{"gene":"TEF","run_date":"2026-04-28T21:42:58","timeline":{"discoveries":[{"year":1988,"finding":"TEF-1 (TEAD1) was purified from HeLa cells and shown to specifically bind two sequence-unrelated motifs (GT-IIC and Sph) of the SV40 enhancer, with cooperative binding occurring on templates containing tandem but not inverted or spaced repeats of its cognate motifs, correlating with enhancer activity in vivo.","method":"Protein purification, DNA-binding assays, in vivo enhancer activity assays","journal":"Cell","confidence":"High","confidence_rationale":"Tier 1-2 — purified protein, cooperative binding characterized with functional correlation, foundational study with >270 citations","pmids":["2843293"],"is_preprint":false},{"year":1991,"finding":"Cloned TEF-1 binds the SV40 GT-IIC and Sph enhansons with sequence specificity; TEF-1 initiates translation exclusively at an AUU codon in vivo; TEF-1 does not activate these enhansons in lymphoid MPC11 cells but represses endogenous HeLa TEF-1 activity via squelching, indicating that TEF-1 trans-activation requires a highly limiting, possibly cell-specific, titratable transcriptional intermediary factor.","method":"cDNA cloning, in vivo and in vitro transcription assays, GAL4 chimera squelching experiments","journal":"Cell","confidence":"High","confidence_rationale":"Tier 1-2 — reconstituted in vitro transcription, chimeric activator assays, replicated squelching; >380 citations","pmids":["1851669"],"is_preprint":false},{"year":1991,"finding":"TEF (thyrotroph embryonic factor, PAR bZIP) was identified as a novel bZIP transcription factor expressed in the embryonic anterior pituitary; TEF binds and trans-activates the TSH-beta promoter; TEF forms heterodimers with DBP; a cluster of basic amino acids unique to TEF and DBP is necessary for proper DNA-binding site specificity; a major trans-activation domain resides outside the bZIP homology region.","method":"cDNA cloning, DNA-binding assays, trans-activation reporter assays, heterodimerization experiments","journal":"Genes & development","confidence":"High","confidence_rationale":"Tier 1-2 — multiple orthogonal methods in a single study; >220 citations; foundational characterization of the PAR bZIP TEF protein","pmids":["1916262"],"is_preprint":false},{"year":1992,"finding":"M-CAT binding factor (MCBF), which governs cardiac troponin T gene promoter activity, is biochemically indistinguishable from TEF-1: it shares identical binding-site specificity, fractionation behavior, apparent molecular weight, and antigenic reactivity with TEF-1 antibodies, establishing MCBF as a TEF-1 family member mediating muscle-specific transcription.","method":"Mutational analysis of M-CAT motif, DNA-agarose fractionation, antibody cross-reactivity, mobility shift assays","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 — multiple biochemical methods; >140 citations","pmids":["1324927"],"is_preprint":false},{"year":1992,"finding":"TEF-1 is the major factor binding a 37-nt HPV-16 enhancer element in keratinocytes; both TEF-1 and a limiting, cell-specific TEF-1 co-activator are required for HPV-16 E6/E7 oncogene transcription; TEF-1 binding in vivo is necessary for P97 promoter activity; squelching by excess TEF-1 or GAL4-TEF-1 chimeras confirms dependence on a limiting co-activator.","method":"Sequence-specific DNA affinity purification, antibody identification, in vivo and in vitro transcription, squelching assays","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal assays; >160 citations","pmids":["1318197"],"is_preprint":false},{"year":1994,"finding":"TEF-1 cloned from chick heart exists as multiple muscle-enriched isoforms (TEF-1A and novel TEF-1B); both bind M-CAT elements with high affinity; the C-terminal region of TEF-1B (containing a 13-amino acid exon) can activate transcription when fused to a heterologous DNA-binding domain, while the same domain of TEF-1A cannot, indicating isoform-specific transcriptional activation roles.","method":"cDNA cloning, gel mobility shift assays, chimeric activator trans-activation assays","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 — functional domain mapping with heterologous constructs; >90 citations","pmids":["8106348"],"is_preprint":false},{"year":1994,"finding":"TEF-1 binds M-CAT sites in the skeletal alpha-actin promoter in cardiac cells and cooperates with SRF at SRE1 to activate transcription; either isolated SRE1 or TEF-1 binding sites can function as TGF-beta response elements; induction of the SkA promoter by TGF-beta requires both SRF and TEF-1 acting in concert.","method":"Mutational analysis of skeletal alpha-actin promoter, EMSA, transient transfection in ventricular myocytes","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 — epistasis-like promoter mutagenesis with TGF-beta response readout; >130 citations","pmids":["8206998"],"is_preprint":false},{"year":1995,"finding":"TEF-1 transrepression of the hCS promoter in BeWo choriocarcinoma cells is mechanistically mediated by direct interaction between the TEF-1 proline-rich domain and TBP (TATA-binding protein): GST-TEF-1 retains in vitro-generated TBP; TEF-1 inhibits TBP binding to the TATA motif; co-expression of TBP relieves TEF-1-mediated repression in vivo.","method":"GST pull-down, EMSA supershift, co-transfection, antisense oligonucleotide depletion","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal methods demonstrating direct TEF-1/TBP interaction and its functional consequence","pmids":["8621623"],"is_preprint":false},{"year":1995,"finding":"A novel negatively acting factor from HeLa/BJA-B cell extracts selectively represses TEF-1-mediated transcriptional activation (but not VP16-mediated activation) by interfering with TBP-associated coactivators; repression is alleviated by addition of immunopurified TFIID.","method":"Chromatographic fractionation of nuclear extracts, reconstituted in vitro transcription assay","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 1 — in vitro reconstitution; single lab, partial mechanistic follow-up","pmids":["7876100"],"is_preprint":false},{"year":1995,"finding":"The TEF-1 gene has a TATA-less promoter with multiple transcription start sites around an initiator element (Inr); cell-type-specific expression is directed by a 137-bp minimal promoter containing Sp1 and ATF-1 binding sites; the Inr is required for the major start site; the proximal Sp1 site and the Inr interact to fix transcription start site usage.","method":"Promoter deletion analysis, in vitro and in vivo transcription, mutagenesis, EMSA","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal methods characterizing the TEF-1 promoter mechanism","pmids":["7642633"],"is_preprint":false},{"year":1996,"finding":"TEF (PAR bZIP) and DBP bind the same DNA sequences in vitro but exhibit different promoter preferences in cells: TEF activates the albumin promoter more potently than DBP, while only DBP efficiently activates the cholesterol 7alpha-hydroxylase promoter; a TEF-DBP chimera carrying N-terminal TEF sequences with the DBP DNA-binding/dimerization domain activates the C7alphaH promoter as strongly as wild-type DBP, indicating that promoter environment rather than DNA-binding affinity determines promoter preference.","method":"In vitro DNA binding, co-transfection reporter assays, chimeric protein analysis","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 2 — chimeric protein dissection with functional readout; >120 citations","pmids":["8617210"],"is_preprint":false},{"year":1996,"finding":"TEF-1-related proteins (RTEF-1A, 57, 54, and 52 kDa) are phosphorylated and bind M-CAT DNA; the 54-kDa phosphorylated form (RTEF-1A) is a component of a muscle-enriched M-CAT transcription complex that is up-regulated upon skeletal muscle cell differentiation, as demonstrated by proteolytic digestion mapping and high-resolution mobility shift assays.","method":"Western blot, proteolytic digestion mapping, phosphorylation analysis, gel mobility shift assays","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2-3 — biochemical characterization with phosphorylation demonstrated; single lab","pmids":["8626521"],"is_preprint":false},{"year":1996,"finding":"TEF (human homolog of HLF/VBP) binds the consensus DNA sequence 5'-GTTACGTAAT-3' (identical to the HLF site); a discrete ~40 amino acid transcriptional activation domain (TAD) shared by TEF and HLF (THAD) was mapped using GAL4 chimeric proteins; deletion of THAD completely abolishes transcriptional activity of TEF and HLF in mammalian cells and yeast.","method":"Binding site selection assay, GAL4 chimera trans-activation, deletion mapping in mammalian cells and yeast","journal":"Blood","confidence":"High","confidence_rationale":"Tier 2 — domain mapping with multiple deletion constructs validated in two cell systems; >30 citations","pmids":["8639829"],"is_preprint":false},{"year":1996,"finding":"SV40 large T antigen (TAg) binds the TEA domain of TEF-1 (the same DNA-binding domain shared with Drosophila Scalloped and S. cerevisiae TEC1); this interaction inhibits TEF-1 DNA binding and activates transcription in vitro from a subset of late start sites; TEF-1 thus functions as a repressor of SV40 late transcription.","method":"In vitro binding assays, in vitro transcription, TEA domain mutagenesis analysis","journal":"Journal of virology","confidence":"High","confidence_rationale":"Tier 1-2 — in vitro binding and transcription with domain-specific interaction; >35 citations","pmids":["8551581"],"is_preprint":false},{"year":1997,"finding":"Human TEF-5 is preferentially expressed in placenta and binds cooperatively to tandemly repeated GT-IIC-like elements in the human chorionic somatomammotropin-B (hCS-B) gene enhancer; a single-base mutation in the corresponding element of the hCS-A enhancer (which is inactive) disrupts TEF-5 binding; the placental factor CSEF-1 is a proteolytic degradation product of TEF factors whose binding is disrupted by anti-TEA domain antibodies.","method":"cDNA cloning, RT-PCR, EMSA, cooperative binding assays, antibody supershift","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2-3 — binding characterization with mutagenesis and antibody validation; single lab","pmids":["9148898"],"is_preprint":false},{"year":1999,"finding":"The human protein TONDU (TDU), which contains a short domain homologous to the Vestigial (Vg) domain required for Scalloped interaction, specifically interacts with a conserved domain present in all mammalian TEF factors; expression of TONDU in Drosophila can substitute for Vestigial in wing formation.","method":"Two-hybrid interaction, in vivo rescue of Drosophila vestigial mutants","journal":"Development","confidence":"High","confidence_rationale":"Tier 2 — yeast/mammalian two-hybrid plus in vivo Drosophila rescue; >115 citations","pmids":["10518497"],"is_preprint":false},{"year":2001,"finding":"TEAD-2/TEF-4 purified from mouse cells is associated with a novel TEAD-binding domain at the amino terminus of YAP65; YAP65 interacts specifically with the carboxyl terminus of all four TEAD/TEF proteins; both the YAP-TEAD interaction and sequence-specific DNA binding by TEAD are required for transcriptional activation; excess YAP65 accumulates in the cytoplasm as a complex with 14-3-3; YAP65 thus provides the transcriptional activation domain for TEAD/TEF transcription factors and its availability is limited by 14-3-3-mediated cytoplasmic sequestration.","method":"Protein purification, co-immunoprecipitation, co-transfection reporter assays, cytoplasmic/nuclear fractionation","journal":"Genes & development","confidence":"High","confidence_rationale":"Tier 1-2 — native protein purification, reciprocal binding assays, functional consequence demonstrated; >600 citations; replicated","pmids":["11358867"],"is_preprint":false},{"year":2001,"finding":"Pur alpha, Pur beta, and MSY1 single-stranded DNA-binding proteins suppress a cryptic MCAT enhancer by competing for TEF-1 binding to a polypurine-polypyrimidine cis-element in the smooth muscle alpha-actin promoter; Pur alpha, Pur beta, and MSY1 also interact weakly with double-stranded DNA and with TEF-1 itself; mutations that selectively impair single-stranded DNA binding by these factors release the MCAT enhancer from repression.","method":"DNA binding studies (EMSA), mutagenesis, transfection reporter assays","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2-3 — mutagenesis with functional readout; single lab","pmids":["11751932"],"is_preprint":false},{"year":2002,"finding":"TEF-1 interacts with the MADS domain of MEF2 transcription factors through additional activation domain sequences; this interaction was demonstrated by co-immunoprecipitation and GST pull-down in vitro and mammalian two-hybrid in vivo; the physiological significance was demonstrated by co-activation of MEF2-dependent muscle-specific promoters on co-transfection.","method":"Co-immunoprecipitation, GST pull-down, mammalian two-hybrid, transient transfection","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 — reciprocal interaction assays with functional consequence; single lab","pmids":["12061776"],"is_preprint":false},{"year":2002,"finding":"Mammalian Vgl-2 (vestigial-like 2) interacts with TEF-1 and with MEF2; Vgl-2 protein translocates from the cytoplasm to the nucleus during skeletal muscle differentiation; Vgl-2 co-activates MEF2-dependent promoters through the MEF2 element; overexpression of Vgl-2 in MyoD-transfected 10T1/2 cells markedly increases myosin heavy chain expression.","method":"Mammalian two-hybrid, GST pull-down, subcellular fractionation, transient transfection, immunofluorescence","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal binding and functional assays; localization tied to differentiation; >135 citations","pmids":["12376544"],"is_preprint":false},{"year":2002,"finding":"DTEF-1 (TEF-5/ETFR-1) is phosphorylated in vivo in neonatal rat cardiac myocytes; alpha1-adrenergic stimulation increases MCAT binding activity of DTEF-1 while phosphatase treatment decreases it, indicating that phosphorylation positively regulates DTEF-1 MCAT binding; DTEF-1 augments the alpha1-adrenergic response of the skeletal muscle alpha-actin gene.","method":"Orthophosphate labeling, immunoprecipitation, EMSA, phosphatase treatment, reporter assays","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 — direct phosphorylation demonstrated with functional consequences; single lab","pmids":["11986313"],"is_preprint":false},{"year":2003,"finding":"Nuclear calcium and MAPK negatively regulate TEAD/TEF transcription factor activity in CHO cells: chelation of nuclear (but not cytosolic) Ca2+ increased TEAD activity two-fold; inhibition of MAPK also increased TEAD activity; cAMP decreased TEAD activity; protein kinase C had no effect.","method":"RT-PCR, selective nuclear/cytosolic calcium chelation, kinase inhibitor assays, TEAD reporter assays","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 3 — pharmacological inhibition with reporter readout; single lab, no direct modification identified","pmids":["12565854"],"is_preprint":false},{"year":2004,"finding":"TEF (thyrotroph embryonic factor, PAR bZIP) binds to an AT-rich region within the telokin promoter core and specifically activates telokin gene expression in smooth muscle cells in a calcium-dependent manner, without affecting other smooth muscle promoters (SM22alpha, smooth muscle alpha-actin, smooth muscle myosin heavy chain); two isoforms (TEFalpha and TEFbeta) arising from alternative promoter usage are expressed in smooth muscle tissues.","method":"Southwestern screen, gel mobility shift assay, reporter gene assays, adenoviral overexpression, RNase protection assay","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal assays with specific promoter selectivity and endogenous gene expression validation","pmids":["14702338"],"is_preprint":false},{"year":2005,"finding":"TEF (PAR bZIP) expressed in FL5.12 IL-3-dependent hematopoietic cells protects against apoptosis upon IL-3 withdrawal and down-regulates expression of the common beta (betac) chain of cytokine receptors, causing G0/G1 accumulation without apoptosis; this indicates TEF regulates hematopoietic cell survival and proliferation by controlling betac chain expression.","method":"Retroviral transduction, apoptosis assays, flow cytometry, gene expression analysis","journal":"Blood","confidence":"Medium","confidence_rationale":"Tier 2 — loss/gain of function with defined cellular and molecular phenotype; single lab","pmids":["15665112"],"is_preprint":false},{"year":2005,"finding":"TAZ (transcriptional co-activator with PDZ-binding motif) interacts with TEF-1 and all four TEF-1 family members via GST pull-down, co-immunoprecipitation, and modified mammalian two-hybrid assays; TAZ interacts with TEF-1 bound to MCAT DNA; TAZ interacts more efficiently with TEF-1 than RTEF-1; exogenous TAZ activates MCAT-dependent reporter promoters through endogenous TEF-1.","method":"GST pull-down, co-immunoprecipitation, mammalian two-hybrid, EMSA, reporter assays","journal":"The Biochemical journal","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal interaction assays with functional reporter validation; >175 citations","pmids":["15628970"],"is_preprint":false},{"year":2006,"finding":"PAR bZIP proteins DBP, TEF, and HLF control expression of many liver and kidney enzymes and regulators involved in xenobiotic detoxification (cytochrome P450 enzymes, carboxylesterases, CAR); mice devoid of all three PAR bZip proteins are hypersensitive to xenobiotic compounds; morbidity includes epilepsy proneness, accelerated aging, and premature death.","method":"Triple knockout mouse model, transcriptome comparison, xenobiotic toxicity assays","journal":"Cell metabolism","confidence":"High","confidence_rationale":"Tier 2 — clean triple KO with defined transcriptomic and physiologic phenotypes; >395 citations","pmids":["16814730"],"is_preprint":false},{"year":2006,"finding":"TEF-1 and C/EBPbeta are the two transcription factors most enriched in promoters of p38alpha MAPK-regulated genes in cardiomyocytes; p38alpha regulates TEF-1 transcriptional activity involved in inhibition of COL1A1 (type I collagen alpha1) transcription in the absence of environmental stress.","method":"Transcriptome profiling, promoter motif analysis, p38alpha knockout cardiomyocytes, reporter assays","journal":"The Biochemical journal","confidence":"Medium","confidence_rationale":"Tier 2-3 — knockout transcriptomics with functional follow-up; single lab","pmids":["16492136"],"is_preprint":false},{"year":2006,"finding":"The TEA domain (TEAD) of TEF-1 adopts a three-helix bundle with a homeodomain fold; the L1 loop is essential for cooperative loading of TEAD molecules onto tandemly duplicated M-CAT sites; microarray chip-based binding assays reveal that known binding sites of the full-length TEF-1 protein are only a subset of DNA elements recognized by TEAD.","method":"NMR solution structure, structure-function mutagenesis, microarray-based DNA-binding assay","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1 — structure solved and validated with mutagenesis and genome-wide binding assay","pmids":["17085591"],"is_preprint":false},{"year":2008,"finding":"Drosophila Scalloped (Sd), the TEAD/TEF family ortholog, is the DNA-binding partner that mediates transcriptional output of the Hippo pathway; Sd binds directly to Yorkie (Yki, YAP ortholog) and recruits it to the diap1 HRE enhancer; a Yki missense mutation abrogating Sd binding inactivates Yki in vivo; sd is required for yki-induced tissue overgrowth; the Sd/Yki interaction is conserved in mammalian homologs.","method":"Epistasis genetics, direct binding assays, in vivo rescue, chromatin assays, mammalian conservation assay","journal":"Developmental cell","confidence":"High","confidence_rationale":"Tier 2 — epistasis, direct binding, in vivo rescue in Drosophila with conservation validated; >560 citations","pmids":["18258486"],"is_preprint":false},{"year":2008,"finding":"Scalloped (Sd) and Yorkie (Yki) form a transcriptional complex inhibited by Hippo signaling; Sd promotes Yki nuclear localization, while Hippo signaling retains Yki in the cytoplasm by phosphorylating Yki at S168; Sd overexpression enhances, while Sd inactivation suppresses, tissue overgrowth caused by Yki overexpression or tumor suppressor mutations; Sd recruits Yki to the diap1 enhancer.","method":"Genetic epistasis, loss-of-function, gain-of-function, phosphorylation analysis, chromatin recruitment assay","journal":"Developmental cell","confidence":"High","confidence_rationale":"Tier 2 — multiple genetic and biochemical approaches; >540 citations; independently replicated","pmids":["18258485"],"is_preprint":false},{"year":2010,"finding":"PAR bZIP triple knockout mice (Dbp/Tef/Hlf -/-) develop cardiac hypertrophy, left ventricular dysfunction, low blood pressure, and abnormally low aldosterone levels, demonstrating that TEF (together with DBP and HLF) regulates circadian control of cardiovascular functions including aldosterone synthesis.","method":"Triple knockout mouse model, cardiac function measurements, blood pressure monitoring, hormone assays","journal":"American journal of physiology. Regulatory, integrative and comparative physiology","confidence":"Medium","confidence_rationale":"Tier 2 — clean triple KO with defined cardiovascular phenotype; single lab","pmids":["20686175"],"is_preprint":false},{"year":2013,"finding":"Genetic knockdown of TEF or YAP in hypothalamic neurons stimulates enkephalin (ENK) expression; prenatal high-fat diet increases inactive TEF protein levels and decreases YAP in hypothalamus; TEF co-localizes with ENK in hypothalamic neurons, and HFD reduces density of TEF/ENK co-labeled neurons, suggesting TEF regulates neuropeptide gene expression and ENK neuron differentiation.","method":"Genetic knockdown, immunofluorescence co-localization, protein expression analysis, prenatal dietary manipulation","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 3 — knockdown with defined cellular phenotype and co-localization; single lab","pmids":["24147051"],"is_preprint":false},{"year":2019,"finding":"A novel TCF3/TEF gene fusion was identified in a pediatric B-ALL/LBL case by mate-pair sequencing, demonstrating that TEF can serve as a translocation partner in acute lymphoblastic leukemia.","method":"Next-generation sequencing (mate-pair sequencing), FISH","journal":"Blood cancer journal","confidence":"Low","confidence_rationale":"Tier 3 — single case identification; no functional characterization of the fusion protein","pmids":["31575852"],"is_preprint":false}],"current_model":"TEF encodes two distinct proteins depending on context: (1) the TEAD/TEF family of transcription factors (TEAD1-4), which bind M-CAT and GT-IIC/Sph DNA elements via a three-helix homeodomain-like TEA domain, require YAP65 or TAZ as transcriptional co-activators (whose availability is controlled by 14-3-3 cytoplasmic sequestration and Hippo pathway phosphorylation), interact with co-factors including Vestigial-like proteins, TBP, SRF, and MEF2, and regulate muscle-specific, placental, and viral gene transcription; and (2) thyrotroph embryonic factor (TEF), a PAR bZIP protein that heterodimerizes with DBP and HLF, binds a consensus DNA sequence, contains a discrete ~40 amino acid transcriptional activation domain, accumulates in a circadian manner, and controls xenobiotic detoxification, cardiovascular function, and anti-apoptotic gene expression in hematopoietic progenitors."},"narrative":{"teleology":[{"year":1991,"claim":"Identification of TEF as a novel PAR bZIP transcription factor in the embryonic pituitary resolved the molecular nature of the factor activating TSH-beta and established its capacity to heterodimerize with DBP and to trans-activate via a domain outside the bZIP region.","evidence":"cDNA cloning, DNA-binding assays, heterodimerization experiments, and reporter assays in transfected cells","pmids":["1916262"],"confidence":"High","gaps":["The precise activation domain boundaries were not yet mapped","Endogenous target genes beyond TSH-beta were unknown","In vivo physiological role of TEF was uncharacterized"]},{"year":1996,"claim":"Mapping of a discrete ~40 amino acid transcriptional activation domain (THAD) shared by TEF and HLF, and demonstration that TEF and DBP have distinct promoter preferences despite identical DNA-binding specificity, revealed that TEF's transcriptional output depends on promoter context rather than simple DNA recognition.","evidence":"GAL4 chimera deletion mapping in mammalian cells and yeast; chimeric TEF-DBP protein reporter assays showing promoter-selective activation","pmids":["8639829","8617210"],"confidence":"High","gaps":["Structural basis for context-dependent promoter preference was not determined","Co-factors mediating promoter selectivity were not identified"]},{"year":2004,"claim":"Discovery that TEF activates the telokin promoter in a calcium-dependent manner in smooth muscle cells, with two tissue-specific isoforms (TEFalpha and TEFbeta), extended TEF's functional repertoire beyond the pituitary to smooth muscle gene regulation.","evidence":"Southwestern screen, gel shift, reporter assays, adenoviral overexpression, and RNase protection in smooth muscle cells","pmids":["14702338"],"confidence":"High","gaps":["Mechanism linking calcium signaling to TEF activity was not resolved","Relative contributions of TEFalpha vs TEFbeta isoforms to smooth muscle physiology were unclear"]},{"year":2005,"claim":"Demonstration that TEF protects hematopoietic progenitor cells from apoptosis by downregulating the cytokine receptor common beta chain established a role for TEF in cell survival decisions outside epithelial or muscle lineages.","evidence":"Retroviral transduction of TEF into IL-3-dependent FL5.12 cells with apoptosis and flow cytometry readout","pmids":["15665112"],"confidence":"Medium","gaps":["Whether TEF directly binds the betac promoter was not shown","Relevance to normal hematopoiesis in vivo was not tested","Mechanism of anti-apoptotic action beyond betac downregulation was unknown"]},{"year":2006,"claim":"Triple knockout of all three PAR bZIP factors (Dbp/Tef/Hlf) revealed their collective, partially redundant control of hepatic and renal xenobiotic detoxification programs and established that loss causes systemic toxicity, epilepsy, and premature death.","evidence":"Triple knockout mouse model with transcriptomic profiling and xenobiotic challenge experiments","pmids":["16814730"],"confidence":"High","gaps":["Individual contribution of TEF vs DBP vs HLF to each detoxification gene was not dissected","Whether TEF single knockout produces a phenotype was not reported"]},{"year":2010,"claim":"The same PAR bZIP triple knockout mice displayed cardiac hypertrophy, left ventricular dysfunction, hypotension, and reduced aldosterone, establishing TEF (with DBP and HLF) as a circadian regulator of cardiovascular homeostasis.","evidence":"Echocardiography, blood pressure telemetry, and hormone assays in Dbp/Tef/Hlf triple knockout mice","pmids":["20686175"],"confidence":"Medium","gaps":["Direct TEF target genes mediating cardiac and aldosterone phenotypes were not identified","Individual contribution of TEF to the cardiovascular phenotype was not resolved","Whether circadian oscillation of TEF is required for the phenotype was not tested"]},{"year":2019,"claim":"Identification of a TCF3/TEF gene fusion in a pediatric B-ALL case suggested TEF can participate in oncogenic translocations in hematopoietic malignancies, though the fusion's functional consequences were not characterized.","evidence":"Mate-pair next-generation sequencing and FISH confirmation in a single patient","pmids":["31575852"],"confidence":"Low","gaps":["Single case without functional characterization of the fusion protein","Whether the fusion drives leukemogenesis or is a passenger event is unknown","No recurrence data from additional patient cohorts"]},{"year":null,"claim":"The individual contribution of TEF (independent of DBP and HLF) to circadian physiology, xenobiotic detoxification, and cardiovascular function remains unresolved, as does the structural basis of THAD-mediated transcriptional activation and the identity of TEF-specific co-activators in different tissues.","evidence":"","pmids":[],"confidence":"High","gaps":["No TEF single-knockout phenotype has been reported","No crystal or cryo-EM structure of TEF or the THAD activation domain exists","Genome-wide direct target identification (ChIP-seq) for TEF has not been performed"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0003677","term_label":"DNA binding","supporting_discovery_ids":[2,10,12,22]},{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[2,10,12,22,23,25]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[2,12,22]}],"pathway":[{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[2,10,12,22,23]},{"term_id":"R-HSA-9909396","term_label":"Circadian clock","supporting_discovery_ids":[25,30]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[32]}],"complexes":[],"partners":["DBP","HLF"],"other_free_text":[]},"mechanistic_narrative":"TEF (thyrotroph embryonic factor) is a PAR basic-leucine-zipper (bZIP) transcription factor that heterodimerizes with the related circadian regulators DBP and HLF, binds the consensus sequence 5'-GTTACGTAAT-3', and contains a discrete ~40 amino acid transcriptional activation domain (THAD) essential for its activity [PMID:1916262, PMID:8639829]. TEF activates tissue-selective promoters including TSH-beta in the embryonic pituitary and telokin in smooth muscle, and together with DBP and HLF controls expression of xenobiotic detoxification enzymes (cytochrome P450s, carboxylesterases, CAR) and cardiovascular functions including aldosterone synthesis; triple knockout of all three PAR bZIP factors causes xenobiotic hypersensitivity, epilepsy, cardiac hypertrophy, and premature death in mice [PMID:16814730, PMID:20686175, PMID:14702338]. In hematopoietic progenitor cells, TEF confers protection from apoptosis upon cytokine withdrawal by downregulating the common beta chain of cytokine receptors [PMID:15665112]. A TCF3/TEF gene fusion has been identified in a pediatric B-cell acute lymphoblastic leukemia case [PMID:31575852]."},"prefetch_data":{"uniprot":{"accession":"Q10587","full_name":"Thyrotroph embryonic factor","aliases":[],"length_aa":303,"mass_kda":33.2,"function":"Transcription factor that binds to and transactivates the TSHB promoter. 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TTF2","url":"https://www.omim.org/entry/604718"},{"mim_id":"603170","title":"TEA DOMAIN FAMILY MEMBER 3; TEAD3","url":"https://www.omim.org/entry/603170"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in 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Trotter].","date":"2006","source":"TAG. Theoretical and applied genetics. Theoretische und angewandte Genetik","url":"https://pubmed.ncbi.nlm.nih.gov/16900349","citation_count":14,"is_preprint":false},{"pmid":"7876100","id":"PMC_7876100","title":"Characterization of a HeLa cell factor which negatively regulates transcriptional activation in vitro by transcriptional enhancer factor-1 (TEF-1).","date":"1995","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/7876100","citation_count":14,"is_preprint":false},{"pmid":"21558500","id":"PMC_21558500","title":"Cantharellus texensis sp. nov. from Texas, a southern lookalike of C. cinnabarinus revealed by tef-1 sequence data.","date":"2011","source":"Mycologia","url":"https://pubmed.ncbi.nlm.nih.gov/21558500","citation_count":14,"is_preprint":false},{"pmid":"24147051","id":"PMC_24147051","title":"Prenatal exposure to dietary fat induces changes in the transcriptional factors, TEF and YAP, which may stimulate differentiation of peptide neurons in rat hypothalamus.","date":"2013","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/24147051","citation_count":13,"is_preprint":false},{"pmid":"7605676","id":"PMC_7605676","title":"Cloning, nucleotide sequence, and expression of tef-1, the gene encoding translation elongation factor 1 alpha (EF-1 alpha) of Neurospora crassa.","date":"1995","source":"Idengaku zasshi","url":"https://pubmed.ncbi.nlm.nih.gov/7605676","citation_count":13,"is_preprint":false},{"pmid":"27489554","id":"PMC_27489554","title":"Nutritional and Sensory Evaluation of Injera Prepared from tef and Eragrostis curvula (Schrad.) Nees. Flours with Sorghum Blends.","date":"2016","source":"Frontiers in plant science","url":"https://pubmed.ncbi.nlm.nih.gov/27489554","citation_count":12,"is_preprint":false},{"pmid":"26833063","id":"PMC_26833063","title":"Identification and characterization of abundant repetitive sequences in Eragrostis tef cv. Enatite genome.","date":"2016","source":"BMC plant biology","url":"https://pubmed.ncbi.nlm.nih.gov/26833063","citation_count":12,"is_preprint":false},{"pmid":"9259314","id":"PMC_9259314","title":"Human chorionic somatomammotropin enhancer function is mediated by cooperative binding of TEF-1 and CSEF-1 to multiple, low-affinity binding sites.","date":"1997","source":"Molecular endocrinology (Baltimore, Md.)","url":"https://pubmed.ncbi.nlm.nih.gov/9259314","citation_count":12,"is_preprint":false},{"pmid":"31212581","id":"PMC_31212581","title":"Variations in Amino Acid and Protein Profiles in White versus Brown Teff (Eragrostis Tef) Seeds, and Effect of Extraction Methods on Protein Yields.","date":"2019","source":"Foods (Basel, Switzerland)","url":"https://pubmed.ncbi.nlm.nih.gov/31212581","citation_count":12,"is_preprint":false},{"pmid":"7745697","id":"PMC_7745697","title":"A TEF-1-independent mechanism for activation of the simian virus 40 (SV40) late promoter by mutant SV40 large T antigens.","date":"1995","source":"Journal of virology","url":"https://pubmed.ncbi.nlm.nih.gov/7745697","citation_count":12,"is_preprint":false},{"pmid":"9434145","id":"PMC_9434145","title":"Cloning and characterization of two isoforms of the zebrafish thyrotroph embryonic factor (tef alpha and tefbeta).","date":"1998","source":"Biochimica et biophysica acta","url":"https://pubmed.ncbi.nlm.nih.gov/9434145","citation_count":11,"is_preprint":false},{"pmid":"29656008","id":"PMC_29656008","title":"Identification of miRNAs linked with the drought response of tef [Eragrostis tef (Zucc.) Trotter].","date":"2018","source":"Journal of plant physiology","url":"https://pubmed.ncbi.nlm.nih.gov/29656008","citation_count":11,"is_preprint":false},{"pmid":"17565675","id":"PMC_17565675","title":"QTL mapping of agronomic traits in tef [Eragrostis tef (Zucc) Trotter].","date":"2007","source":"BMC plant biology","url":"https://pubmed.ncbi.nlm.nih.gov/17565675","citation_count":11,"is_preprint":false},{"pmid":"24623695","id":"PMC_24623695","title":"Structural characterization of arabinoxylans from two African plant species Eragrostis nindensis and Eragrostis tef using various mass spectrometric methods.","date":"2014","source":"Rapid communications in mass spectrometry : RCM","url":"https://pubmed.ncbi.nlm.nih.gov/24623695","citation_count":11,"is_preprint":false},{"pmid":"17916448","id":"PMC_17916448","title":"Vestigial-like-2b (VITO-1b) and Tead-3a (Tef-5a) expression in zebrafish skeletal muscle, brain and notochord.","date":"2007","source":"Gene expression patterns : GEP","url":"https://pubmed.ncbi.nlm.nih.gov/17916448","citation_count":11,"is_preprint":false},{"pmid":"32596045","id":"PMC_32596045","title":"Comparative analyses of 32 complete plastomes of Tef (Eragrostis tef ) accessions from Ethiopia: phylogenetic relationships and mutational hotspots.","date":"2020","source":"PeerJ","url":"https://pubmed.ncbi.nlm.nih.gov/32596045","citation_count":10,"is_preprint":false},{"pmid":"30155476","id":"PMC_30155476","title":"Isolation and Molecular Identification of Lactic Acid Bacteria Using 16s rRNA Genes from Fermented Teff (Eragrostis tef (Zucc.)) Dough.","date":"2018","source":"International journal of food science","url":"https://pubmed.ncbi.nlm.nih.gov/30155476","citation_count":10,"is_preprint":false},{"pmid":"33329679","id":"PMC_33329679","title":"Silicon Enhances Biomass and Grain Yield in an Ancient Crop Tef [Eragrostis tef (Zucc.) Trotter].","date":"2020","source":"Frontiers in plant science","url":"https://pubmed.ncbi.nlm.nih.gov/33329679","citation_count":9,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":46067,"output_tokens":7881,"usd":0.128208},"stage2":{"model":"claude-opus-4-6","input_tokens":11600,"output_tokens":2156,"usd":0.16785},"total_usd":0.296058,"stage1_batch_id":"msgbatch_01RPbVc9PDH9zQmYK5Hs6srm","stage2_batch_id":"msgbatch_01JVbVLzeKN2yVrsGp3zC8aM","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1988,\n      \"finding\": \"TEF-1 (TEAD1) was purified from HeLa cells and shown to specifically bind two sequence-unrelated motifs (GT-IIC and Sph) of the SV40 enhancer, with cooperative binding occurring on templates containing tandem but not inverted or spaced repeats of its cognate motifs, correlating with enhancer activity in vivo.\",\n      \"method\": \"Protein purification, DNA-binding assays, in vivo enhancer activity assays\",\n      \"journal\": \"Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — purified protein, cooperative binding characterized with functional correlation, foundational study with >270 citations\",\n      \"pmids\": [\"2843293\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1991,\n      \"finding\": \"Cloned TEF-1 binds the SV40 GT-IIC and Sph enhansons with sequence specificity; TEF-1 initiates translation exclusively at an AUU codon in vivo; TEF-1 does not activate these enhansons in lymphoid MPC11 cells but represses endogenous HeLa TEF-1 activity via squelching, indicating that TEF-1 trans-activation requires a highly limiting, possibly cell-specific, titratable transcriptional intermediary factor.\",\n      \"method\": \"cDNA cloning, in vivo and in vitro transcription assays, GAL4 chimera squelching experiments\",\n      \"journal\": \"Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — reconstituted in vitro transcription, chimeric activator assays, replicated squelching; >380 citations\",\n      \"pmids\": [\"1851669\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1991,\n      \"finding\": \"TEF (thyrotroph embryonic factor, PAR bZIP) was identified as a novel bZIP transcription factor expressed in the embryonic anterior pituitary; TEF binds and trans-activates the TSH-beta promoter; TEF forms heterodimers with DBP; a cluster of basic amino acids unique to TEF and DBP is necessary for proper DNA-binding site specificity; a major trans-activation domain resides outside the bZIP homology region.\",\n      \"method\": \"cDNA cloning, DNA-binding assays, trans-activation reporter assays, heterodimerization experiments\",\n      \"journal\": \"Genes & development\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — multiple orthogonal methods in a single study; >220 citations; foundational characterization of the PAR bZIP TEF protein\",\n      \"pmids\": [\"1916262\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1992,\n      \"finding\": \"M-CAT binding factor (MCBF), which governs cardiac troponin T gene promoter activity, is biochemically indistinguishable from TEF-1: it shares identical binding-site specificity, fractionation behavior, apparent molecular weight, and antigenic reactivity with TEF-1 antibodies, establishing MCBF as a TEF-1 family member mediating muscle-specific transcription.\",\n      \"method\": \"Mutational analysis of M-CAT motif, DNA-agarose fractionation, antibody cross-reactivity, mobility shift assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple biochemical methods; >140 citations\",\n      \"pmids\": [\"1324927\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1992,\n      \"finding\": \"TEF-1 is the major factor binding a 37-nt HPV-16 enhancer element in keratinocytes; both TEF-1 and a limiting, cell-specific TEF-1 co-activator are required for HPV-16 E6/E7 oncogene transcription; TEF-1 binding in vivo is necessary for P97 promoter activity; squelching by excess TEF-1 or GAL4-TEF-1 chimeras confirms dependence on a limiting co-activator.\",\n      \"method\": \"Sequence-specific DNA affinity purification, antibody identification, in vivo and in vitro transcription, squelching assays\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal assays; >160 citations\",\n      \"pmids\": [\"1318197\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1994,\n      \"finding\": \"TEF-1 cloned from chick heart exists as multiple muscle-enriched isoforms (TEF-1A and novel TEF-1B); both bind M-CAT elements with high affinity; the C-terminal region of TEF-1B (containing a 13-amino acid exon) can activate transcription when fused to a heterologous DNA-binding domain, while the same domain of TEF-1A cannot, indicating isoform-specific transcriptional activation roles.\",\n      \"method\": \"cDNA cloning, gel mobility shift assays, chimeric activator trans-activation assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — functional domain mapping with heterologous constructs; >90 citations\",\n      \"pmids\": [\"8106348\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1994,\n      \"finding\": \"TEF-1 binds M-CAT sites in the skeletal alpha-actin promoter in cardiac cells and cooperates with SRF at SRE1 to activate transcription; either isolated SRE1 or TEF-1 binding sites can function as TGF-beta response elements; induction of the SkA promoter by TGF-beta requires both SRF and TEF-1 acting in concert.\",\n      \"method\": \"Mutational analysis of skeletal alpha-actin promoter, EMSA, transient transfection in ventricular myocytes\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — epistasis-like promoter mutagenesis with TGF-beta response readout; >130 citations\",\n      \"pmids\": [\"8206998\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1995,\n      \"finding\": \"TEF-1 transrepression of the hCS promoter in BeWo choriocarcinoma cells is mechanistically mediated by direct interaction between the TEF-1 proline-rich domain and TBP (TATA-binding protein): GST-TEF-1 retains in vitro-generated TBP; TEF-1 inhibits TBP binding to the TATA motif; co-expression of TBP relieves TEF-1-mediated repression in vivo.\",\n      \"method\": \"GST pull-down, EMSA supershift, co-transfection, antisense oligonucleotide depletion\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods demonstrating direct TEF-1/TBP interaction and its functional consequence\",\n      \"pmids\": [\"8621623\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1995,\n      \"finding\": \"A novel negatively acting factor from HeLa/BJA-B cell extracts selectively represses TEF-1-mediated transcriptional activation (but not VP16-mediated activation) by interfering with TBP-associated coactivators; repression is alleviated by addition of immunopurified TFIID.\",\n      \"method\": \"Chromatographic fractionation of nuclear extracts, reconstituted in vitro transcription assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 — in vitro reconstitution; single lab, partial mechanistic follow-up\",\n      \"pmids\": [\"7876100\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1995,\n      \"finding\": \"The TEF-1 gene has a TATA-less promoter with multiple transcription start sites around an initiator element (Inr); cell-type-specific expression is directed by a 137-bp minimal promoter containing Sp1 and ATF-1 binding sites; the Inr is required for the major start site; the proximal Sp1 site and the Inr interact to fix transcription start site usage.\",\n      \"method\": \"Promoter deletion analysis, in vitro and in vivo transcription, mutagenesis, EMSA\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods characterizing the TEF-1 promoter mechanism\",\n      \"pmids\": [\"7642633\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1996,\n      \"finding\": \"TEF (PAR bZIP) and DBP bind the same DNA sequences in vitro but exhibit different promoter preferences in cells: TEF activates the albumin promoter more potently than DBP, while only DBP efficiently activates the cholesterol 7alpha-hydroxylase promoter; a TEF-DBP chimera carrying N-terminal TEF sequences with the DBP DNA-binding/dimerization domain activates the C7alphaH promoter as strongly as wild-type DBP, indicating that promoter environment rather than DNA-binding affinity determines promoter preference.\",\n      \"method\": \"In vitro DNA binding, co-transfection reporter assays, chimeric protein analysis\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — chimeric protein dissection with functional readout; >120 citations\",\n      \"pmids\": [\"8617210\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1996,\n      \"finding\": \"TEF-1-related proteins (RTEF-1A, 57, 54, and 52 kDa) are phosphorylated and bind M-CAT DNA; the 54-kDa phosphorylated form (RTEF-1A) is a component of a muscle-enriched M-CAT transcription complex that is up-regulated upon skeletal muscle cell differentiation, as demonstrated by proteolytic digestion mapping and high-resolution mobility shift assays.\",\n      \"method\": \"Western blot, proteolytic digestion mapping, phosphorylation analysis, gel mobility shift assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — biochemical characterization with phosphorylation demonstrated; single lab\",\n      \"pmids\": [\"8626521\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1996,\n      \"finding\": \"TEF (human homolog of HLF/VBP) binds the consensus DNA sequence 5'-GTTACGTAAT-3' (identical to the HLF site); a discrete ~40 amino acid transcriptional activation domain (TAD) shared by TEF and HLF (THAD) was mapped using GAL4 chimeric proteins; deletion of THAD completely abolishes transcriptional activity of TEF and HLF in mammalian cells and yeast.\",\n      \"method\": \"Binding site selection assay, GAL4 chimera trans-activation, deletion mapping in mammalian cells and yeast\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — domain mapping with multiple deletion constructs validated in two cell systems; >30 citations\",\n      \"pmids\": [\"8639829\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1996,\n      \"finding\": \"SV40 large T antigen (TAg) binds the TEA domain of TEF-1 (the same DNA-binding domain shared with Drosophila Scalloped and S. cerevisiae TEC1); this interaction inhibits TEF-1 DNA binding and activates transcription in vitro from a subset of late start sites; TEF-1 thus functions as a repressor of SV40 late transcription.\",\n      \"method\": \"In vitro binding assays, in vitro transcription, TEA domain mutagenesis analysis\",\n      \"journal\": \"Journal of virology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — in vitro binding and transcription with domain-specific interaction; >35 citations\",\n      \"pmids\": [\"8551581\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1997,\n      \"finding\": \"Human TEF-5 is preferentially expressed in placenta and binds cooperatively to tandemly repeated GT-IIC-like elements in the human chorionic somatomammotropin-B (hCS-B) gene enhancer; a single-base mutation in the corresponding element of the hCS-A enhancer (which is inactive) disrupts TEF-5 binding; the placental factor CSEF-1 is a proteolytic degradation product of TEF factors whose binding is disrupted by anti-TEA domain antibodies.\",\n      \"method\": \"cDNA cloning, RT-PCR, EMSA, cooperative binding assays, antibody supershift\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — binding characterization with mutagenesis and antibody validation; single lab\",\n      \"pmids\": [\"9148898\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"The human protein TONDU (TDU), which contains a short domain homologous to the Vestigial (Vg) domain required for Scalloped interaction, specifically interacts with a conserved domain present in all mammalian TEF factors; expression of TONDU in Drosophila can substitute for Vestigial in wing formation.\",\n      \"method\": \"Two-hybrid interaction, in vivo rescue of Drosophila vestigial mutants\",\n      \"journal\": \"Development\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — yeast/mammalian two-hybrid plus in vivo Drosophila rescue; >115 citations\",\n      \"pmids\": [\"10518497\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"TEAD-2/TEF-4 purified from mouse cells is associated with a novel TEAD-binding domain at the amino terminus of YAP65; YAP65 interacts specifically with the carboxyl terminus of all four TEAD/TEF proteins; both the YAP-TEAD interaction and sequence-specific DNA binding by TEAD are required for transcriptional activation; excess YAP65 accumulates in the cytoplasm as a complex with 14-3-3; YAP65 thus provides the transcriptional activation domain for TEAD/TEF transcription factors and its availability is limited by 14-3-3-mediated cytoplasmic sequestration.\",\n      \"method\": \"Protein purification, co-immunoprecipitation, co-transfection reporter assays, cytoplasmic/nuclear fractionation\",\n      \"journal\": \"Genes & development\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — native protein purification, reciprocal binding assays, functional consequence demonstrated; >600 citations; replicated\",\n      \"pmids\": [\"11358867\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"Pur alpha, Pur beta, and MSY1 single-stranded DNA-binding proteins suppress a cryptic MCAT enhancer by competing for TEF-1 binding to a polypurine-polypyrimidine cis-element in the smooth muscle alpha-actin promoter; Pur alpha, Pur beta, and MSY1 also interact weakly with double-stranded DNA and with TEF-1 itself; mutations that selectively impair single-stranded DNA binding by these factors release the MCAT enhancer from repression.\",\n      \"method\": \"DNA binding studies (EMSA), mutagenesis, transfection reporter assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — mutagenesis with functional readout; single lab\",\n      \"pmids\": [\"11751932\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"TEF-1 interacts with the MADS domain of MEF2 transcription factors through additional activation domain sequences; this interaction was demonstrated by co-immunoprecipitation and GST pull-down in vitro and mammalian two-hybrid in vivo; the physiological significance was demonstrated by co-activation of MEF2-dependent muscle-specific promoters on co-transfection.\",\n      \"method\": \"Co-immunoprecipitation, GST pull-down, mammalian two-hybrid, transient transfection\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal interaction assays with functional consequence; single lab\",\n      \"pmids\": [\"12061776\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"Mammalian Vgl-2 (vestigial-like 2) interacts with TEF-1 and with MEF2; Vgl-2 protein translocates from the cytoplasm to the nucleus during skeletal muscle differentiation; Vgl-2 co-activates MEF2-dependent promoters through the MEF2 element; overexpression of Vgl-2 in MyoD-transfected 10T1/2 cells markedly increases myosin heavy chain expression.\",\n      \"method\": \"Mammalian two-hybrid, GST pull-down, subcellular fractionation, transient transfection, immunofluorescence\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal binding and functional assays; localization tied to differentiation; >135 citations\",\n      \"pmids\": [\"12376544\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"DTEF-1 (TEF-5/ETFR-1) is phosphorylated in vivo in neonatal rat cardiac myocytes; alpha1-adrenergic stimulation increases MCAT binding activity of DTEF-1 while phosphatase treatment decreases it, indicating that phosphorylation positively regulates DTEF-1 MCAT binding; DTEF-1 augments the alpha1-adrenergic response of the skeletal muscle alpha-actin gene.\",\n      \"method\": \"Orthophosphate labeling, immunoprecipitation, EMSA, phosphatase treatment, reporter assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct phosphorylation demonstrated with functional consequences; single lab\",\n      \"pmids\": [\"11986313\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"Nuclear calcium and MAPK negatively regulate TEAD/TEF transcription factor activity in CHO cells: chelation of nuclear (but not cytosolic) Ca2+ increased TEAD activity two-fold; inhibition of MAPK also increased TEAD activity; cAMP decreased TEAD activity; protein kinase C had no effect.\",\n      \"method\": \"RT-PCR, selective nuclear/cytosolic calcium chelation, kinase inhibitor assays, TEAD reporter assays\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — pharmacological inhibition with reporter readout; single lab, no direct modification identified\",\n      \"pmids\": [\"12565854\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"TEF (thyrotroph embryonic factor, PAR bZIP) binds to an AT-rich region within the telokin promoter core and specifically activates telokin gene expression in smooth muscle cells in a calcium-dependent manner, without affecting other smooth muscle promoters (SM22alpha, smooth muscle alpha-actin, smooth muscle myosin heavy chain); two isoforms (TEFalpha and TEFbeta) arising from alternative promoter usage are expressed in smooth muscle tissues.\",\n      \"method\": \"Southwestern screen, gel mobility shift assay, reporter gene assays, adenoviral overexpression, RNase protection assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal assays with specific promoter selectivity and endogenous gene expression validation\",\n      \"pmids\": [\"14702338\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"TEF (PAR bZIP) expressed in FL5.12 IL-3-dependent hematopoietic cells protects against apoptosis upon IL-3 withdrawal and down-regulates expression of the common beta (betac) chain of cytokine receptors, causing G0/G1 accumulation without apoptosis; this indicates TEF regulates hematopoietic cell survival and proliferation by controlling betac chain expression.\",\n      \"method\": \"Retroviral transduction, apoptosis assays, flow cytometry, gene expression analysis\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — loss/gain of function with defined cellular and molecular phenotype; single lab\",\n      \"pmids\": [\"15665112\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"TAZ (transcriptional co-activator with PDZ-binding motif) interacts with TEF-1 and all four TEF-1 family members via GST pull-down, co-immunoprecipitation, and modified mammalian two-hybrid assays; TAZ interacts with TEF-1 bound to MCAT DNA; TAZ interacts more efficiently with TEF-1 than RTEF-1; exogenous TAZ activates MCAT-dependent reporter promoters through endogenous TEF-1.\",\n      \"method\": \"GST pull-down, co-immunoprecipitation, mammalian two-hybrid, EMSA, reporter assays\",\n      \"journal\": \"The Biochemical journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal interaction assays with functional reporter validation; >175 citations\",\n      \"pmids\": [\"15628970\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"PAR bZIP proteins DBP, TEF, and HLF control expression of many liver and kidney enzymes and regulators involved in xenobiotic detoxification (cytochrome P450 enzymes, carboxylesterases, CAR); mice devoid of all three PAR bZip proteins are hypersensitive to xenobiotic compounds; morbidity includes epilepsy proneness, accelerated aging, and premature death.\",\n      \"method\": \"Triple knockout mouse model, transcriptome comparison, xenobiotic toxicity assays\",\n      \"journal\": \"Cell metabolism\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — clean triple KO with defined transcriptomic and physiologic phenotypes; >395 citations\",\n      \"pmids\": [\"16814730\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"TEF-1 and C/EBPbeta are the two transcription factors most enriched in promoters of p38alpha MAPK-regulated genes in cardiomyocytes; p38alpha regulates TEF-1 transcriptional activity involved in inhibition of COL1A1 (type I collagen alpha1) transcription in the absence of environmental stress.\",\n      \"method\": \"Transcriptome profiling, promoter motif analysis, p38alpha knockout cardiomyocytes, reporter assays\",\n      \"journal\": \"The Biochemical journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — knockout transcriptomics with functional follow-up; single lab\",\n      \"pmids\": [\"16492136\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"The TEA domain (TEAD) of TEF-1 adopts a three-helix bundle with a homeodomain fold; the L1 loop is essential for cooperative loading of TEAD molecules onto tandemly duplicated M-CAT sites; microarray chip-based binding assays reveal that known binding sites of the full-length TEF-1 protein are only a subset of DNA elements recognized by TEAD.\",\n      \"method\": \"NMR solution structure, structure-function mutagenesis, microarray-based DNA-binding assay\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — structure solved and validated with mutagenesis and genome-wide binding assay\",\n      \"pmids\": [\"17085591\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Drosophila Scalloped (Sd), the TEAD/TEF family ortholog, is the DNA-binding partner that mediates transcriptional output of the Hippo pathway; Sd binds directly to Yorkie (Yki, YAP ortholog) and recruits it to the diap1 HRE enhancer; a Yki missense mutation abrogating Sd binding inactivates Yki in vivo; sd is required for yki-induced tissue overgrowth; the Sd/Yki interaction is conserved in mammalian homologs.\",\n      \"method\": \"Epistasis genetics, direct binding assays, in vivo rescue, chromatin assays, mammalian conservation assay\",\n      \"journal\": \"Developmental cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — epistasis, direct binding, in vivo rescue in Drosophila with conservation validated; >560 citations\",\n      \"pmids\": [\"18258486\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Scalloped (Sd) and Yorkie (Yki) form a transcriptional complex inhibited by Hippo signaling; Sd promotes Yki nuclear localization, while Hippo signaling retains Yki in the cytoplasm by phosphorylating Yki at S168; Sd overexpression enhances, while Sd inactivation suppresses, tissue overgrowth caused by Yki overexpression or tumor suppressor mutations; Sd recruits Yki to the diap1 enhancer.\",\n      \"method\": \"Genetic epistasis, loss-of-function, gain-of-function, phosphorylation analysis, chromatin recruitment assay\",\n      \"journal\": \"Developmental cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple genetic and biochemical approaches; >540 citations; independently replicated\",\n      \"pmids\": [\"18258485\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"PAR bZIP triple knockout mice (Dbp/Tef/Hlf -/-) develop cardiac hypertrophy, left ventricular dysfunction, low blood pressure, and abnormally low aldosterone levels, demonstrating that TEF (together with DBP and HLF) regulates circadian control of cardiovascular functions including aldosterone synthesis.\",\n      \"method\": \"Triple knockout mouse model, cardiac function measurements, blood pressure monitoring, hormone assays\",\n      \"journal\": \"American journal of physiology. Regulatory, integrative and comparative physiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — clean triple KO with defined cardiovascular phenotype; single lab\",\n      \"pmids\": [\"20686175\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Genetic knockdown of TEF or YAP in hypothalamic neurons stimulates enkephalin (ENK) expression; prenatal high-fat diet increases inactive TEF protein levels and decreases YAP in hypothalamus; TEF co-localizes with ENK in hypothalamic neurons, and HFD reduces density of TEF/ENK co-labeled neurons, suggesting TEF regulates neuropeptide gene expression and ENK neuron differentiation.\",\n      \"method\": \"Genetic knockdown, immunofluorescence co-localization, protein expression analysis, prenatal dietary manipulation\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — knockdown with defined cellular phenotype and co-localization; single lab\",\n      \"pmids\": [\"24147051\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"A novel TCF3/TEF gene fusion was identified in a pediatric B-ALL/LBL case by mate-pair sequencing, demonstrating that TEF can serve as a translocation partner in acute lymphoblastic leukemia.\",\n      \"method\": \"Next-generation sequencing (mate-pair sequencing), FISH\",\n      \"journal\": \"Blood cancer journal\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — single case identification; no functional characterization of the fusion protein\",\n      \"pmids\": [\"31575852\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"TEF encodes two distinct proteins depending on context: (1) the TEAD/TEF family of transcription factors (TEAD1-4), which bind M-CAT and GT-IIC/Sph DNA elements via a three-helix homeodomain-like TEA domain, require YAP65 or TAZ as transcriptional co-activators (whose availability is controlled by 14-3-3 cytoplasmic sequestration and Hippo pathway phosphorylation), interact with co-factors including Vestigial-like proteins, TBP, SRF, and MEF2, and regulate muscle-specific, placental, and viral gene transcription; and (2) thyrotroph embryonic factor (TEF), a PAR bZIP protein that heterodimerizes with DBP and HLF, binds a consensus DNA sequence, contains a discrete ~40 amino acid transcriptional activation domain, accumulates in a circadian manner, and controls xenobiotic detoxification, cardiovascular function, and anti-apoptotic gene expression in hematopoietic progenitors.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"TEF (thyrotroph embryonic factor) is a PAR basic-leucine-zipper (bZIP) transcription factor that heterodimerizes with the related circadian regulators DBP and HLF, binds the consensus sequence 5'-GTTACGTAAT-3', and contains a discrete ~40 amino acid transcriptional activation domain (THAD) essential for its activity [PMID:1916262, PMID:8639829]. TEF activates tissue-selective promoters including TSH-beta in the embryonic pituitary and telokin in smooth muscle, and together with DBP and HLF controls expression of xenobiotic detoxification enzymes (cytochrome P450s, carboxylesterases, CAR) and cardiovascular functions including aldosterone synthesis; triple knockout of all three PAR bZIP factors causes xenobiotic hypersensitivity, epilepsy, cardiac hypertrophy, and premature death in mice [PMID:16814730, PMID:20686175, PMID:14702338]. In hematopoietic progenitor cells, TEF confers protection from apoptosis upon cytokine withdrawal by downregulating the common beta chain of cytokine receptors [PMID:15665112]. A TCF3/TEF gene fusion has been identified in a pediatric B-cell acute lymphoblastic leukemia case [PMID:31575852].\",\n  \"teleology\": [\n    {\n      \"year\": 1991,\n      \"claim\": \"Identification of TEF as a novel PAR bZIP transcription factor in the embryonic pituitary resolved the molecular nature of the factor activating TSH-beta and established its capacity to heterodimerize with DBP and to trans-activate via a domain outside the bZIP region.\",\n      \"evidence\": \"cDNA cloning, DNA-binding assays, heterodimerization experiments, and reporter assays in transfected cells\",\n      \"pmids\": [\"1916262\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"The precise activation domain boundaries were not yet mapped\",\n        \"Endogenous target genes beyond TSH-beta were unknown\",\n        \"In vivo physiological role of TEF was uncharacterized\"\n      ]\n    },\n    {\n      \"year\": 1996,\n      \"claim\": \"Mapping of a discrete ~40 amino acid transcriptional activation domain (THAD) shared by TEF and HLF, and demonstration that TEF and DBP have distinct promoter preferences despite identical DNA-binding specificity, revealed that TEF's transcriptional output depends on promoter context rather than simple DNA recognition.\",\n      \"evidence\": \"GAL4 chimera deletion mapping in mammalian cells and yeast; chimeric TEF-DBP protein reporter assays showing promoter-selective activation\",\n      \"pmids\": [\"8639829\", \"8617210\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Structural basis for context-dependent promoter preference was not determined\",\n        \"Co-factors mediating promoter selectivity were not identified\"\n      ]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Discovery that TEF activates the telokin promoter in a calcium-dependent manner in smooth muscle cells, with two tissue-specific isoforms (TEFalpha and TEFbeta), extended TEF's functional repertoire beyond the pituitary to smooth muscle gene regulation.\",\n      \"evidence\": \"Southwestern screen, gel shift, reporter assays, adenoviral overexpression, and RNase protection in smooth muscle cells\",\n      \"pmids\": [\"14702338\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Mechanism linking calcium signaling to TEF activity was not resolved\",\n        \"Relative contributions of TEFalpha vs TEFbeta isoforms to smooth muscle physiology were unclear\"\n      ]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Demonstration that TEF protects hematopoietic progenitor cells from apoptosis by downregulating the cytokine receptor common beta chain established a role for TEF in cell survival decisions outside epithelial or muscle lineages.\",\n      \"evidence\": \"Retroviral transduction of TEF into IL-3-dependent FL5.12 cells with apoptosis and flow cytometry readout\",\n      \"pmids\": [\"15665112\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Whether TEF directly binds the betac promoter was not shown\",\n        \"Relevance to normal hematopoiesis in vivo was not tested\",\n        \"Mechanism of anti-apoptotic action beyond betac downregulation was unknown\"\n      ]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Triple knockout of all three PAR bZIP factors (Dbp/Tef/Hlf) revealed their collective, partially redundant control of hepatic and renal xenobiotic detoxification programs and established that loss causes systemic toxicity, epilepsy, and premature death.\",\n      \"evidence\": \"Triple knockout mouse model with transcriptomic profiling and xenobiotic challenge experiments\",\n      \"pmids\": [\"16814730\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Individual contribution of TEF vs DBP vs HLF to each detoxification gene was not dissected\",\n        \"Whether TEF single knockout produces a phenotype was not reported\"\n      ]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"The same PAR bZIP triple knockout mice displayed cardiac hypertrophy, left ventricular dysfunction, hypotension, and reduced aldosterone, establishing TEF (with DBP and HLF) as a circadian regulator of cardiovascular homeostasis.\",\n      \"evidence\": \"Echocardiography, blood pressure telemetry, and hormone assays in Dbp/Tef/Hlf triple knockout mice\",\n      \"pmids\": [\"20686175\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Direct TEF target genes mediating cardiac and aldosterone phenotypes were not identified\",\n        \"Individual contribution of TEF to the cardiovascular phenotype was not resolved\",\n        \"Whether circadian oscillation of TEF is required for the phenotype was not tested\"\n      ]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Identification of a TCF3/TEF gene fusion in a pediatric B-ALL case suggested TEF can participate in oncogenic translocations in hematopoietic malignancies, though the fusion's functional consequences were not characterized.\",\n      \"evidence\": \"Mate-pair next-generation sequencing and FISH confirmation in a single patient\",\n      \"pmids\": [\"31575852\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"Single case without functional characterization of the fusion protein\",\n        \"Whether the fusion drives leukemogenesis or is a passenger event is unknown\",\n        \"No recurrence data from additional patient cohorts\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The individual contribution of TEF (independent of DBP and HLF) to circadian physiology, xenobiotic detoxification, and cardiovascular function remains unresolved, as does the structural basis of THAD-mediated transcriptional activation and the identity of TEF-specific co-activators in different tissues.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"No TEF single-knockout phenotype has been reported\",\n        \"No crystal or cryo-EM structure of TEF or the THAD activation domain exists\",\n        \"Genome-wide direct target identification (ChIP-seq) for TEF has not been performed\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0003677\", \"supporting_discovery_ids\": [2, 10, 12, 22]},\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [2, 10, 12, 22, 23, 25]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [2, 12, 22]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [2, 10, 12, 22, 23]},\n      {\"term_id\": \"R-HSA-9909396\", \"supporting_discovery_ids\": [25, 30]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [32]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\n      \"DBP\",\n      \"HLF\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}