journal of cellular physiology","url":"https://pubmed.ncbi.nlm.nih.gov/33611789","citation_count":3,"is_preprint":false},{"pmid":"29431239","id":"PMC_29431239","title":"Significance of blood and salivary IEX-1 expression in diagnosis of epithelial ovarian carcinoma.","date":"2018","source":"The journal of obstetrics and gynaecology research","url":"https://pubmed.ncbi.nlm.nih.gov/29431239","citation_count":3,"is_preprint":false},{"pmid":"39377902","id":"PMC_39377902","title":"Correlation study of NF-κB, IER3, and Recurrence of Ovarian Endometrioid 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Yi xue ban = Journal of Central South University. Medical sciences","url":"https://pubmed.ncbi.nlm.nih.gov/21464552","citation_count":0,"is_preprint":false},{"pmid":"41334660","id":"PMC_41334660","title":"Study on the analgesic mechanism of massage on NPP by LNCRNAH19 regulating miR-342-3p/IER3.","date":"2025","source":"Pakistan journal of pharmaceutical sciences","url":"https://pubmed.ncbi.nlm.nih.gov/41334660","citation_count":0,"is_preprint":false},{"pmid":"42209919","id":"PMC_42209919","title":"IER3 as an RFX5 transcriptional co-activator promotes hepatocellular carcinoma progression via AKR1B10-mediated p53 transcriptional regulation.","date":"2026","source":"Discover oncology","url":"https://pubmed.ncbi.nlm.nih.gov/42209919","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2025.05.22.655446","title":"Pneumococcal H  <sub>2</sub>  O  <sub>2</sub>  Reshapes Mitochondrial Function and Reprograms Host Cell Metabolism","date":"2025-05-22","source":"bioRxiv","url":"https://doi.org/10.1101/2025.05.22.655446","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2025.02.10.637415","title":"Complex Human hear bearing Skin Organoids reveal Cell Type Specific Susceptibility and Innate Immune Responses to Herpes Simplex Virus 1","date":"2025-02-11","source":"bioRxiv","url":"https://doi.org/10.1101/2025.02.10.637415","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":49003,"output_tokens":9473,"usd":0.144552,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":19713,"output_tokens":5536,"usd":0.118483,"stage2_stop_reason":"end_turn"},"total_usd":0.263035,"stage1_batch_id":"msgbatch_01DUPACZi7AAWwuZiUjseQF4","stage2_batch_id":"msgbatch_018yt7chE3f48PEFtDwtj6AE","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1998,\n      \"finding\": \"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.\",\n      \"method\": \"Antisense transfection, overexpression in Jurkat cells, NF-κB deficient cell lines, apoptosis assays\",\n      \"journal\": \"Science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — overexpression and antisense knockdown with functional apoptosis readout, but the IEX-1L variant was later disputed as a non-physiological splice variant (PMID:10448082); the NF-κB-dependent transcription of IER3 itself is independently corroborated\",\n      \"pmids\": [\"9703517\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"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.\",\n      \"method\": \"RT-PCR with direct DNA sequencing of nuclear and cytoplasmic RNA fractions from PMA-stimulated Jurkat cells; PCR of human genomic DNA\",\n      \"journal\": \"Biochemical and Biophysical Research Communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct sequencing of endogenous transcripts in multiple RNA fractions, single lab\",\n      \"pmids\": [\"10448082\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"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.\",\n      \"method\": \"Phosphorylation screening with active ERK2 in vitro, in vivo phosphorylation assay, co-immunoprecipitation with phospho-ERK, IER3 phosphoacceptor and docking-site mutants, apoptosis assays\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — in vitro kinase assay, in vivo phosphorylation, reciprocal co-IP, structure-function mutagenesis, multiple orthogonal readouts in one study\",\n      \"pmids\": [\"12356731\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"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.\",\n      \"method\": \"Transgenic mouse model (Eμ-IEX-1), in vivo immune challenge, flow cytometry, apoptosis assays\",\n      \"journal\": \"PNAS\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic gain-of-function in vivo with defined cellular phenotype, replicated across multiple immune readouts\",\n      \"pmids\": [\"11782530\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"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.\",\n      \"method\": \"Inducible overexpression vector, antisense hammerhead ribozyme, caspase activity assays, cell cycle analysis\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — bidirectional genetic manipulation (OE and KD) with specific functional readouts, single lab\",\n      \"pmids\": [\"11244505\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"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.\",\n      \"method\": \"Fluorescent antibody and GFP-fusion protein microscopy in keratinocytes, vitamin D3 treatment\",\n      \"journal\": \"Biochemical and Biophysical Research Communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — direct imaging of endogenous and fusion protein, functional correlation with growth state, replicated across two groups (PMID:9878538, PMID:9791001)\",\n      \"pmids\": [\"9878538\", \"9791001\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"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.\",\n      \"method\": \"EMSA, promoter/luciferase reporter assay, chromatin immunoprecipitation (ChIP)\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — EMSA, reporter assay, and ChIP in living cells together constitute multiple orthogonal methods confirming promoter regulation\",\n      \"pmids\": [\"12360408\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"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.\",\n      \"method\": \"Systematic promoter truncation/luciferase assay, EMSA\",\n      \"journal\": \"Journal of Biological Chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — promoter-reporter and EMSA, single lab\",\n      \"pmids\": [\"11844788\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"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.\",\n      \"method\": \"In vivo pressure-overload mouse model, primary cardiomyocyte mechanical stimulation, adenoviral IER3 gene transfer, IκBα overexpression\",\n      \"journal\": \"Circulation Research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic epistasis (IκBα blocks iex-1 induction) combined with adenoviral overexpression and hypertrophy readout, single lab\",\n      \"pmids\": [\"11934837\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"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.\",\n      \"method\": \"Stable inducible overexpression and anti-IER3 ribozyme in HEK-293 cells, gel-shift, luciferase reporter, fluorometric proteasome assay, nuclear p65 accumulation\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — bidirectional manipulation with multiple mechanistic assays, single lab\",\n      \"pmids\": [\"12761504\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"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.\",\n      \"method\": \"RNAi of PP2A B subunits, overexpression of individual B subunits, co-immunoprecipitation, in vitro phosphorylation assay, B56 phospho-site mutagenesis\",\n      \"journal\": \"The EMBO Journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — in vitro phosphorylation of B56 in complex, mutagenesis of phospho-acceptor site, co-IP, RNAi, multiple orthogonal methods\",\n      \"pmids\": [\"16456541\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"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.\",\n      \"method\": \"Site-directed and truncation mutagenesis, apoptosis assays, ROS measurement\",\n      \"journal\": \"Journal of Biological Chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — systematic structure-function mutagenesis across multiple domains with dual functional readouts (pro- and anti-apoptotic) and ROS measurements\",\n      \"pmids\": [\"16567805\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"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.\",\n      \"method\": \"Overexpression, RNAi, dominant-negative ERK mutants, phospho-Akt immunoblotting, B56 phospho-site mutagenesis, ERK-binding-deficient IER3 mutant\",\n      \"journal\": \"Journal of Biological Chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — epistasis via dominant-negative and binding-deficient mutants, bidirectional manipulation, replicated by prior paper (PMID:16456541) from same lab with orthogonal methods\",\n      \"pmids\": [\"17200115\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"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.\",\n      \"method\": \"GST-pulldown, co-immunoprecipitation, GAL4/luciferase transactivation assay, ChIP, deletion constructs\",\n      \"journal\": \"Biochimica et Biophysica Acta\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — GST-pulldown with co-IP of endogenous proteins, ChIP, and functional reporter assay confirming direct interaction and transcriptional consequence\",\n      \"pmids\": [\"18191642\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"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.\",\n      \"method\": \"C-terminal truncation of IF1, siRNA knockdown of IF1, co-immunoprecipitation, measurement of ATP hydrolysis and ROS, IER3 knockout mouse model\",\n      \"journal\": \"Cell Death and Differentiation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic loss-of-function in vitro and in vivo, IF1 siRNA phenocopy of IER3, binding domain mapping, multiple metabolic readouts\",\n      \"pmids\": [\"19096392\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"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.\",\n      \"method\": \"Yeast two-hybrid, co-immunoprecipitation, siRNA knockdown of BIM/NOXA/PUMA, overexpression apoptosis assay, mitochondrial membrane potential measurement\",\n      \"journal\": \"Biochemical and Biophysical Research Communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — yeast two-hybrid confirmed by endogenous co-IP, genetic epistasis with siRNA knockouts, single lab\",\n      \"pmids\": [\"19285955\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"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.\",\n      \"method\": \"γ-irradiation, ATM inhibitor, proteasome inhibitor, subcellular fractionation, Chk1 phosphorylation assay, genomic instability assay, IER3 loss-of-function\",\n      \"journal\": \"Cell Death and Differentiation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic loss-of-function, pharmacological inhibition of ATM, subcellular fractionation with multiple mechanistic readouts (Mcl-1 localization, Chk1, genomic instability)\",\n      \"pmids\": [\"20467439\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"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.\",\n      \"method\": \"Confocal microscopy with GFP-IER3 fusion and endogenous protein, NLS deletion mutant, leptomycin B treatment, PML overexpression, co-immunoprecipitation\",\n      \"journal\": \"Journal of Biological Chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct imaging, pharmacological inhibition of CRM1, co-IP of PML interaction, single lab\",\n      \"pmids\": [\"15855159\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"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.\",\n      \"method\": \"IER3 knockout mouse model, collagen-induced arthritis, mitochondrial ROS measurement, pharmacological ROS scavengers (NAC, MitoQ), flow cytometry, ELISA\",\n      \"journal\": \"Journal of Immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic KO in vivo, pharmacological rescue of mitochondrial ROS, multiple immune readouts\",\n      \"pmids\": [\"22798682\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"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.\",\n      \"method\": \"TPO signaling pathway analysis, co-immunoprecipitation of IER3/pERK/DNA-PK complex, NHEJ efficiency assay, IER3 loss-of-function in mouse and human HSPCs\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — ternary complex identified by co-IP, genetic loss-of-function, functional NHEJ assay, validated in both mouse and human cells\",\n      \"pmids\": [\"24184684\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"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.\",\n      \"method\": \"Ier3(-/-) mouse colitis model, shRNA knockdown in colonocytes, IER3 overexpression, Nrf2 reporter, pharmacological PI3K inhibitor (LY294002), siRNA for Akt and Fyn\",\n      \"journal\": \"Journal of Biological Chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic in vivo KO, in vitro bidirectional manipulation, pharmacological and siRNA epistasis defining pathway position\",\n      \"pmids\": [\"24311782\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"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.\",\n      \"method\": \"Genetic mouse model (IER3-deficient × KrasG12D), PP2A phosphatase activity assay, immunohistochemistry co-localization, human pancreatic cancer cells\",\n      \"journal\": \"Journal of Clinical Investigation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — compound genetic mouse model, PP2A activity assay, replicated in human cancer cells, multiple lesion stages examined\",\n      \"pmids\": [\"25250570\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"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.\",\n      \"method\": \"Overexpression of TAp73β/p53/TAp63, IER3 siRNA, c-Abl inhibitor, apoptosis assays\",\n      \"journal\": \"Scientific Reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — pharmacological epistasis with c-Abl inhibitor, genetic knockdown, comparison of p53 family members, single lab\",\n      \"pmids\": [\"25666857\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"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.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay, site-directed mutagenesis (K60R), siRNA knockdown of MDM2 and FHL2\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — co-IP of endogenous and overexpressed proteins, ubiquitination assay, specific Lys60 mutagenesis abolishes degradation, scaffold function of FHL2 confirmed by knockdown\",\n      \"pmids\": [\"26973248\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"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.\",\n      \"method\": \"Northern/Western blot, adenoviral gene transfer, [3H]-thymidine incorporation, carotid injury mouse model, IκB overexpression\",\n      \"journal\": \"Circulation Research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vitro and in vivo genetic manipulation, NF-κB epistasis, cell cycle molecular markers, and neointima readout\",\n      \"pmids\": [\"14592999\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"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.\",\n      \"method\": \"IER3 promoter truncation/luciferase assay, EMSA with VDR and RXRα, 1α,25(OH)2D3 treatment of HaCaT cells\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — EMSA and promoter-reporter with identified response element and specific nuclear receptors, single lab\",\n      \"pmids\": [\"12032839\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"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.\",\n      \"method\": \"Dual luciferase assay with IER3 3'UTR, stem-loop deletion mutagenesis, IF-combined single-molecule RNA FISH, RNA immunoprecipitation\",\n      \"journal\": \"Biology Open\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (luciferase, smFISH, RIP), single lab\",\n      \"pmids\": [\"27256408\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"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.\",\n      \"method\": \"IER3 promoter mutants, luciferase reporter, ChIP for Elk-1, Elk-1 phosphorylation assay\",\n      \"journal\": \"Cytokine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — promoter mutagenesis, ChIP, and kinase activity assay, single lab\",\n      \"pmids\": [\"25066273\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"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.\",\n      \"method\": \"Luciferase assay, EMSA, ChIP, western blot, EGR2 overexpression and knockdown, IER3 as mediator confirmed by knockdown rescue\",\n      \"journal\": \"Biochemical and Biophysical Research Communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — EMSA, ChIP, and luciferase confirm direct transcription, single lab\",\n      \"pmids\": [\"27890615\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"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.\",\n      \"method\": \"In vivo IPC rat model, adenoviral IER3 gene delivery/knockdown, PKCε phosphorylation and translocation assay, ROS measurement, infarct size measurement\",\n      \"journal\": \"Oxidative Medicine and Cellular Longevity\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo and in vitro genetic manipulation, PKCε signaling readout, single lab\",\n      \"pmids\": [\"29213350\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"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.\",\n      \"method\": \"Co-immunoprecipitation, immunofluorescence, Wnt/β-catenin reporter assay, in vitro and xenograft in vivo models\",\n      \"journal\": \"Cancer Cell International\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — co-IP and immunofluorescence identifying interaction, functional assays in vitro and in vivo, single lab\",\n      \"pmids\": [\"33472635\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"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.\",\n      \"method\": \"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\",\n      \"journal\": \"Free Radical Biology and Medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — bidirectional genetic manipulation with pathway rescue experiments, multiple mechanistic readouts, single lab\",\n      \"pmids\": [\"41581578\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"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.\",\n      \"method\": \"IER3 knockout mouse model, RNA-seq, co-immunoprecipitation (IER3-PARL), PRDX5 mitochondrial fractionation, PRDX5 inhibition, cellular senescence assays\",\n      \"journal\": \"Cellular and Molecular Life Sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic KO in vivo, co-IP identifying PARL as binding partner, PRDX5 fractionation, PRDX5 inhibitor epistasis, single lab\",\n      \"pmids\": [\"41359162\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"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.\",\n      \"method\": \"RNA-sequencing of primed hMSCs, siRNA knockdown, osteogenic differentiation assay, ERK1/2 phosphorylation immunoblot\",\n      \"journal\": \"FASEB Journal\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single knockdown experiment with pathway readout, single lab, no reconstitution or mutagenesis\",\n      \"pmids\": [\"39373973\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"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.\",\n      \"method\": \"shRNA lentiviral knockdown, in vitro osteogenic induction, in vivo subcutaneous implantation, ERK1/2 phosphorylation assay, MAPK inhibitor rescue\",\n      \"journal\": \"Biomedicines\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic KD in vitro and in vivo, pharmacological epistasis with MAPK inhibitor, single lab\",\n      \"pmids\": [\"40299640\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"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.\",\n      \"method\": \"Co-immunoprecipitation, dual-luciferase reporter, siRNA knockdown, western blot\",\n      \"journal\": \"Discover Oncology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — co-IP and reporter assay identifying IER3-RFX5-AKR1B10 axis, no mutagenesis or in vivo validation of this mechanism, single lab\",\n      \"pmids\": [\"42209919\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"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.\",\n      \"method\": \"Overexpression and siRNA knockdown, colony formation, flow cytometry, transwell assay, ECAR/OCR measurement, xenograft tumor model, western blot for Wnt/β-catenin components\",\n      \"journal\": \"Advanced Biology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — pathway activation inferred from downstream markers without direct reconstitution or epistasis of specific Wnt components, single lab\",\n      \"pmids\": [\"40128149\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"IER3 (IEX-1) is a stress- and NF-κB-inducible immediate early response protein that functions as an ERK substrate and dual regulator of ERK and Akt signaling: phosphorylated by ERK, IER3 inhibits B56-containing PP2A holoenzymes (by enabling ERK-mediated phosphorylation of B56 regulatory subunits, causing their dissociation from the catalytic subunit), thereby sustaining phospho-ERK and phospho-Akt levels; IER3 also directly binds RelA/p65 to attenuate NF-κB transactivation, targets the mitochondrial F1Fo-ATPase inhibitor IF1 for degradation to reduce ROS and promote ATP hydrolysis, interacts with MCL-1 to regulate BIM-dependent apoptosis, forms a complex with pERK and DNA-PK to facilitate NHEJ repair, controls nuclear MCL-1 accumulation after ATM-dependent DNA damage, and is itself subject to MDM2/FHL2-mediated ubiquitination and proteasomal degradation; the net outcome of IER3 activity—pro- or anti-apoptotic, oncogenic or tumor-suppressive—is highly context- and cell-type-dependent.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"IER3 (IEX-1) is a stress- and NF-\\u03baB-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 [#0, #4]. Its expression is directly driven at the promoter level by NF-\\u03baB/Rel complexes, synergized by p53 and antagonized by c-Myc, and is further controlled by VDR/RXR\\u03b1, Sp1, Elk-1, EGR2, and TAp73\\u03b2, as well as post-transcriptionally by MCPIP1-mediated degradation of its 3'UTR [#6, #25, #27, #28, #22, #26]. 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\\u2013B56\\u2013ERK complex, which dissociates B56 from the PP2A catalytic subunit and thereby sustains both ERK and Akt phosphorylation [#2, #10, #12]. Through sustained ERK signaling and PP2A inhibition, IER3 enhances KrasG12D-driven pancreatic oncogenesis [#21]. IER3 directly binds the transactivation domain of RelA/p65 to attenuate NF-\\u03baB-dependent transcription of anti-apoptotic genes, constituting a negative-feedback loop [#13, #9]. 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 [#14, #18]. 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 [#16, #19]. IER3 also tunes Nrf2 antioxidant signaling through the PI3K/Akt\\u2013Fyn axis [#20]. 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 [#3, #18].\",\n  \"teleology\": [\n    {\n      \"year\": 1998,\n      \"claim\": \"Established IER3 as an NF-\\u03baB-driven anti-apoptotic effector downstream of death-receptor signaling, defining its place in the survival arm of TNF biology.\",\n      \"evidence\": \"Antisense and overexpression in Jurkat and NF-\\u03baB-deficient cells with apoptosis readout\",\n      \"pmids\": [\"9703517\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"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\"]\n    },\n    {\n      \"year\": 1999,\n      \"claim\": \"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.\",\n      \"evidence\": \"RT-PCR with direct sequencing of nuclear/cytoplasmic RNA fractions from Jurkat cells\",\n      \"pmids\": [\"10448082\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab\", \"Did not address function of correctly spliced IER3\"]\n    },\n    {\n      \"year\": 2001,\n      \"claim\": \"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.\",\n      \"evidence\": \"Inducible overexpression and antisense ribozyme in HeLa with caspase and cell cycle assays; nuclear localization imaging in keratinocytes\",\n      \"pmids\": [\"11244505\", \"9878538\", \"9791001\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular basis of context switch unknown\", \"Nuclear function of IER3 not mechanistically defined\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Identified IER3 as a direct ERK2 substrate whose phosphorylation confers survival and whose ERK association potentiates ERK activation, linking it to MAPK signaling.\",\n      \"evidence\": \"In vitro kinase assay, in vivo phosphorylation, reciprocal co-IP with phospho-ERK, phosphoacceptor/docking mutants\",\n      \"pmids\": [\"12356731\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Downstream effector of phospho-IER3 not yet identified\", \"How ERK association potentiates ERK was unexplained\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Mapped the transcriptional control of IER3, showing combinatorial regulation by NF-\\u03baB/Rel, p53, c-Myc, Sp1, and VDR/RXR\\u03b1.\",\n      \"evidence\": \"EMSA, promoter/luciferase reporters, ChIP in living cells across multiple studies\",\n      \"pmids\": [\"12360408\", \"11844788\", \"12032839\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Cell-type specificity of competing inputs not resolved\", \"Quantitative contribution of each factor unclear\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Demonstrated in vivo gain-of-function consequences, showing transgenic IER3 impairs T-cell apoptosis and drives lupus-like autoimmunity, establishing physiological relevance.\",\n      \"evidence\": \"E\\u03bc-IEX-1 transgenic mice with immune challenge, flow cytometry, apoptosis assays\",\n      \"pmids\": [\"11782530\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular target mediating T-cell survival not defined here\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Defined IER3 as a counter-regulatory negative-feedback brake on NF-\\u03baB and as an anti-hypertrophic/anti-proliferative effector of mechanical stress.\",\n      \"evidence\": \"Bidirectional manipulation with reporter, proteasome, and I\\u03baB\\u03b1 epistasis assays in HEK293, cardiomyocytes, and vascular smooth muscle\",\n      \"pmids\": [\"12761504\", \"11934837\", \"14592999\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism of proteasome inhibition unclear\", \"Direct molecular target within NF-\\u03baB pathway not yet RelA\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"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.\",\n      \"evidence\": \"RNAi, B56 co-IP, in-complex in vitro phosphorylation, phospho-site mutagenesis; systematic domain mutagenesis with apoptosis/ROS readouts\",\n      \"pmids\": [\"16456541\", \"16567805\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Akt arm not yet connected\", \"Structural basis of B56-ERK-IER3 ternary complex unknown\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Extended the PP2A-B56 mechanism to sustained Akt activation and identified direct IER3\\u2013RelA/p65 binding that represses anti-apoptotic NF-\\u03baB target genes.\",\n      \"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\",\n      \"pmids\": [\"17200115\", \"18191642\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Selectivity for B56 versus other PP2A B subunits in vivo\", \"How nuclear RelA binding integrates with cytoplasmic ERK/Akt role\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Connected IER3 to the mitochondrial apoptotic machinery via direct IF1 degradation (controlling ROS and ATP hydrolysis) and MCL-1 binding with BIM-dependent apoptosis.\",\n      \"evidence\": \"IF1 binding/degradation with KO mouse metabolic readouts; yeast two-hybrid and co-IP for MCL-1 with BIM/NOXA/PUMA siRNA epistasis\",\n      \"pmids\": [\"19096392\", \"19285955\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How IF1 binding leads to its degradation mechanistically unclear\", \"MCL-1 interaction surface and stoichiometry undefined\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Placed IER3 in the ATM-dependent DNA-damage response, controlling nuclear MCL-1 trafficking, Chk1 activation, G2 arrest, and genomic stability.\",\n      \"evidence\": \"\\u03b3-irradiation, ATM and proteasome inhibitors, subcellular fractionation, Chk1 phospho and genomic instability assays with IER3 loss-of-function\",\n      \"pmids\": [\"20467439\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How IER3 mediates MCL-1 nuclear import not defined\", \"Link between nuclear MCL-1 and checkpoint mechanistically incomplete\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Showed IER3 directly promotes NHEJ via a phospho-ERK\\u2013DNA-PK complex and modulates Nrf2 antioxidant output through the PI3K/Akt-Fyn axis, broadening its DNA-repair and redox roles.\",\n      \"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\",\n      \"pmids\": [\"24184684\", \"24311782\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether DNA-PK and B56-PP2A mechanisms are coupled unknown\", \"Direct vs indirect effect on Fyn localization unresolved\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Demonstrated oncogenic cooperation in vivo, with IER3-sustained ERK signaling accelerating KrasG12D-driven pancreatic carcinogenesis, and mapped additional transcriptional inputs (Elk-1).\",\n      \"evidence\": \"Compound IER3-deficient \\u00d7 KrasG12D mice with PP2A activity assays and IHC; Elk-1 promoter mutagenesis and ChIP\",\n      \"pmids\": [\"25250570\", \"25066273\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Therapeutic targetability of the IER3-PP2A node untested\", \"Generalizability beyond pancreatic context\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"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.\",\n      \"evidence\": \"Co-IP, ubiquitination assay, K60R mutagenesis, MDM2/FHL2 knockdown; luciferase, smFISH, and RIP for MCPIP1-3'UTR interaction\",\n      \"pmids\": [\"26973248\", \"27256408\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Signals controlling MDM2/FHL2 recruitment to IER3 unknown\", \"Physiological triggers of MCPIP1-mediated turnover undefined\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Recent work links IER3 to ferroptosis suppression and senescence control through AKT/GSK3\\u03b2-NRF2 and PARL-PRDX5 axes, and reinforces context-dependent oncogenic roles via Wnt/\\u03b2-catenin.\",\n      \"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\",\n      \"pmids\": [\"41581578\", \"41359162\", \"30472635\", \"42209919\", \"40128149\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Several mechanisms rest on single-lab co-IP/reporter without mutagenesis\", \"Whether ferroptosis and senescence axes converge on the same IER3 redox function unclear\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"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.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"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\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [10, 12, 9, 14]},\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [13, 35]},\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [2, 10]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [5, 17, 16]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [2, 5]},\n      {\"term_id\": \"GO:0005739\", \"supporting_discovery_ids\": [14, 32]},\n      {\"term_id\": \"GO:0005730\", \"supporting_discovery_ids\": [17]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [2, 10, 12, 20]},\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [0, 4, 15, 16]},\n      {\"term_id\": \"R-HSA-73894\", \"supporting_discovery_ids\": [16, 19]},\n      {\"term_id\": \"R-HSA-8953897\", \"supporting_discovery_ids\": [14, 18, 31]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [3, 18]},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [23]}\n    ],\n    \"complexes\": [\n      \"IER3-B56-ERK (PP2A regulatory complex)\",\n      \"IER3-pERK-DNA-PK (NHEJ complex)\"\n    ],\n    \"partners\": [\n      \"MAPK1/ERK2\",\n      \"PPP2R5/B56\",\n      \"RELA\",\n      \"MCL1\",\n      \"ATPIF1/IF1\",\n      \"PRKDC/DNA-PK\",\n      \"MDM2\",\n      \"PARL\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":9,"faith_total":9,"faith_pct":100.0}}