{"gene":"JUND","run_date":"2026-06-10T01:55:23","timeline":{"discoveries":[{"year":1989,"finding":"JunD (jun-D) encodes a transcription factor with a DNA-binding domain homologous to c-Jun and JunB, binds AP-1/TRE sequences, and can trans-activate TRE-containing promoters; activation is further enhanced by c-Fos co-expression.","method":"cDNA cloning, DNA-binding assays with truncated proteins, transactivation reporter assays","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 1 / Strong — direct in vitro DNA-binding and transactivation assays replicated across two independent cloning papers (PMID:2504580, PMID:2493644)","pmids":["2504580","2493644"],"is_preprint":false},{"year":1991,"finding":"JunD homodimerizes and binds a cAMP/phorbol ester/Ca2+-inducible enhancer in the proenkephalin gene, activating its transcription in a protein kinase A-dependent manner; JunB inhibits this JunD-mediated activation.","method":"Transient transfection reporter assays, DNA-binding assays demonstrating homodimer binding, co-expression experiments","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro DNA-binding plus functional transactivation assays with mechanistic dissection of PKA dependence, single lab but multiple orthogonal methods","pmids":["1719551"],"is_preprint":false},{"year":1991,"finding":"JunD overexpression results in slower growth and accumulation of cells in G0/G1, whereas c-Jun overexpression promotes S/G2/M; JunD partially suppresses Ras-induced transformation, opposing c-Jun function.","method":"Retroviral overexpression in NIH 3T3 fibroblasts, cell cycle analysis, focus/soft-agar transformation assay","journal":"Cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — loss/gain-of-function in fibroblasts with defined cell-cycle and transformation phenotypes, replicated in multiple cell assays within the study","pmids":["8124713"],"is_preprint":false},{"year":1991,"finding":"The high constitutive expression of junD is driven by an octamer motif in its promoter, which is the major determinant of basal promoter activity; SP1, CAAT box, Zif268, and TRE-like elements contribute lesser roles.","method":"Promoter cloning, deletion analysis, transient transfection reporter assays, mutagenesis of cis-elements","journal":"The EMBO journal","confidence":"Medium","confidence_rationale":"Tier 1 / Weak — functional promoter dissection in single lab with multiple deletion/mutagenesis constructs","pmids":["1714380"],"is_preprint":false},{"year":1991,"finding":"Unlike c-Jun (which undergoes multi-ubiquitination and rapid degradation), JunD is not efficiently ubiquitinated and has a correspondingly longer half-life; this difference maps to the N-terminal delta-domain of c-Jun.","method":"Ubiquitination assays, protein stability measurements, N-terminal deletion/chimeric mutant analysis","journal":"Biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro ubiquitination assay plus mutational analysis identifying the regulatory domain, single lab but multiple orthogonal methods","pmids":["8922589"],"is_preprint":false},{"year":1992,"finding":"JunD (together with c-Jun) transactivates the human c-myb promoter via an AP-1-like element at -149; JunB does not. Antisense oligonucleotides to junD inhibit T-lymphocyte proliferation and reduce c-myb mRNA.","method":"Transient transfection reporter assays, gel-shift/supershift assays, site-directed mutagenesis of AP-1 element, antisense oligonucleotide treatment","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reporter assays with mutagenesis plus loss-of-function antisense, single lab but multiple orthogonal methods","pmids":["1527086"],"is_preprint":false},{"year":1993,"finding":"JunD mutants with spontaneously acquired transforming activity show enhanced transactivation specifically when forming heterodimers with Fra-2, but not with c-Fos or Fra-1; the mutated regions function as transactivation domains in a partner-specific manner.","method":"Retroviral mutagenesis, transformation assays, transient reporter assays with Fos/Fra family co-expression","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional transformation plus reporter assays with defined partner proteins, single lab","pmids":["8415709"],"is_preprint":false},{"year":1994,"finding":"JunD is identified as the key mediator of nur77 induction by NGF and membrane depolarization in PC12 cells: JunD binds NAP1/NAP2 AP-1-like elements in the nur77 promoter, transactivates through them, and a dominant-negative JunD abolishes nur77 activation by both stimuli.","method":"Nuclear extract binding assays (EMSA/supershift), transient reporter transfection, dominant-negative JunD expression","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 2 / Moderate — reciprocal EMSA/supershift + dominant-negative epistasis + reporter assays, single lab with multiple orthogonal methods","pmids":["7969116"],"is_preprint":false},{"year":1994,"finding":"JunD positively auto-regulates its own promoter through its unique TRE element, creating a positive autoregulatory loop that may account for its constitutive expression.","method":"Promoter-reporter transfection assays comparing junD vs. c-jun/junB transactivation of hjunD promoter constructs","journal":"DNA and cell biology","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — reporter assays showing preferential self-activation, single lab, single method","pmids":["8172655"],"is_preprint":false},{"year":1999,"finding":"Menin (MEN1 tumor suppressor) directly interacts with JunD and represses JunD-activated transcription. Menin does not directly interact with other Jun or Fos family members. Several MEN1 missense mutations disrupt menin–JunD interaction.","method":"Yeast two-hybrid screen, in vitro binding assay, in vivo co-immunoprecipitation, Gal4-fusion reporter and AP-1-responsive reporter assays, MEN1 missense mutant panel","journal":"Cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal in vitro + in vivo binding, multiple functional reporter assays, mutant panel, replicated independently (PMID:9989505, PMID:10500243)","pmids":["9989505","10500243"],"is_preprint":false},{"year":1999,"finding":"Menin-mediated repression of JunD transcriptional activity is dependent on histone deacetylase activity: the HDAC inhibitor trichostatin A relieves menin-dependent repression of JunD.","method":"Co-transfection reporter assays, trichostatin A treatment, C-terminal deletion mutants of menin","journal":"Biochimica et biophysica acta","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — pharmacological HDAC inhibition plus domain-mapping mutants, single lab","pmids":["10500243"],"is_preprint":false},{"year":1999,"finding":"TGF-β1 induces IL-6 expression in primary human lung fibroblasts via an AP-1 site; the TGF-β1-activated AP-1 complex is a JunD homodimer (absent of Fos isoforms), as shown by supershift analysis.","method":"EMSA supershift analysis, luciferase reporter with 5'-deletions and site-directed mutagenesis, RT-PCR, ELISA","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — EMSA supershift plus mutagenesis of AP-1 site, single lab with multiple methods","pmids":["10212284"],"is_preprint":false},{"year":2000,"finding":"JunD-deficient primary fibroblasts exhibit p53-dependent growth arrest, upregulated p19Arf, and premature senescence. JunD also protects against p53-dependent apoptosis in response to UV irradiation and TNF-α in vivo.","method":"JunD knockout mouse-derived primary fibroblasts, senescence assays, UV/TNF apoptosis assays, in vivo TNF-mediated hepatitis model","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 2 / Moderate — genetic KO with multiple phenotypic readouts across in vitro and in vivo systems, single lab","pmids":["11106750"],"is_preprint":false},{"year":2000,"finding":"Targeted disruption of murine junD causes multiple age-dependent defects in male reproductive function and impaired spermatogenesis, demonstrating specific in vivo functions. JunD-/- animals are viable, with no compensatory upregulation of c-Jun or JunB.","method":"Gene targeting (lacZ knock-in), histology, hormone assays, spermatogenesis analysis","journal":"Development (Cambridge, England)","confidence":"High","confidence_rationale":"Tier 2 / Moderate — constitutive KO with specific organ-level phenotypic readouts, single lab","pmids":["10654608"],"is_preprint":false},{"year":2001,"finding":"JunD regulates TIMP-1 gene promoter activity in activated hepatic stellate cells, acting primarily as JunD homodimers; JunD also activates IL-6 transcription as a heterodimer at an alternative AP-1 site.","method":"Expression vectors for wild-type, dominant-negative, and forced-homodimer JunD/eb1 chimeras; AP-1 EMSA from activated HSCs; promoter-reporter and mutagenesis assays","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Moderate — genetic dominant-negative plus forced homodimer chimeras plus mutagenesis, single lab with multiple orthogonal approaches","pmids":["11337499"],"is_preprint":false},{"year":2001,"finding":"PGF2α induces JunD phosphorylation via a calcium/calmodulin-dependent activation of ERK1/2; JunD bound constitutively to AP-1 sites in the nur77 promoter is activated by this phosphorylation to induce nur77 and 20α-HSD gene expression.","method":"Serial 5'-deletion promoter assays, dominant-negative JunD, AP-1 site mutagenesis, calcium/calmodulin and ERK inhibitors, in vitro kinase assays","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — in vitro kinase assay + dominant-negative epistasis + inhibitor pharmacology + promoter mutagenesis, single lab with multiple orthogonal methods","pmids":["11719525"],"is_preprint":false},{"year":2002,"finding":"Both JunD isoforms (full-length JunD-FL and truncated ΔJunD, generated by alternative translation initiation) are phosphorylated by JNK at three identical residues; JunD-FL contains a JNK docking domain, binds JNK more efficiently, and is a more potent transcriptional activator than ΔJunD.","method":"In vitro kinase assays, docking domain mutagenesis, transcriptional reporter assays, site-directed mutagenesis of JNK phosphorylation sites","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro kinase assay plus mutagenesis of phosphorylation sites and docking domain, single lab with multiple orthogonal methods","pmids":["12052834"],"is_preprint":false},{"year":2002,"finding":"JunD mRNA produces two protein isoforms (JunD-FL 39 kDa and ΔJunD 34 kDa) by alternative translation initiation from two in-frame AUGs; the 5'-UTR structure regulates the ratio of the two isoforms, and translation is cap-dependent (no IRES).","method":"Translational reporter assays, mutagenesis of start codons (AUG, ACG, CUG), cap-dependent translation assay","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — systematic start-site mutagenesis with functional readout in multiple constructs, single lab","pmids":["12105216"],"is_preprint":false},{"year":2002,"finding":"Menin inhibits ERK-dependent phosphorylation of JunD and JNK-mediated phosphorylation of JunD and c-Jun without affecting upstream ERK2 or JNK1 activation, acting downstream of MAPK to uncouple kinase activation from nuclear target phosphorylation; two distinct inhibitory mechanisms for ERK and JNK pathways are indicated by N-terminal deletion analysis.","method":"In vitro kinase assays, overexpression of Menin, N-terminal deletion mutants of Menin, phosphorylation analysis","journal":"Oncogene","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro kinase assay plus domain-mapping mutants showing two distinct inhibitory mechanisms, single lab","pmids":["12226747"],"is_preprint":false},{"year":2003,"finding":"JNK-stimulated survival signaling is mediated by JunD; the JNK/JunD pathway collaborates with NF-κB to increase antiapoptotic gene expression, providing a mechanistic basis for dual JNK roles in apoptosis versus survival.","method":"Genetic mouse models (JunD KO), JNK signaling pathway analysis, NF-κB activity assays, antiapoptotic gene expression analysis","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 2 / Moderate — genetic KO plus signaling pathway dissection, single lab with multiple readouts","pmids":["12820962"],"is_preprint":false},{"year":2003,"finding":"JunD transcription factor switches from growth suppressor to growth promoter when its binding to menin is prevented (either by a JunD G42E mutant unable to bind menin or by Men1-null background), demonstrating that menin interaction is required for JunD's anti-proliferative function.","method":"Stable cell lines with wild-type or menin-binding-deficient JunD mutant in JunD-/- or Men1-/- immortalized fibroblasts; proliferation assays; morphological analysis; cyclin D1 measurement","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic epistasis with menin-null background and binding-deficient point mutant, replicated across multiple cell-line conditions","pmids":["12960363"],"is_preprint":false},{"year":2003,"finding":"JunD is required to halt a second wave of cell proliferation and prevent glomerular sclerosis and fibrosis after nephron reduction; the effect is non-cell-autonomous and involves upregulation of the paracrine mitogen TGF-α (EGFR ligand).","method":"JunD-/- mice with 75% nephron reduction, bitransgenic JunD-/-/REM (dominant-negative EGFR) rescue, TGF-α expression analysis","journal":"The Journal of clinical investigation","confidence":"High","confidence_rationale":"Tier 2 / Moderate — genetic KO with rescue via dominant-negative EGFR transgene establishes pathway position, single lab","pmids":["12975469"],"is_preprint":false},{"year":2004,"finding":"JunD limits tumor angiogenesis by regulating antioxidant defense genes, reducing H2O2 production. In junD-/- cells, H2O2 accumulation decreases FeII availability, reduces HIF prolyl hydroxylase (PHD) activity, leading to HIF-α accumulation and VEGF-A transcription.","method":"junD-/- cell lines, ROS measurement, PHD activity assays, HIF-α western blot, VEGF-A expression, iron chelation experiments","journal":"Cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic KO with multiple orthogonal biochemical readouts establishing pathway mechanism, single lab with rigorous controls","pmids":["15369676"],"is_preprint":false},{"year":2004,"finding":"HBZ (HTLV-1 bZIP factor) interacts with JunD via the bZIP domains of both proteins in vitro and in vivo, and this interaction activates JunD-dependent transcription (in contrast to HBZ's repression of c-Jun).","method":"Co-immunoprecipitation (in vivo), in vitro binding assay, co-transfection reporter assays","journal":"FEBS letters","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal in vitro and in vivo binding plus functional reporter assay, single lab","pmids":["15044019"],"is_preprint":false},{"year":2004,"finding":"JunD promotes osteoblast differentiation (upregulating Runx2, COL1, osteocalcin, ALP); menin co-immunoprecipitates with JunD in osteoblasts, and menin overexpression suppresses JunD-induced AP-1 reporter activity and alkaline phosphatase activity.","method":"Stable overexpression, menin antisense knockdown, co-immunoprecipitation, AP-1 luciferase reporter, ALP activity assay","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP plus functional reporter in osteoblast-specific context, single lab","pmids":["15563473"],"is_preprint":false},{"year":2005,"finding":"JunD binds the antioxidant response element (ARE) of the human ferritin H gene, is phosphorylated at Ser-100 by H2O2 or t-BHQ treatment, and activates ferritin H transcription; ChIP confirmed H2O2-induced JunD binding to the ferritin H ARE in vivo.","method":"EMSA/gel retardation, chromatin immunoprecipitation (ChIP), phosphorylation analysis, JunD overexpression with endogenous ferritin H protein measurement","journal":"Oncogene","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — ChIP (in vivo binding), EMSA, phosphorylation analysis, and functional overexpression assay, single lab with multiple orthogonal methods","pmids":["16007120"],"is_preprint":false},{"year":2006,"finding":"JunD is a profibrogenic transcription factor in liver: junD-/- mice are protected from CCl4-induced fibrosis with reduced TIMP-1 expression; Ser100 phosphorylation of JunD (mediated by ERK1/2, not JNK) regulates JunD-dependent TIMP-1 expression in activated HSCs.","method":"junD-/- mice with CCl4 fibrosis model, alpha-SMA immunostaining, TIMP-1 mRNA analysis, phospho-mutant analysis, JNK inhibitor ruling-out experiments","journal":"Hepatology","confidence":"High","confidence_rationale":"Tier 2 / Moderate — in vivo genetic KO plus phospho-site mutant analysis with defined readouts, single lab","pmids":["17133482"],"is_preprint":false},{"year":2007,"finding":"HBZ and JunD co-occupy the proximal region of the hTERT promoter (via ChIP) and form heterodimers that interact with Sp1; activation of hTERT transcription by HBZ/JunD heterodimers is mediated through Sp1 GC-rich binding sites.","method":"Co-transfection luciferase reporter assays, RT-PCR, ChIP, Sp1 co-immunoprecipitation","journal":"Retrovirology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP plus co-IP plus reporter assays, single lab","pmids":["18078517"],"is_preprint":false},{"year":2008,"finding":"JunD is a major determinant of macrophage activation in WKY rats; JunD knockdown in rat and human primary macrophages reduces Fc receptor-mediated macrophage activation and cytokine production, demonstrating conserved function.","method":"Congenic mapping, siRNA knockdown in rat and human macrophages, Fc receptor-mediated activation assays, cytokine measurement","journal":"Nature genetics","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic mapping plus siRNA knockdown in primary cells from two species with defined functional readouts","pmids":["18443593"],"is_preprint":false},{"year":2008,"finding":"JunD negatively regulates ZO-1 expression at both transcriptional and translational levels in intestinal epithelial cells: transcriptional repression is mediated through a CREB-binding site in the ZO-1 promoter, and translational repression involves enhanced binding of RNA-binding protein TIA-1-related (TIAR) to the ZO-1 3'-UTR.","method":"Ectopic JunD overexpression, polyamine depletion, luciferase reporter with ZO-1 promoter, RNA co-immunoprecipitation for TIAR binding to ZO-1 3'-UTR, epithelial permeability assays","journal":"Molecular biology of the cell","confidence":"High","confidence_rationale":"Tier 2 / Moderate — dual transcriptional/translational mechanism established by reporter assays plus RNA-IP, single lab with multiple orthogonal methods","pmids":["18562690"],"is_preprint":false},{"year":2008,"finding":"THC activates JunD by upregulating gene expression and translocating the protein to the nuclear compartment, and these events are accompanied by decreased breast cancer cell proliferation; JunD knockdown and genetic ablation reduce THC's antiproliferative effect.","method":"siRNA knockdown, JunD KO fibroblasts, nuclear fractionation, RT-PCR/western blot, proliferation assays","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — nuclear translocation by fractionation plus loss-of-function in two models (siRNA + KO), single lab","pmids":["18454173"],"is_preprint":false},{"year":2008,"finding":"JunD protects the liver from ischemia/reperfusion injury by suppressing AP-1 transcriptional activation; in the absence of JunD, c-Jun phosphorylation and AP-1 activation are elevated, correlating with increased caspase activation. JunD counterbalances JNK1 and regulates NADPH oxidase (Nox2/Nox4) expression.","method":"JunD-/- mice with I/R model, dominant-negative JNK1 transgene rescue, AP-1 reporter assays, caspase activation assays, Nox2/Nox4 mRNA analysis","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Moderate — genetic KO plus JNK1 dominant-negative rescue establishes pathway position, single lab with multiple readouts","pmids":["18182393"],"is_preprint":false},{"year":2009,"finding":"JunD and HIF-1α co-operatively mediate TGF-β1-induced transcriptional activation of the angiotensinogen gene in human lung fibroblasts; both proteins bind the AGT core promoter as shown by oligonucleotide pulldown and ChIP; simultaneous knockdown of both completely eliminates TGF-β1-inducible AGT promoter activity.","method":"Oligonucleotide pulldown, ChIP, serial deletion/site-directed mutagenesis of AGT promoter, siRNA knockdown of JunD and HIF-1α, luciferase reporter assays","journal":"FASEB journal","confidence":"High","confidence_rationale":"Tier 2 / Moderate — ChIP plus pulldown plus combinatorial siRNA knockdown plus reporter mutagenesis, single lab","pmids":["19211927"],"is_preprint":false},{"year":2010,"finding":"Polyamines regulate JunD mRNA stability by modulating competitive binding of HuR (stabilizing) and AUF1 (destabilizing) to the JunD 3'-UTR: polyamine depletion increases HuR binding and decreases AUF1 association, stabilizing JunD mRNA; HuR silencing prevents polyamine depletion-induced JunD upregulation.","method":"RNA-immunoprecipitation, HuR/AUF1 silencing by siRNA, polyamine depletion/repletion experiments, mRNA stability assays","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 2 / Moderate — competitive RNA-IP plus loss-of-function for both HuR and AUF1, single lab with multiple orthogonal methods","pmids":["20805360"],"is_preprint":false},{"year":2010,"finding":"Androgen receptor (AR) forms a complex with JunD in androgen-treated prostate cancer cells (co-immunoprecipitation and Gaussia luciferase reconstitution); JunD binds directly to the SSAT promoter only in androgen-treated LNCaP cells (ChIP), and JunD is essential for androgen-induced SSAT gene expression and the resulting ROS production.","method":"Co-immunoprecipitation, Gaussia luciferase reconstitution assay, ChIP, luciferase reporter, JunD-silenced (siRNA) stable cell line, DCF ROS assay","journal":"Cancer research","confidence":"High","confidence_rationale":"Tier 2 / Moderate — ChIP plus co-IP plus complementary reconstitution assay establishing direct AR-JunD complex, single lab with multiple orthogonal methods","pmids":["20460526"],"is_preprint":false},{"year":2011,"finding":"JunD mediates TGF-β-induced fibroblast activation in systemic sclerosis; JunD overexpression is Smad3/Smad4-dependent (siRNA silencing of Smad3/4 prevents JunD induction). JunD-/- fibroblasts are less responsive to TGF-β and release less collagen; JunD-/- mice are protected from bleomycin-induced fibrosis.","method":"siRNA knockdown of Smad3/Smad4, JunD-/- fibroblasts and mice, bleomycin fibrosis model, hydroxyproline assays, alpha-SMA counting","journal":"Annals of the rheumatic diseases","confidence":"High","confidence_rationale":"Tier 2 / Moderate — genetic KO plus Smad pathway epistasis by siRNA, in vitro and in vivo, single lab","pmids":["21515915"],"is_preprint":false},{"year":2012,"finding":"Crystal structures of human menin in complex with MLL1 or JUND reveal that the same deep pocket binds short peptides of MLL1 or JUND in identical manners; menin-JUND interaction blocks JNK-mediated JUND phosphorylation and suppresses JUND-induced transcription, whereas menin promotes MLL1-mediated transcription.","method":"X-ray crystallography (crystal structures of free menin, menin–MLL1, menin–JUND, menin–MLL1–LEDGF complexes), kinase phosphorylation assays, transcriptional reporter assays","journal":"Nature","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structure plus functional kinase assay plus reporter assays, replicated concept across multiple complexes in one rigorous study","pmids":["22327296"],"is_preprint":false},{"year":2013,"finding":"JunD is identified as a primary regulator of oxidative stress and IL-1β synthesis in macrophages via combined ChIP-Seq and transcriptome analysis; JunD binding events correlate with gene expression changes for oxidative stress and inflammatory genes in primary macrophages.","method":"ChIP-Seq, microarray transcriptomics after Jund siRNA knockdown, comparative expression in congenic strains with different JunD levels","journal":"BMC genomics","confidence":"High","confidence_rationale":"Tier 2 / Strong — ChIP-Seq combined with genome-wide expression profiling in primary cells and replicated across congenic strains","pmids":["23398888"],"is_preprint":false},{"year":2013,"finding":"JunD deficiency accelerates age-related endothelial dysfunction by reducing scavenger enzymes (MnSOD, ecSOD, ALDH2) and upregulating NADPH oxidase subunits (p47phox, Nox2, Nox4), leading to mitochondrial superoxide formation, reduced eNOS activity, and premature vascular senescence; old WT mice show reduced JunD due to promoter hypermethylation and increased menin binding.","method":"JunD-/- mice (young and old), eNOS activity assays, ESR spectroscopy, NADPH oxidase subunit analysis, telomerase activity, senescence markers, JunD overexpression rescue, siRNA knockdown in human endothelial cells, promoter methylation analysis","journal":"Circulation","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic KO plus JunD overexpression rescue plus siRNA in human cells with multiple orthogonal biochemical readouts, single lab with comprehensive controls","pmids":["23410942"],"is_preprint":false},{"year":2013,"finding":"BAG3 stabilizes JunD mRNA, contributing to JunD-mediated growth inhibition; c-Jun transcriptionally activates BAG3 expression.","method":"BAG3 knockdown/overexpression, mRNA stability assays, proliferation assays","journal":"Biochimica et biophysica acta","confidence":"Low","confidence_rationale":"Tier 3 / Weak — mRNA stability assay single lab, mechanism of stabilization not fully characterized in abstract","pmids":["24140207"],"is_preprint":false},{"year":2016,"finding":"TGF-β reduces JunD protein (not mRNA) in RWPE-1 and DU145 prostate cells via proteasomal degradation, correlating with inhibition of proliferation; selective siRNA knockdown of JunD reduces proliferation while knockdown of c-Jun or JunB has little effect.","method":"siRNA knockdown of individual Jun family members, proteasome inhibitor treatment, JunD overexpression, proliferation assays","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — proteasomal degradation pathway established pharmacologically plus selective siRNA for each Jun family member, single lab","pmids":["27358408"],"is_preprint":false},{"year":2019,"finding":"JunD transcriptional activity is increased in obese hearts; JunD directly binds the PPARγ promoter (ChIP) to drive transcription of TG synthesis/uptake/storage genes (Fas, Cd36, Lpl, Plin5), causing myocardial lipid accumulation; JunD is a direct target of miR-494-3p (Ago2 IP + luciferase assay).","method":"ChIP for JunD at PPARγ promoter, Ago2 immunoprecipitation, luciferase reporter assay, cardiac-specific JunD overexpression, JunD-/- DIO mice, miR-494-3p overexpression","journal":"European heart journal","confidence":"High","confidence_rationale":"Tier 2 / Moderate — ChIP establishing direct promoter binding plus Ago2-IP for miRNA targeting plus genetic KO and OE rescue, single lab with multiple orthogonal methods","pmids":["30629164"],"is_preprint":false},{"year":2019,"finding":"JunD blunts ischemia/reperfusion-induced brain injury by suppressing IL-1β; JunD knockdown increases brain IL-1β and worsens stroke outcomes; anti-IL-1β antibody rescues the deleterious effects of JunD silencing.","method":"In vivo siRNA knockdown in mice, MCAO stroke model, brain IL-1β measurement, cytokine panels, anti-IL-1β antibody rescue experiment","journal":"Stroke","confidence":"High","confidence_rationale":"Tier 2 / Moderate — in vivo siRNA knockdown with specific cytokine rescue establishes IL-1β as downstream effector, single lab","pmids":["30626291"],"is_preprint":false},{"year":2020,"finding":"Hyperglycemia-induced JunD downregulation in the diabetic myocardium is mediated by a complex epigenetic mechanism involving DNA promoter hypermethylation, histone modifications, and translational repression by miR-673/menin; cardiac-specific JunD overexpression protects against hyperglycemia-induced dysfunction.","method":"Streptozotocin diabetes model, cardiac-specific αMHC-JunD transgenic mice, ESR spectroscopy for ROS, echocardiography, promoter methylation analysis, histone mark analysis, miRNA-673 and menin analysis","journal":"Circulation research","confidence":"High","confidence_rationale":"Tier 2 / Strong — cardiac-specific OE rescue plus multiple orthogonal epigenetic mechanisms characterized, validated in human diabetic hearts","pmids":["32815777"],"is_preprint":false},{"year":2021,"finding":"JunD (not c-Jun) is the crucial AP-1 substrate of JNK signaling required for Ras-driven lung tumorigenesis: c-Jun deletion increases JunD protein and lung tumor burden; deletion of JunD completely abolishes K-Ras-driven lung adenocarcinoma; phosphorylation of JunD is increased in c-Jun-deficient lung cells.","method":"Inducible lung-specific conditional KO (c-Jun and JunD), K-RasG12D lung tumor model, dominant-active JNKK2-JNK1 transgene, tumor burden quantification, JunD phosphorylation analysis","journal":"JCI insight","confidence":"High","confidence_rationale":"Tier 2 / Strong — combinatorial conditional KO with tumor formation assay plus epistasis with JNK transgene, single lab with multiple genetic models","pmids":["34236045"],"is_preprint":false},{"year":2022,"finding":"JunD directly binds the linc00976 promoter and activates its transcription (established by ChIP-PCR), thereby promoting cholangiocarcinoma progression.","method":"ChIP-PCR for JunD binding at linc00976 promoter, luciferase reporter assay","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — ChIP-PCR demonstrating direct promoter binding, single lab, single method for the JUND-specific mechanistic finding","pmids":["36400758"],"is_preprint":false}],"current_model":"JUND encodes a constitutively expressed AP-1 family bZIP transcription factor that forms homo- and heterodimers to bind TRE/AP-1 sequences; it is phosphorylated and activated by JNK (at N-terminal sites via a specific docking domain) and ERK1/2 (at Ser100), unlike c-Jun it escapes efficient ubiquitination and has a long half-life, its transcriptional activity and growth-suppressive function are directly inhibited by menin (MEN1 tumor suppressor) via a shared peptide-binding pocket that also blocks JNK-mediated JUND phosphorylation, it acts as the critical JNK substrate driving Ras-induced lung tumorigenesis, it limits oxidative stress by transcriptionally regulating antioxidant defense genes and NADPH oxidase subunits (thereby suppressing HIF-α/VEGF-A angiogenesis and protecting the vasculature, heart, liver, and brain from injury), and its mRNA stability is post-transcriptionally controlled by competitive HuR/AUF1 binding to its 3'-UTR in a polyamine-dependent manner."},"narrative":{"mechanistic_narrative":"JUND encodes a constitutively expressed AP-1 family bZIP transcription factor that binds AP-1/TRE sequences as a homodimer or as heterodimer with Fos/Fra partners to trans-activate target promoters [PMID:2504580, PMID:2493644, PMID:1719551, PMID:8415709]. Its high basal expression is driven by an octamer-dominated promoter and reinforced by TRE-mediated positive autoregulation [PMID:1714380, PMID:8172655], and it generates two isoforms (JunD-FL and ΔJunD) by alternative translation initiation, with the full-length form carrying a JNK docking domain and acting as the stronger activator [PMID:12052834, PMID:12105216]. Unlike c-Jun, JunD escapes efficient ubiquitination and is correspondingly stable, a difference mapping to the c-Jun N-terminal delta-domain [PMID:8922589]. JunD is activated by MAPK signaling — phosphorylated by JNK at N-terminal sites and by ERK1/2 at Ser-100 — to drive transcription of targets including nur77, ferritin H, and TIMP-1 [PMID:11719525, PMID:12052834, PMID:16007120, PMID:17133482]. Functionally JunD opposes c-Jun: it slows proliferation, arrests cells in G0/G1, and suppresses Ras transformation, and its growth-suppressive activity requires direct binding by the MEN1 tumor suppressor menin, which represses JunD transcription in an HDAC-dependent manner and, through a shared peptide-binding pocket revealed by crystallography, blocks JNK-mediated JunD phosphorylation [PMID:8124713, PMID:9989505, PMID:10500243, PMID:12960363, PMID:22327296]. Conversely, JunD is the critical JNK substrate driving K-Ras–induced lung tumorigenesis [PMID:34236045]. A central physiological role is limitation of oxidative stress: JunD regulates antioxidant defense genes and NADPH oxidase subunits, controlling H2O2/ROS levels, restraining HIF-α/VEGF-A–driven angiogenesis, and protecting the vasculature, heart, liver, and brain from injury [PMID:15369676, PMID:18182393, PMID:23410942, PMID:30626291, PMID:32815777]. JunD also mediates TGF-β–induced fibroblast activation and fibrosis via Smad-dependent induction [PMID:17133482, PMID:21515915], regulates macrophage activation and inflammatory cytokine output [PMID:18443593, PMID:23398888], and is post-transcriptionally controlled through polyamine-dependent competitive binding of HuR and AUF1 to its 3'-UTR [PMID:20805360].","teleology":[{"year":1989,"claim":"Established JUND as a bona fide AP-1 transcription factor, defining its molecular identity as a DNA-binding, TRE-activating protein related to c-Jun.","evidence":"cDNA cloning, DNA-binding and transactivation reporter assays, with c-Fos co-expression","pmids":["2504580","2493644"],"confidence":"High","gaps":["Did not define partner-specific dimer preferences","No in vivo target genes identified"]},{"year":1991,"claim":"Showed that JunD has functions opposite to c-Jun — it suppresses proliferation and Ras transformation — framing JunD as a growth-suppressive AP-1 member, and identified the constitutive high-expression promoter.","evidence":"Retroviral overexpression in NIH 3T3 with cell-cycle and transformation assays; promoter deletion/mutagenesis","pmids":["8124713","1714380"],"confidence":"High","gaps":["Mechanism of growth suppression not defined at this stage","Did not identify the menin requirement later established"]},{"year":1996,"claim":"Explained why JunD is more stable than c-Jun by showing it escapes efficient ubiquitination, mapping the difference to the c-Jun delta-domain.","evidence":"Ubiquitination assays, protein stability measurements, chimeric/deletion mutants","pmids":["8922589"],"confidence":"High","gaps":["E3 ligase machinery not identified","Did not connect stability to specific physiological outputs"]},{"year":1999,"claim":"Identified menin (MEN1) as a direct, JunD-specific repressor, linking JunD growth suppression to a tumor-suppressor pathway and showing repression is HDAC-dependent.","evidence":"Yeast two-hybrid, reciprocal in vitro/in vivo binding, reporter assays, MEN1 mutant panel, TSA treatment","pmids":["9989505","10500243"],"confidence":"High","gaps":["Structural basis of binding not yet defined","Did not establish whether menin binding is required for growth suppression"]},{"year":2000,"claim":"Genetic knockout established physiological JunD functions: protection against p53-dependent senescence/apoptosis and a specific role in male reproduction, with no Jun-family compensation.","evidence":"JunD-/- mice and primary fibroblasts; senescence, UV/TNF apoptosis, hepatitis models; histology","pmids":["11106750","10654608"],"confidence":"High","gaps":["Molecular targets mediating p53/p19Arf control not defined","Tissue-specific mechanisms distinct"]},{"year":2002,"claim":"Defined the kinase-substrate logic of JunD activation — JNK docking/phosphorylation and isoform-specific potency — and showed menin uncouples MAPK activation from JunD phosphorylation downstream of ERK/JNK.","evidence":"In vitro kinase assays, docking-domain and start-codon mutagenesis, menin deletion mutants","pmids":["12052834","12105216","12226747"],"confidence":"High","gaps":["Endogenous stoichiometry of the two isoforms in tissues unclear","Precise mechanism by which menin blocks phosphorylation not yet structural"]},{"year":2003,"claim":"Established menin binding as required for JunD's anti-proliferative function and showed JunD mediates JNK-driven survival signaling, positioning JunD at a switch between growth suppression and survival.","evidence":"Menin-binding-deficient JunD mutant in Men1-null/JunD-null fibroblasts; JunD KO with JNK/NF-κB analysis; nephron-reduction model with EGFR rescue","pmids":["12960363","12820962","12975469"],"confidence":"High","gaps":["Target genes downstream of the JunD survival program incompletely defined","How menin binding toggles JunD output mechanistically unresolved at this stage"]},{"year":2004,"claim":"Revealed JunD as a master regulator of oxidative stress, controlling antioxidant genes and ROS to restrain HIF-α/VEGF-A angiogenesis, defining its protective vascular/anti-tumor role.","evidence":"junD-/- cells, ROS/PHD activity assays, HIF-α/VEGF-A measurement, iron chelation; ferritin H ARE ChIP and Ser-100 phosphorylation","pmids":["15369676","16007120"],"confidence":"High","gaps":["Full antioxidant gene repertoire not enumerated","Relative contribution of each redox target uncertain"]},{"year":2008,"claim":"Extended JunD function to fibrosis, inflammation, and barrier regulation, and revealed dual transcriptional and post-transcriptional control mechanisms.","evidence":"junD-/- fibrosis models, macrophage siRNA in rat/human, ZO-1 promoter/3'-UTR (TIAR) analysis, liver I/R with JNK1 dominant-negative rescue","pmids":["17133482","18443593","18562690","18182393"],"confidence":"High","gaps":["Tissue-specific dimer partners not fully mapped","Crosstalk between transcriptional and translational repression unresolved"]},{"year":2010,"claim":"Defined post-transcriptional regulation of JunD by competitive HuR/AUF1 binding to its 3'-UTR in a polyamine-dependent manner, and identified AR-JunD complexes driving polyamine-oxidase-linked ROS.","evidence":"RNA-IP, HuR/AUF1 silencing, polyamine depletion/repletion; AR co-IP, ChIP at SSAT promoter, ROS assays","pmids":["20805360","20460526"],"confidence":"High","gaps":["3'-UTR cis-elements for HuR/AUF1 not finely mapped","Generality of AR-JunD interaction beyond prostate cells unclear"]},{"year":2012,"claim":"Solved the structural basis of menin-JUND regulation, showing menin uses one pocket to bind JUND or MLL1, blocking JNK phosphorylation of JUND while promoting MLL1 transcription.","evidence":"X-ray crystallography of menin–JUND/MLL1 complexes, kinase and reporter assays","pmids":["22327296"],"confidence":"High","gaps":["Does not resolve dynamics of competition with MLL1 in cells","In vivo consequences of pocket occupancy not directly tested"]},{"year":2013,"claim":"Genome-wide profiling and vascular studies cemented JunD as the central regulator linking antioxidant defense, NADPH oxidase, and inflammation to age-related endothelial dysfunction.","evidence":"ChIP-Seq/transcriptomics in macrophages; JunD-/- and overexpression in mice/human endothelial cells, eNOS/ROS/senescence assays, promoter methylation","pmids":["23398888","23410942"],"confidence":"High","gaps":["Causal direct vs indirect targets among bound genes not fully separated","Mechanism coupling promoter hypermethylation to menin binding incompletely defined"]},{"year":2021,"claim":"Demonstrated that JunD, not c-Jun, is the essential JNK/AP-1 substrate required for Ras-driven lung tumorigenesis, clarifying the oncogenic versus suppressive division within the AP-1 family.","evidence":"Conditional c-Jun and JunD knockouts in K-RasG12D lung model, JNK transgene epistasis, phosphorylation analysis","pmids":["34236045"],"confidence":"High","gaps":["Critical JunD transcriptional targets driving tumorigenesis not defined","Context-dependence relative to JunD's growth-suppressive role unresolved"]},{"year":2022,"claim":"Extended JunD direct-target repertoire to disease-promoting noncoding and metabolic genes, including linc00976 in cholangiocarcinoma and PPARγ in obese hearts.","evidence":"ChIP/ChIP-PCR at linc00976 and PPARγ promoters, luciferase assays, cardiac JunD overexpression/KO, miRNA targeting","pmids":["36400758","30629164"],"confidence":"High","gaps":["Dimer composition at these promoters not defined","Tissue-selectivity of JunD pro-disease versus protective output unexplained"]},{"year":null,"claim":"How JunD's opposing activities — growth suppression versus Ras-driven tumorigenesis, vascular protection versus pro-fibrotic/pro-disease transcription — are switched by dimer partner choice, phosphorylation state, and menin occupancy in a given tissue remains unresolved.","evidence":"","pmids":[],"confidence":"High","gaps":["No unified model linking partner selection to context-specific output","Direct genome-wide targets across tissues not comprehensively defined","Predictive rules for when JunD protects versus promotes disease unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[0,1,5,7,14,25,32,34,41,45]},{"term_id":"GO:0003677","term_label":"DNA binding","supporting_discovery_ids":[0,25,32,41]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[25,30,34,41]}],"pathway":[{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[0,1,7,25,32,41]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[15,16,18,19,35]},{"term_id":"R-HSA-8953897","term_label":"Cellular responses to stimuli","supporting_discovery_ids":[22,25,31,38]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[28,37,42]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[22,44,45]}],"complexes":["AP-1 (JunD homodimer / Jun-Fos heterodimer)"],"partners":["MEN1","JUN","FOS","FOSL2","HIF1A","AR","SP1","HBZ"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P17535","full_name":"Transcription factor JunD","aliases":["Transcription factor AP-1 subunit JunD"],"length_aa":347,"mass_kda":35.2,"function":"Transcription factor binding AP-1 sites (PubMed:9989505). Heterodimerizes with proteins of the FOS family to form an AP-1 transcription factor complex, thereby enhancing their DNA binding activity to an AP-1 consensus sequence 3'-TGA[GC]TCA-5' and enhancing their transcriptional activity (PubMed:28981703, PubMed:9989505)","subcellular_location":"Nucleus","url":"https://www.uniprot.org/uniprotkb/P17535/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/JUND","classification":"Not Classified","n_dependent_lines":92,"n_total_lines":1208,"dependency_fraction":0.076158940397351},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"CAPZB","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/JUND","total_profiled":1310},"omim":[{"mim_id":"615093","title":"LYMPHOCYTE ANTIGEN 6 COMPLEX, LOCUS K; LY6K","url":"https://www.omim.org/entry/615093"},{"mim_id":"613733","title":"MENIN 1; MEN1","url":"https://www.omim.org/entry/613733"},{"mim_id":"612476","title":"BASIC LEUCINE ZIPPER TRANSCRIPTION FACTOR, ATF-LIKE; BATF","url":"https://www.omim.org/entry/612476"},{"mim_id":"608657","title":"JUN DIMERIZATION PROTEIN 2; JDP2","url":"https://www.omim.org/entry/608657"},{"mim_id":"608067","title":"RING FINGER AND WD REPEAT DOMAINS-CONTAINING PROTEIN 2; RFWD2","url":"https://www.omim.org/entry/608067"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Enhanced","locations":[{"location":"Nucleoplasm","reliability":"Enhanced"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/JUND"},"hgnc":{"alias_symbol":["AP-1"],"prev_symbol":[]},"alphafold":{"accession":"P17535","domains":[{"cath_id":"1.20.5","chopping":"269-334","consensus_level":"medium","plddt":97.233,"start":269,"end":334}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P17535","model_url":"https://alphafold.ebi.ac.uk/files/AF-P17535-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P17535-F1-predicted_aligned_error_v6.png","plddt_mean":62.19},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=JUND","jax_strain_url":"https://www.jax.org/strain/search?query=JUND"},"sequence":{"accession":"P17535","fasta_url":"https://rest.uniprot.org/uniprotkb/P17535.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P17535/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P17535"}},"corpus_meta":[{"pmid":"2493644","id":"PMC_2493644","title":"jun-D: a third member of the jun gene 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gene and its product.","date":"1991","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/1923529","citation_count":32,"is_preprint":false},{"pmid":"27358408","id":"PMC_27358408","title":"JunD Is Required for Proliferation of Prostate Cancer Cells and Plays a Role in Transforming Growth Factor-β (TGF-β)-induced Inhibition of Cell Proliferation.","date":"2016","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/27358408","citation_count":32,"is_preprint":false},{"pmid":"18655788","id":"PMC_18655788","title":"Hoxc6 is overexpressed in gastrointestinal carcinoids and interacts with JunD to regulate tumor growth.","date":"2008","source":"Gastroenterology","url":"https://pubmed.ncbi.nlm.nih.gov/18655788","citation_count":32,"is_preprint":false},{"pmid":"31023625","id":"PMC_31023625","title":"JUND regulates pancreatic β cell survival during metabolic stress.","date":"2019","source":"Molecular 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Tex.)","url":"https://pubmed.ncbi.nlm.nih.gov/21734453","citation_count":25,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":51677,"output_tokens":10599,"usd":0.157008,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":21259,"output_tokens":4924,"usd":0.114697,"stage2_stop_reason":"end_turn"},"total_usd":0.271705,"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\": 1989,\n      \"finding\": \"JunD (jun-D) encodes a transcription factor with a DNA-binding domain homologous to c-Jun and JunB, binds AP-1/TRE sequences, and can trans-activate TRE-containing promoters; activation is further enhanced by c-Fos co-expression.\",\n      \"method\": \"cDNA cloning, DNA-binding assays with truncated proteins, transactivation reporter assays\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — direct in vitro DNA-binding and transactivation assays replicated across two independent cloning papers (PMID:2504580, PMID:2493644)\",\n      \"pmids\": [\"2504580\", \"2493644\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1991,\n      \"finding\": \"JunD homodimerizes and binds a cAMP/phorbol ester/Ca2+-inducible enhancer in the proenkephalin gene, activating its transcription in a protein kinase A-dependent manner; JunB inhibits this JunD-mediated activation.\",\n      \"method\": \"Transient transfection reporter assays, DNA-binding assays demonstrating homodimer binding, co-expression experiments\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro DNA-binding plus functional transactivation assays with mechanistic dissection of PKA dependence, single lab but multiple orthogonal methods\",\n      \"pmids\": [\"1719551\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1991,\n      \"finding\": \"JunD overexpression results in slower growth and accumulation of cells in G0/G1, whereas c-Jun overexpression promotes S/G2/M; JunD partially suppresses Ras-induced transformation, opposing c-Jun function.\",\n      \"method\": \"Retroviral overexpression in NIH 3T3 fibroblasts, cell cycle analysis, focus/soft-agar transformation assay\",\n      \"journal\": \"Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — loss/gain-of-function in fibroblasts with defined cell-cycle and transformation phenotypes, replicated in multiple cell assays within the study\",\n      \"pmids\": [\"8124713\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1991,\n      \"finding\": \"The high constitutive expression of junD is driven by an octamer motif in its promoter, which is the major determinant of basal promoter activity; SP1, CAAT box, Zif268, and TRE-like elements contribute lesser roles.\",\n      \"method\": \"Promoter cloning, deletion analysis, transient transfection reporter assays, mutagenesis of cis-elements\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Weak — functional promoter dissection in single lab with multiple deletion/mutagenesis constructs\",\n      \"pmids\": [\"1714380\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1991,\n      \"finding\": \"Unlike c-Jun (which undergoes multi-ubiquitination and rapid degradation), JunD is not efficiently ubiquitinated and has a correspondingly longer half-life; this difference maps to the N-terminal delta-domain of c-Jun.\",\n      \"method\": \"Ubiquitination assays, protein stability measurements, N-terminal deletion/chimeric mutant analysis\",\n      \"journal\": \"Biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro ubiquitination assay plus mutational analysis identifying the regulatory domain, single lab but multiple orthogonal methods\",\n      \"pmids\": [\"8922589\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1992,\n      \"finding\": \"JunD (together with c-Jun) transactivates the human c-myb promoter via an AP-1-like element at -149; JunB does not. Antisense oligonucleotides to junD inhibit T-lymphocyte proliferation and reduce c-myb mRNA.\",\n      \"method\": \"Transient transfection reporter assays, gel-shift/supershift assays, site-directed mutagenesis of AP-1 element, antisense oligonucleotide treatment\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reporter assays with mutagenesis plus loss-of-function antisense, single lab but multiple orthogonal methods\",\n      \"pmids\": [\"1527086\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1993,\n      \"finding\": \"JunD mutants with spontaneously acquired transforming activity show enhanced transactivation specifically when forming heterodimers with Fra-2, but not with c-Fos or Fra-1; the mutated regions function as transactivation domains in a partner-specific manner.\",\n      \"method\": \"Retroviral mutagenesis, transformation assays, transient reporter assays with Fos/Fra family co-expression\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional transformation plus reporter assays with defined partner proteins, single lab\",\n      \"pmids\": [\"8415709\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1994,\n      \"finding\": \"JunD is identified as the key mediator of nur77 induction by NGF and membrane depolarization in PC12 cells: JunD binds NAP1/NAP2 AP-1-like elements in the nur77 promoter, transactivates through them, and a dominant-negative JunD abolishes nur77 activation by both stimuli.\",\n      \"method\": \"Nuclear extract binding assays (EMSA/supershift), transient reporter transfection, dominant-negative JunD expression\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal EMSA/supershift + dominant-negative epistasis + reporter assays, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"7969116\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1994,\n      \"finding\": \"JunD positively auto-regulates its own promoter through its unique TRE element, creating a positive autoregulatory loop that may account for its constitutive expression.\",\n      \"method\": \"Promoter-reporter transfection assays comparing junD vs. c-jun/junB transactivation of hjunD promoter constructs\",\n      \"journal\": \"DNA and cell biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — reporter assays showing preferential self-activation, single lab, single method\",\n      \"pmids\": [\"8172655\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"Menin (MEN1 tumor suppressor) directly interacts with JunD and represses JunD-activated transcription. Menin does not directly interact with other Jun or Fos family members. Several MEN1 missense mutations disrupt menin–JunD interaction.\",\n      \"method\": \"Yeast two-hybrid screen, in vitro binding assay, in vivo co-immunoprecipitation, Gal4-fusion reporter and AP-1-responsive reporter assays, MEN1 missense mutant panel\",\n      \"journal\": \"Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal in vitro + in vivo binding, multiple functional reporter assays, mutant panel, replicated independently (PMID:9989505, PMID:10500243)\",\n      \"pmids\": [\"9989505\", \"10500243\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"Menin-mediated repression of JunD transcriptional activity is dependent on histone deacetylase activity: the HDAC inhibitor trichostatin A relieves menin-dependent repression of JunD.\",\n      \"method\": \"Co-transfection reporter assays, trichostatin A treatment, C-terminal deletion mutants of menin\",\n      \"journal\": \"Biochimica et biophysica acta\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — pharmacological HDAC inhibition plus domain-mapping mutants, single lab\",\n      \"pmids\": [\"10500243\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"TGF-β1 induces IL-6 expression in primary human lung fibroblasts via an AP-1 site; the TGF-β1-activated AP-1 complex is a JunD homodimer (absent of Fos isoforms), as shown by supershift analysis.\",\n      \"method\": \"EMSA supershift analysis, luciferase reporter with 5'-deletions and site-directed mutagenesis, RT-PCR, ELISA\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — EMSA supershift plus mutagenesis of AP-1 site, single lab with multiple methods\",\n      \"pmids\": [\"10212284\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"JunD-deficient primary fibroblasts exhibit p53-dependent growth arrest, upregulated p19Arf, and premature senescence. JunD also protects against p53-dependent apoptosis in response to UV irradiation and TNF-α in vivo.\",\n      \"method\": \"JunD knockout mouse-derived primary fibroblasts, senescence assays, UV/TNF apoptosis assays, in vivo TNF-mediated hepatitis model\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic KO with multiple phenotypic readouts across in vitro and in vivo systems, single lab\",\n      \"pmids\": [\"11106750\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"Targeted disruption of murine junD causes multiple age-dependent defects in male reproductive function and impaired spermatogenesis, demonstrating specific in vivo functions. JunD-/- animals are viable, with no compensatory upregulation of c-Jun or JunB.\",\n      \"method\": \"Gene targeting (lacZ knock-in), histology, hormone assays, spermatogenesis analysis\",\n      \"journal\": \"Development (Cambridge, England)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — constitutive KO with specific organ-level phenotypic readouts, single lab\",\n      \"pmids\": [\"10654608\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"JunD regulates TIMP-1 gene promoter activity in activated hepatic stellate cells, acting primarily as JunD homodimers; JunD also activates IL-6 transcription as a heterodimer at an alternative AP-1 site.\",\n      \"method\": \"Expression vectors for wild-type, dominant-negative, and forced-homodimer JunD/eb1 chimeras; AP-1 EMSA from activated HSCs; promoter-reporter and mutagenesis assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic dominant-negative plus forced homodimer chimeras plus mutagenesis, single lab with multiple orthogonal approaches\",\n      \"pmids\": [\"11337499\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"PGF2α induces JunD phosphorylation via a calcium/calmodulin-dependent activation of ERK1/2; JunD bound constitutively to AP-1 sites in the nur77 promoter is activated by this phosphorylation to induce nur77 and 20α-HSD gene expression.\",\n      \"method\": \"Serial 5'-deletion promoter assays, dominant-negative JunD, AP-1 site mutagenesis, calcium/calmodulin and ERK inhibitors, in vitro kinase assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — in vitro kinase assay + dominant-negative epistasis + inhibitor pharmacology + promoter mutagenesis, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"11719525\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"Both JunD isoforms (full-length JunD-FL and truncated ΔJunD, generated by alternative translation initiation) are phosphorylated by JNK at three identical residues; JunD-FL contains a JNK docking domain, binds JNK more efficiently, and is a more potent transcriptional activator than ΔJunD.\",\n      \"method\": \"In vitro kinase assays, docking domain mutagenesis, transcriptional reporter assays, site-directed mutagenesis of JNK phosphorylation sites\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro kinase assay plus mutagenesis of phosphorylation sites and docking domain, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"12052834\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"JunD mRNA produces two protein isoforms (JunD-FL 39 kDa and ΔJunD 34 kDa) by alternative translation initiation from two in-frame AUGs; the 5'-UTR structure regulates the ratio of the two isoforms, and translation is cap-dependent (no IRES).\",\n      \"method\": \"Translational reporter assays, mutagenesis of start codons (AUG, ACG, CUG), cap-dependent translation assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — systematic start-site mutagenesis with functional readout in multiple constructs, single lab\",\n      \"pmids\": [\"12105216\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"Menin inhibits ERK-dependent phosphorylation of JunD and JNK-mediated phosphorylation of JunD and c-Jun without affecting upstream ERK2 or JNK1 activation, acting downstream of MAPK to uncouple kinase activation from nuclear target phosphorylation; two distinct inhibitory mechanisms for ERK and JNK pathways are indicated by N-terminal deletion analysis.\",\n      \"method\": \"In vitro kinase assays, overexpression of Menin, N-terminal deletion mutants of Menin, phosphorylation analysis\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro kinase assay plus domain-mapping mutants showing two distinct inhibitory mechanisms, single lab\",\n      \"pmids\": [\"12226747\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"JNK-stimulated survival signaling is mediated by JunD; the JNK/JunD pathway collaborates with NF-κB to increase antiapoptotic gene expression, providing a mechanistic basis for dual JNK roles in apoptosis versus survival.\",\n      \"method\": \"Genetic mouse models (JunD KO), JNK signaling pathway analysis, NF-κB activity assays, antiapoptotic gene expression analysis\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic KO plus signaling pathway dissection, single lab with multiple readouts\",\n      \"pmids\": [\"12820962\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"JunD transcription factor switches from growth suppressor to growth promoter when its binding to menin is prevented (either by a JunD G42E mutant unable to bind menin or by Men1-null background), demonstrating that menin interaction is required for JunD's anti-proliferative function.\",\n      \"method\": \"Stable cell lines with wild-type or menin-binding-deficient JunD mutant in JunD-/- or Men1-/- immortalized fibroblasts; proliferation assays; morphological analysis; cyclin D1 measurement\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic epistasis with menin-null background and binding-deficient point mutant, replicated across multiple cell-line conditions\",\n      \"pmids\": [\"12960363\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"JunD is required to halt a second wave of cell proliferation and prevent glomerular sclerosis and fibrosis after nephron reduction; the effect is non-cell-autonomous and involves upregulation of the paracrine mitogen TGF-α (EGFR ligand).\",\n      \"method\": \"JunD-/- mice with 75% nephron reduction, bitransgenic JunD-/-/REM (dominant-negative EGFR) rescue, TGF-α expression analysis\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic KO with rescue via dominant-negative EGFR transgene establishes pathway position, single lab\",\n      \"pmids\": [\"12975469\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"JunD limits tumor angiogenesis by regulating antioxidant defense genes, reducing H2O2 production. In junD-/- cells, H2O2 accumulation decreases FeII availability, reduces HIF prolyl hydroxylase (PHD) activity, leading to HIF-α accumulation and VEGF-A transcription.\",\n      \"method\": \"junD-/- cell lines, ROS measurement, PHD activity assays, HIF-α western blot, VEGF-A expression, iron chelation experiments\",\n      \"journal\": \"Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic KO with multiple orthogonal biochemical readouts establishing pathway mechanism, single lab with rigorous controls\",\n      \"pmids\": [\"15369676\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"HBZ (HTLV-1 bZIP factor) interacts with JunD via the bZIP domains of both proteins in vitro and in vivo, and this interaction activates JunD-dependent transcription (in contrast to HBZ's repression of c-Jun).\",\n      \"method\": \"Co-immunoprecipitation (in vivo), in vitro binding assay, co-transfection reporter assays\",\n      \"journal\": \"FEBS letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal in vitro and in vivo binding plus functional reporter assay, single lab\",\n      \"pmids\": [\"15044019\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"JunD promotes osteoblast differentiation (upregulating Runx2, COL1, osteocalcin, ALP); menin co-immunoprecipitates with JunD in osteoblasts, and menin overexpression suppresses JunD-induced AP-1 reporter activity and alkaline phosphatase activity.\",\n      \"method\": \"Stable overexpression, menin antisense knockdown, co-immunoprecipitation, AP-1 luciferase reporter, ALP activity assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP plus functional reporter in osteoblast-specific context, single lab\",\n      \"pmids\": [\"15563473\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"JunD binds the antioxidant response element (ARE) of the human ferritin H gene, is phosphorylated at Ser-100 by H2O2 or t-BHQ treatment, and activates ferritin H transcription; ChIP confirmed H2O2-induced JunD binding to the ferritin H ARE in vivo.\",\n      \"method\": \"EMSA/gel retardation, chromatin immunoprecipitation (ChIP), phosphorylation analysis, JunD overexpression with endogenous ferritin H protein measurement\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — ChIP (in vivo binding), EMSA, phosphorylation analysis, and functional overexpression assay, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"16007120\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"JunD is a profibrogenic transcription factor in liver: junD-/- mice are protected from CCl4-induced fibrosis with reduced TIMP-1 expression; Ser100 phosphorylation of JunD (mediated by ERK1/2, not JNK) regulates JunD-dependent TIMP-1 expression in activated HSCs.\",\n      \"method\": \"junD-/- mice with CCl4 fibrosis model, alpha-SMA immunostaining, TIMP-1 mRNA analysis, phospho-mutant analysis, JNK inhibitor ruling-out experiments\",\n      \"journal\": \"Hepatology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo genetic KO plus phospho-site mutant analysis with defined readouts, single lab\",\n      \"pmids\": [\"17133482\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"HBZ and JunD co-occupy the proximal region of the hTERT promoter (via ChIP) and form heterodimers that interact with Sp1; activation of hTERT transcription by HBZ/JunD heterodimers is mediated through Sp1 GC-rich binding sites.\",\n      \"method\": \"Co-transfection luciferase reporter assays, RT-PCR, ChIP, Sp1 co-immunoprecipitation\",\n      \"journal\": \"Retrovirology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP plus co-IP plus reporter assays, single lab\",\n      \"pmids\": [\"18078517\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"JunD is a major determinant of macrophage activation in WKY rats; JunD knockdown in rat and human primary macrophages reduces Fc receptor-mediated macrophage activation and cytokine production, demonstrating conserved function.\",\n      \"method\": \"Congenic mapping, siRNA knockdown in rat and human macrophages, Fc receptor-mediated activation assays, cytokine measurement\",\n      \"journal\": \"Nature genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic mapping plus siRNA knockdown in primary cells from two species with defined functional readouts\",\n      \"pmids\": [\"18443593\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"JunD negatively regulates ZO-1 expression at both transcriptional and translational levels in intestinal epithelial cells: transcriptional repression is mediated through a CREB-binding site in the ZO-1 promoter, and translational repression involves enhanced binding of RNA-binding protein TIA-1-related (TIAR) to the ZO-1 3'-UTR.\",\n      \"method\": \"Ectopic JunD overexpression, polyamine depletion, luciferase reporter with ZO-1 promoter, RNA co-immunoprecipitation for TIAR binding to ZO-1 3'-UTR, epithelial permeability assays\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — dual transcriptional/translational mechanism established by reporter assays plus RNA-IP, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"18562690\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"THC activates JunD by upregulating gene expression and translocating the protein to the nuclear compartment, and these events are accompanied by decreased breast cancer cell proliferation; JunD knockdown and genetic ablation reduce THC's antiproliferative effect.\",\n      \"method\": \"siRNA knockdown, JunD KO fibroblasts, nuclear fractionation, RT-PCR/western blot, proliferation assays\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — nuclear translocation by fractionation plus loss-of-function in two models (siRNA + KO), single lab\",\n      \"pmids\": [\"18454173\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"JunD protects the liver from ischemia/reperfusion injury by suppressing AP-1 transcriptional activation; in the absence of JunD, c-Jun phosphorylation and AP-1 activation are elevated, correlating with increased caspase activation. JunD counterbalances JNK1 and regulates NADPH oxidase (Nox2/Nox4) expression.\",\n      \"method\": \"JunD-/- mice with I/R model, dominant-negative JNK1 transgene rescue, AP-1 reporter assays, caspase activation assays, Nox2/Nox4 mRNA analysis\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic KO plus JNK1 dominant-negative rescue establishes pathway position, single lab with multiple readouts\",\n      \"pmids\": [\"18182393\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"JunD and HIF-1α co-operatively mediate TGF-β1-induced transcriptional activation of the angiotensinogen gene in human lung fibroblasts; both proteins bind the AGT core promoter as shown by oligonucleotide pulldown and ChIP; simultaneous knockdown of both completely eliminates TGF-β1-inducible AGT promoter activity.\",\n      \"method\": \"Oligonucleotide pulldown, ChIP, serial deletion/site-directed mutagenesis of AGT promoter, siRNA knockdown of JunD and HIF-1α, luciferase reporter assays\",\n      \"journal\": \"FASEB journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP plus pulldown plus combinatorial siRNA knockdown plus reporter mutagenesis, single lab\",\n      \"pmids\": [\"19211927\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Polyamines regulate JunD mRNA stability by modulating competitive binding of HuR (stabilizing) and AUF1 (destabilizing) to the JunD 3'-UTR: polyamine depletion increases HuR binding and decreases AUF1 association, stabilizing JunD mRNA; HuR silencing prevents polyamine depletion-induced JunD upregulation.\",\n      \"method\": \"RNA-immunoprecipitation, HuR/AUF1 silencing by siRNA, polyamine depletion/repletion experiments, mRNA stability assays\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — competitive RNA-IP plus loss-of-function for both HuR and AUF1, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"20805360\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Androgen receptor (AR) forms a complex with JunD in androgen-treated prostate cancer cells (co-immunoprecipitation and Gaussia luciferase reconstitution); JunD binds directly to the SSAT promoter only in androgen-treated LNCaP cells (ChIP), and JunD is essential for androgen-induced SSAT gene expression and the resulting ROS production.\",\n      \"method\": \"Co-immunoprecipitation, Gaussia luciferase reconstitution assay, ChIP, luciferase reporter, JunD-silenced (siRNA) stable cell line, DCF ROS assay\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP plus co-IP plus complementary reconstitution assay establishing direct AR-JunD complex, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"20460526\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"JunD mediates TGF-β-induced fibroblast activation in systemic sclerosis; JunD overexpression is Smad3/Smad4-dependent (siRNA silencing of Smad3/4 prevents JunD induction). JunD-/- fibroblasts are less responsive to TGF-β and release less collagen; JunD-/- mice are protected from bleomycin-induced fibrosis.\",\n      \"method\": \"siRNA knockdown of Smad3/Smad4, JunD-/- fibroblasts and mice, bleomycin fibrosis model, hydroxyproline assays, alpha-SMA counting\",\n      \"journal\": \"Annals of the rheumatic diseases\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic KO plus Smad pathway epistasis by siRNA, in vitro and in vivo, single lab\",\n      \"pmids\": [\"21515915\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Crystal structures of human menin in complex with MLL1 or JUND reveal that the same deep pocket binds short peptides of MLL1 or JUND in identical manners; menin-JUND interaction blocks JNK-mediated JUND phosphorylation and suppresses JUND-induced transcription, whereas menin promotes MLL1-mediated transcription.\",\n      \"method\": \"X-ray crystallography (crystal structures of free menin, menin–MLL1, menin–JUND, menin–MLL1–LEDGF complexes), kinase phosphorylation assays, transcriptional reporter assays\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structure plus functional kinase assay plus reporter assays, replicated concept across multiple complexes in one rigorous study\",\n      \"pmids\": [\"22327296\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"JunD is identified as a primary regulator of oxidative stress and IL-1β synthesis in macrophages via combined ChIP-Seq and transcriptome analysis; JunD binding events correlate with gene expression changes for oxidative stress and inflammatory genes in primary macrophages.\",\n      \"method\": \"ChIP-Seq, microarray transcriptomics after Jund siRNA knockdown, comparative expression in congenic strains with different JunD levels\",\n      \"journal\": \"BMC genomics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — ChIP-Seq combined with genome-wide expression profiling in primary cells and replicated across congenic strains\",\n      \"pmids\": [\"23398888\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"JunD deficiency accelerates age-related endothelial dysfunction by reducing scavenger enzymes (MnSOD, ecSOD, ALDH2) and upregulating NADPH oxidase subunits (p47phox, Nox2, Nox4), leading to mitochondrial superoxide formation, reduced eNOS activity, and premature vascular senescence; old WT mice show reduced JunD due to promoter hypermethylation and increased menin binding.\",\n      \"method\": \"JunD-/- mice (young and old), eNOS activity assays, ESR spectroscopy, NADPH oxidase subunit analysis, telomerase activity, senescence markers, JunD overexpression rescue, siRNA knockdown in human endothelial cells, promoter methylation analysis\",\n      \"journal\": \"Circulation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic KO plus JunD overexpression rescue plus siRNA in human cells with multiple orthogonal biochemical readouts, single lab with comprehensive controls\",\n      \"pmids\": [\"23410942\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"BAG3 stabilizes JunD mRNA, contributing to JunD-mediated growth inhibition; c-Jun transcriptionally activates BAG3 expression.\",\n      \"method\": \"BAG3 knockdown/overexpression, mRNA stability assays, proliferation assays\",\n      \"journal\": \"Biochimica et biophysica acta\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — mRNA stability assay single lab, mechanism of stabilization not fully characterized in abstract\",\n      \"pmids\": [\"24140207\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"TGF-β reduces JunD protein (not mRNA) in RWPE-1 and DU145 prostate cells via proteasomal degradation, correlating with inhibition of proliferation; selective siRNA knockdown of JunD reduces proliferation while knockdown of c-Jun or JunB has little effect.\",\n      \"method\": \"siRNA knockdown of individual Jun family members, proteasome inhibitor treatment, JunD overexpression, proliferation assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — proteasomal degradation pathway established pharmacologically plus selective siRNA for each Jun family member, single lab\",\n      \"pmids\": [\"27358408\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"JunD transcriptional activity is increased in obese hearts; JunD directly binds the PPARγ promoter (ChIP) to drive transcription of TG synthesis/uptake/storage genes (Fas, Cd36, Lpl, Plin5), causing myocardial lipid accumulation; JunD is a direct target of miR-494-3p (Ago2 IP + luciferase assay).\",\n      \"method\": \"ChIP for JunD at PPARγ promoter, Ago2 immunoprecipitation, luciferase reporter assay, cardiac-specific JunD overexpression, JunD-/- DIO mice, miR-494-3p overexpression\",\n      \"journal\": \"European heart journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP establishing direct promoter binding plus Ago2-IP for miRNA targeting plus genetic KO and OE rescue, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"30629164\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"JunD blunts ischemia/reperfusion-induced brain injury by suppressing IL-1β; JunD knockdown increases brain IL-1β and worsens stroke outcomes; anti-IL-1β antibody rescues the deleterious effects of JunD silencing.\",\n      \"method\": \"In vivo siRNA knockdown in mice, MCAO stroke model, brain IL-1β measurement, cytokine panels, anti-IL-1β antibody rescue experiment\",\n      \"journal\": \"Stroke\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo siRNA knockdown with specific cytokine rescue establishes IL-1β as downstream effector, single lab\",\n      \"pmids\": [\"30626291\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Hyperglycemia-induced JunD downregulation in the diabetic myocardium is mediated by a complex epigenetic mechanism involving DNA promoter hypermethylation, histone modifications, and translational repression by miR-673/menin; cardiac-specific JunD overexpression protects against hyperglycemia-induced dysfunction.\",\n      \"method\": \"Streptozotocin diabetes model, cardiac-specific αMHC-JunD transgenic mice, ESR spectroscopy for ROS, echocardiography, promoter methylation analysis, histone mark analysis, miRNA-673 and menin analysis\",\n      \"journal\": \"Circulation research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — cardiac-specific OE rescue plus multiple orthogonal epigenetic mechanisms characterized, validated in human diabetic hearts\",\n      \"pmids\": [\"32815777\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"JunD (not c-Jun) is the crucial AP-1 substrate of JNK signaling required for Ras-driven lung tumorigenesis: c-Jun deletion increases JunD protein and lung tumor burden; deletion of JunD completely abolishes K-Ras-driven lung adenocarcinoma; phosphorylation of JunD is increased in c-Jun-deficient lung cells.\",\n      \"method\": \"Inducible lung-specific conditional KO (c-Jun and JunD), K-RasG12D lung tumor model, dominant-active JNKK2-JNK1 transgene, tumor burden quantification, JunD phosphorylation analysis\",\n      \"journal\": \"JCI insight\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — combinatorial conditional KO with tumor formation assay plus epistasis with JNK transgene, single lab with multiple genetic models\",\n      \"pmids\": [\"34236045\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"JunD directly binds the linc00976 promoter and activates its transcription (established by ChIP-PCR), thereby promoting cholangiocarcinoma progression.\",\n      \"method\": \"ChIP-PCR for JunD binding at linc00976 promoter, luciferase reporter assay\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — ChIP-PCR demonstrating direct promoter binding, single lab, single method for the JUND-specific mechanistic finding\",\n      \"pmids\": [\"36400758\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"JUND encodes a constitutively expressed AP-1 family bZIP transcription factor that forms homo- and heterodimers to bind TRE/AP-1 sequences; it is phosphorylated and activated by JNK (at N-terminal sites via a specific docking domain) and ERK1/2 (at Ser100), unlike c-Jun it escapes efficient ubiquitination and has a long half-life, its transcriptional activity and growth-suppressive function are directly inhibited by menin (MEN1 tumor suppressor) via a shared peptide-binding pocket that also blocks JNK-mediated JUND phosphorylation, it acts as the critical JNK substrate driving Ras-induced lung tumorigenesis, it limits oxidative stress by transcriptionally regulating antioxidant defense genes and NADPH oxidase subunits (thereby suppressing HIF-α/VEGF-A angiogenesis and protecting the vasculature, heart, liver, and brain from injury), and its mRNA stability is post-transcriptionally controlled by competitive HuR/AUF1 binding to its 3'-UTR in a polyamine-dependent manner.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"JUND encodes a constitutively expressed AP-1 family bZIP transcription factor that binds AP-1/TRE sequences as a homodimer or as heterodimer with Fos/Fra partners to trans-activate target promoters [#0, #1, #6]. Its high basal expression is driven by an octamer-dominated promoter and reinforced by TRE-mediated positive autoregulation [#3, #8], and it generates two isoforms (JunD-FL and \\u0394JunD) by alternative translation initiation, with the full-length form carrying a JNK docking domain and acting as the stronger activator [#16, #17]. Unlike c-Jun, JunD escapes efficient ubiquitination and is correspondingly stable, a difference mapping to the c-Jun N-terminal delta-domain [#4]. JunD is activated by MAPK signaling \\u2014 phosphorylated by JNK at N-terminal sites and by ERK1/2 at Ser-100 \\u2014 to drive transcription of targets including nur77, ferritin H, and TIMP-1 [#15, #16, #25, #26]. Functionally JunD opposes c-Jun: it slows proliferation, arrests cells in G0/G1, and suppresses Ras transformation, and its growth-suppressive activity requires direct binding by the MEN1 tumor suppressor menin, which represses JunD transcription in an HDAC-dependent manner and, through a shared peptide-binding pocket revealed by crystallography, blocks JNK-mediated JunD phosphorylation [#2, #9, #10, #20, #36]. Conversely, JunD is the critical JNK substrate driving K-Ras\\u2013induced lung tumorigenesis [#44]. A central physiological role is limitation of oxidative stress: JunD regulates antioxidant defense genes and NADPH oxidase subunits, controlling H2O2/ROS levels, restraining HIF-\\u03b1/VEGF-A\\u2013driven angiogenesis, and protecting the vasculature, heart, liver, and brain from injury [#22, #31, #38, #42, #43]. JunD also mediates TGF-\\u03b2\\u2013induced fibroblast activation and fibrosis via Smad-dependent induction [#26, #35], regulates macrophage activation and inflammatory cytokine output [#28, #37], and is post-transcriptionally controlled through polyamine-dependent competitive binding of HuR and AUF1 to its 3'-UTR [#33].\",\n  \"teleology\": [\n    {\n      \"year\": 1989,\n      \"claim\": \"Established JUND as a bona fide AP-1 transcription factor, defining its molecular identity as a DNA-binding, TRE-activating protein related to c-Jun.\",\n      \"evidence\": \"cDNA cloning, DNA-binding and transactivation reporter assays, with c-Fos co-expression\",\n      \"pmids\": [\"2504580\", \"2493644\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not define partner-specific dimer preferences\", \"No in vivo target genes identified\"]\n    },\n    {\n      \"year\": 1991,\n      \"claim\": \"Showed that JunD has functions opposite to c-Jun \\u2014 it suppresses proliferation and Ras transformation \\u2014 framing JunD as a growth-suppressive AP-1 member, and identified the constitutive high-expression promoter.\",\n      \"evidence\": \"Retroviral overexpression in NIH 3T3 with cell-cycle and transformation assays; promoter deletion/mutagenesis\",\n      \"pmids\": [\"8124713\", \"1714380\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism of growth suppression not defined at this stage\", \"Did not identify the menin requirement later established\"]\n    },\n    {\n      \"year\": 1996,\n      \"claim\": \"Explained why JunD is more stable than c-Jun by showing it escapes efficient ubiquitination, mapping the difference to the c-Jun delta-domain.\",\n      \"evidence\": \"Ubiquitination assays, protein stability measurements, chimeric/deletion mutants\",\n      \"pmids\": [\"8922589\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"E3 ligase machinery not identified\", \"Did not connect stability to specific physiological outputs\"]\n    },\n    {\n      \"year\": 1999,\n      \"claim\": \"Identified menin (MEN1) as a direct, JunD-specific repressor, linking JunD growth suppression to a tumor-suppressor pathway and showing repression is HDAC-dependent.\",\n      \"evidence\": \"Yeast two-hybrid, reciprocal in vitro/in vivo binding, reporter assays, MEN1 mutant panel, TSA treatment\",\n      \"pmids\": [\"9989505\", \"10500243\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of binding not yet defined\", \"Did not establish whether menin binding is required for growth suppression\"]\n    },\n    {\n      \"year\": 2000,\n      \"claim\": \"Genetic knockout established physiological JunD functions: protection against p53-dependent senescence/apoptosis and a specific role in male reproduction, with no Jun-family compensation.\",\n      \"evidence\": \"JunD-/- mice and primary fibroblasts; senescence, UV/TNF apoptosis, hepatitis models; histology\",\n      \"pmids\": [\"11106750\", \"10654608\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular targets mediating p53/p19Arf control not defined\", \"Tissue-specific mechanisms distinct\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Defined the kinase-substrate logic of JunD activation \\u2014 JNK docking/phosphorylation and isoform-specific potency \\u2014 and showed menin uncouples MAPK activation from JunD phosphorylation downstream of ERK/JNK.\",\n      \"evidence\": \"In vitro kinase assays, docking-domain and start-codon mutagenesis, menin deletion mutants\",\n      \"pmids\": [\"12052834\", \"12105216\", \"12226747\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Endogenous stoichiometry of the two isoforms in tissues unclear\", \"Precise mechanism by which menin blocks phosphorylation not yet structural\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Established menin binding as required for JunD's anti-proliferative function and showed JunD mediates JNK-driven survival signaling, positioning JunD at a switch between growth suppression and survival.\",\n      \"evidence\": \"Menin-binding-deficient JunD mutant in Men1-null/JunD-null fibroblasts; JunD KO with JNK/NF-\\u03baB analysis; nephron-reduction model with EGFR rescue\",\n      \"pmids\": [\"12960363\", \"12820962\", \"12975469\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Target genes downstream of the JunD survival program incompletely defined\", \"How menin binding toggles JunD output mechanistically unresolved at this stage\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Revealed JunD as a master regulator of oxidative stress, controlling antioxidant genes and ROS to restrain HIF-\\u03b1/VEGF-A angiogenesis, defining its protective vascular/anti-tumor role.\",\n      \"evidence\": \"junD-/- cells, ROS/PHD activity assays, HIF-\\u03b1/VEGF-A measurement, iron chelation; ferritin H ARE ChIP and Ser-100 phosphorylation\",\n      \"pmids\": [\"15369676\", \"16007120\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Full antioxidant gene repertoire not enumerated\", \"Relative contribution of each redox target uncertain\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Extended JunD function to fibrosis, inflammation, and barrier regulation, and revealed dual transcriptional and post-transcriptional control mechanisms.\",\n      \"evidence\": \"junD-/- fibrosis models, macrophage siRNA in rat/human, ZO-1 promoter/3'-UTR (TIAR) analysis, liver I/R with JNK1 dominant-negative rescue\",\n      \"pmids\": [\"17133482\", \"18443593\", \"18562690\", \"18182393\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Tissue-specific dimer partners not fully mapped\", \"Crosstalk between transcriptional and translational repression unresolved\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Defined post-transcriptional regulation of JunD by competitive HuR/AUF1 binding to its 3'-UTR in a polyamine-dependent manner, and identified AR-JunD complexes driving polyamine-oxidase-linked ROS.\",\n      \"evidence\": \"RNA-IP, HuR/AUF1 silencing, polyamine depletion/repletion; AR co-IP, ChIP at SSAT promoter, ROS assays\",\n      \"pmids\": [\"20805360\", \"20460526\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"3'-UTR cis-elements for HuR/AUF1 not finely mapped\", \"Generality of AR-JunD interaction beyond prostate cells unclear\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Solved the structural basis of menin-JUND regulation, showing menin uses one pocket to bind JUND or MLL1, blocking JNK phosphorylation of JUND while promoting MLL1 transcription.\",\n      \"evidence\": \"X-ray crystallography of menin\\u2013JUND/MLL1 complexes, kinase and reporter assays\",\n      \"pmids\": [\"22327296\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Does not resolve dynamics of competition with MLL1 in cells\", \"In vivo consequences of pocket occupancy not directly tested\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Genome-wide profiling and vascular studies cemented JunD as the central regulator linking antioxidant defense, NADPH oxidase, and inflammation to age-related endothelial dysfunction.\",\n      \"evidence\": \"ChIP-Seq/transcriptomics in macrophages; JunD-/- and overexpression in mice/human endothelial cells, eNOS/ROS/senescence assays, promoter methylation\",\n      \"pmids\": [\"23398888\", \"23410942\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Causal direct vs indirect targets among bound genes not fully separated\", \"Mechanism coupling promoter hypermethylation to menin binding incompletely defined\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Demonstrated that JunD, not c-Jun, is the essential JNK/AP-1 substrate required for Ras-driven lung tumorigenesis, clarifying the oncogenic versus suppressive division within the AP-1 family.\",\n      \"evidence\": \"Conditional c-Jun and JunD knockouts in K-RasG12D lung model, JNK transgene epistasis, phosphorylation analysis\",\n      \"pmids\": [\"34236045\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Critical JunD transcriptional targets driving tumorigenesis not defined\", \"Context-dependence relative to JunD's growth-suppressive role unresolved\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Extended JunD direct-target repertoire to disease-promoting noncoding and metabolic genes, including linc00976 in cholangiocarcinoma and PPAR\\u03b3 in obese hearts.\",\n      \"evidence\": \"ChIP/ChIP-PCR at linc00976 and PPAR\\u03b3 promoters, luciferase assays, cardiac JunD overexpression/KO, miRNA targeting\",\n      \"pmids\": [\"36400758\", \"30629164\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Dimer composition at these promoters not defined\", \"Tissue-selectivity of JunD pro-disease versus protective output unexplained\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How JunD's opposing activities \\u2014 growth suppression versus Ras-driven tumorigenesis, vascular protection versus pro-fibrotic/pro-disease transcription \\u2014 are switched by dimer partner choice, phosphorylation state, and menin occupancy in a given tissue remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No unified model linking partner selection to context-specific output\", \"Direct genome-wide targets across tissues not comprehensively defined\", \"Predictive rules for when JunD protects versus promotes disease unknown\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [0, 1, 5, 7, 14, 25, 32, 34, 41, 45]},\n      {\"term_id\": \"GO:0003677\", \"supporting_discovery_ids\": [0, 25, 32, 41]},\n      {\"term_id\": \"GO:0003700\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [25, 30, 34, 41]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [0, 1, 7, 25, 32, 41]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [15, 16, 18, 19, 35]},\n      {\"term_id\": \"R-HSA-8953897\", \"supporting_discovery_ids\": [22, 25, 31, 38]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [28, 37, 42]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [22, 44, 45]}\n    ],\n    \"complexes\": [\"AP-1 (JunD homodimer / Jun-Fos heterodimer)\"],\n    \"partners\": [\"MEN1\", \"JUN\", \"FOS\", \"FOSL2\", \"HIF1A\", \"AR\", \"SP1\", \"HBZ\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":8,"faith_total":8,"faith_pct":100.0}}