{"gene":"RREB1","run_date":"2026-06-10T07:46:28","timeline":{"discoveries":[{"year":1996,"finding":"RREB-1 is a zinc finger transcription factor that binds to the Ras-responsive element (RRE) in the calcitonin gene promoter (consensus binding site CCCCAAACCACCCC) and, upon overexpression, mediates Ras- and Raf-induced transactivation of the calcitonin gene promoter in medullary thyroid cancer cells.","method":"Affinity screening/cDNA cloning, DNase I protection assay, reporter transactivation assay with overexpression","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 1 / Strong — direct DNA-binding demonstrated by DNase I footprinting, functional transactivation confirmed by reporter assay, founding mechanistic paper replicated across many subsequent studies","pmids":["8816445"],"is_preprint":false},{"year":2008,"finding":"RREB1 (mammalian homolog of Drosophila Hindsight/HNT) is required for collective cell migration; siRNA knockdown of RREB1 in MCF10A mammary epithelial cells inhibited collective migration in scratch-wound assays, suppressed surface activity, retarded cell spreading, and caused formation of immobile, tightly adherent colonies, indicating RREB1 reduces cell-cell adhesion to enable dynamic epithelial cell movements.","method":"siRNA knockdown, scratch-wound healing assay, live-cell imaging, Drosophila genetic analysis (hnt mutants)","journal":"Current biology : CB","confidence":"High","confidence_rationale":"Tier 2 / Moderate — direct loss-of-function with defined cellular phenotype in mammalian cells, supported by orthologous Drosophila genetic evidence","pmids":["18394891"],"is_preprint":false},{"year":2009,"finding":"RREB-1 represses HLA-G transcriptional activity by binding three Ras-response elements within the HLA-G promoter; in HLA-G-negative cells, RREB-1 interacts with subunits of the CtBP co-repressor complex implicated in chromatin remodeling.","method":"Promoter pull-down assay followed by mass spectrometry, reporter assay, Co-IP (RREB-1 with CtBP complex subunits)","journal":"Journal of immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — promoter pull-down with MS identification, reporter functional assay, and co-immunoprecipitation; single lab","pmids":["19890057"],"is_preprint":false},{"year":2009,"finding":"RREB-1 binds the p53 core promoter element and transactivates p53 expression; upon genotoxic stress, RREB-1 recruitment to the p53 promoter increases, and RREB-1 silencing reduces p53 mRNA and protein levels and suppresses downstream p53 target gene expression, controlling apoptosis in a p53-dependent manner.","method":"ChIP, luciferase reporter assay, siRNA knockdown, qRT-PCR, Western blot","journal":"The Biochemical journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP and reporter assays in one lab; functional consequence of silencing with defined molecular readout","pmids":["19558368"],"is_preprint":false},{"year":2010,"finding":"RREB-1 binds to a specific RRE site in the hZIP1 promoter and represses hZIP1 zinc transporter transcription in prostate cancer cells; this binding was demonstrated by gel shift and ChIP, and site-directed mutagenesis of the binding site relieved repression.","method":"Luciferase reporter assay, site-directed mutagenesis, EMSA (gel shift), ChIP","journal":"The Prostate","confidence":"High","confidence_rationale":"Tier 1 / Moderate — multiple orthogonal methods including mutagenesis, EMSA, and ChIP confirming direct promoter binding and functional repression","pmids":["19802870"],"is_preprint":false},{"year":2011,"finding":"Overexpression of RREB-1 decreases hZIP1 abundance at the plasma membrane of PC-3 prostate cancer cells, while siRNA knockdown of RREB-1 significantly increases hZIP1 expression, establishing RREB-1 as a transcriptional repressor of hZIP1 in vivo.","method":"Overexpression, siRNA knockdown, immunohistochemistry/Western blot","journal":"The Prostate","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — bidirectional manipulation (OE and KD) with consistent cellular readout; single lab, replicates prior promoter study","pmids":["21360563"],"is_preprint":false},{"year":2012,"finding":"RREB1 is activated by the MAPK pathway downstream of oncogenic KRAS and negatively represses the miR-143/145 promoter through interaction with two RREs, constituting a regulatory feedback loop where miR-143/145 in turn targets KRAS and RREB1.","method":"Reporter assay, ChIP, qRT-PCR, overexpression/knockdown, MAPK pathway inhibition","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP confirming direct promoter binding, reporter assay, and functional MAPK dependency; single lab","pmids":["22751122"],"is_preprint":false},{"year":2013,"finding":"DJ-1 acts as a coactivator by physically interacting with RREB1; the DJ-1/RREB1 complex (but not a DJ-1/Sp1 complex) binds to the RRE in the cholecystokinin (CCK) gene promoter, stimulating CCK transcription. DJ-1 knockout mice show reduced serum CCK levels.","method":"Co-immunoprecipitation, promoter binding assay, luciferase reporter, qRT-PCR, ELISA in DJ-1-knockout mice","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP demonstrating direct interaction, functional reporter assay, and in vivo mouse confirmation; single lab","pmids":["24348900"],"is_preprint":false},{"year":2014,"finding":"The Drosophila HNT C-terminal region (containing the last five zinc fingers) binds DNA elements similar to those of human RREB-1; human RREB-1 expressed in Drosophila binds the same polytene chromosome sites as HNT, attenuates expression of hnt and nvy target genes, and rescues the germ band retraction phenotype, demonstrating functional conservation of DNA binding and transcriptional attenuation.","method":"In vitro DNA binding assay, polytene chromosome binding, rescue genetics, loss-of-function and overexpression in Drosophila","journal":"Differentiation; research in biological diversity","confidence":"High","confidence_rationale":"Tier 1 / Strong — multiple orthogonal methods (in vitro binding, in vivo polytene mapping, genetic rescue) establishing functional conservation","pmids":["24418439"],"is_preprint":false},{"year":2017,"finding":"RREB1 cooperates with the lncRNA linc-ADAMTS5 to repress ADAMTS5 expression in nucleus pulposus cells; RREB1 is recruited to the ADAMTS5 promoter via a physical interaction with splicing factor SFPQ (facilitated by linc-ADAMTS5 binding to SFPQ), and this complex induces chromatin remodeling involving histone deacetylases to suppress ADAMTS5 transcription.","method":"RNA pulldown, RIP, in vitro binding assay, ChIP, gain/loss-of-function studies","journal":"Clinical science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple binding assays (pulldown, RIP, ChIP) and functional gain/loss-of-function; single lab","pmids":["28341660"],"is_preprint":false},{"year":2018,"finding":"The Drosophila RREB1 ortholog Pebbled (Peb) is required in glutamatergic sensory neurons for axon death after injury; loss of peb results in preservation or incomplete fragmentation of severed axons, and human RREB1 rescues peb mutant phenotypes. Dominant genetic interactions between peb and dsarm place peb/RREB1 in the axon death signaling cascade.","method":"Drosophila genetics (loss-of-function mutants), human RREB1 rescue, axotomy assay, genetic epistasis with dsarm","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic epistasis with defined signaling pathway, human RREB1 rescue across species, multiple neuronal subtypes tested","pmids":["29295933"],"is_preprint":false},{"year":2020,"finding":"RREB1 is a MAPK-activated RAS transcriptional effector that physically recruits TGF-β-activated SMAD transcription factors to the SNAIL promoter; RREB1 and SMAD together drive expression of SNAIL and context-dependent EMT gene programs. In carcinoma cells, RREB1-SMAD drive fibrogenic EMT; in mouse epiblast progenitors, RREB1-Nodal-SMAD drive developmental EMT/gastrulation.","method":"Co-IP, ChIP-seq, reporter assay, CRISPR/KO, mouse embryo genetics, biochemical reconstitution of RREB1-SMAD complex","journal":"Nature","confidence":"High","confidence_rationale":"Tier 1 / Strong — Co-IP of RREB1-SMAD complex, ChIP-seq establishing genomic co-occupancy, genetic KO with developmental phenotype, multiple cell systems; replicated conceptually in accompanying commentary","pmids":["31915377"],"is_preprint":false},{"year":2020,"finding":"Rreb1 haploinsufficiency in mice sensitizes MAPK signaling; RREB1 recruits Sin3a and Kdm1a (KDM1A) to MAPK pathway gene promoters to control H3K4 methylation, thereby epigenetically reprogramming RAS-MAPK target gene expression. Loss of one Rreb1 allele phenocopies Noonan syndrome features (orbital hypertelorism, cardiac hypertrophy).","method":"Rreb1 hemizygous mouse model, ChIP, Co-immunoprecipitation (RREB1-Sin3a-Kdm1a complex), H3K4 methylation analysis, MAPK signaling assays","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — Co-IP establishing trimeric complex, ChIP showing histone modification changes at MAPK gene promoters, in vivo mouse phenotype matching human syndrome; multiple orthogonal methods","pmids":["32938917"],"is_preprint":false},{"year":2021,"finding":"Loss of Rreb1 in mouse embryos reduces expression of vasculogenic factors, causes cardiovascular defects and embryonic lethality; during gastrulation, absence of Rreb1 upregulates cytoskeleton-associated genes, alters F-actin and adherens junction organization in the epiblast, and causes ectopic exit of cells through the basement membrane, paralleling metastatic behavior.","method":"Rreb1 knockout mouse model, immunofluorescence (F-actin, E-cadherin), RNA-seq, histology","journal":"eLife","confidence":"High","confidence_rationale":"Tier 2 / Strong — full KO mouse model with multiple orthogonal molecular and cellular readouts; extends earlier mechanistic findings","pmids":["33929320"],"is_preprint":false},{"year":2021,"finding":"miR-26a promotes deacetylation of RREB1 at the Lys-60 residue; deacetylated RREB1 binds the AKT1 promoter to activate AKT transcription and downstream glycolytic signaling in colorectal cancer cells.","method":"Quantitative proteomics, ChIP, luciferase reporter, loss-of-function analysis, site-specific mutagenesis of Lys-60, xenograft mouse model","journal":"Cancer letters","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — proteomics identification of PTM site, ChIP and reporter confirming promoter binding, functional KO in vivo; single lab","pmids":["34419497"],"is_preprint":false},{"year":2022,"finding":"Ras signaling and RREB1 are required for dissociation of medial edge epithelial (MEE) cells during murine palatogenesis; siRNA knockdown of Rreb1 in palatal organ culture inhibited MEE cell dissociation and caused palatal fusion defects, placing RREB1 downstream of RAS in this EMT-like process.","method":"siRNA knockdown in palatal organ culture, pan-Ras inhibitor treatment, morphological analysis","journal":"Disease models & mechanisms","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss-of-function with defined developmental phenotype in organ culture; single method, single lab","pmids":["34897389"],"is_preprint":false},{"year":2024,"finding":"RREB1 is essential for neuronal survival in the mammalian brain; a spontaneous mouse mutation in the nervous-system-enriched Rreb1 transcript causes progressive Purkinje cell loss and ataxia. ChIP-seq and RNA-seq reveal RREB1 regulates genes associated with the microtubule cytoskeleton and the endomembrane system; loss of RREB1 disrupts dendritic complexity, reduces autophagosomes/lysosomes, and causes accumulation of P62- and ubiquitin-positive inclusions.","method":"Spontaneous mouse mutant, ChIP-seq, RNA-seq, immunofluorescence (P62, ubiquitin, autophagosomes), dendritic morphology analysis","journal":"Science advances","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo mouse genetic model with multiple orthogonal molecular readouts (ChIP-seq, RNA-seq, immunofluorescence); defines RREB1 transcriptional targets and neuronal phenotypes","pmids":["38198538"],"is_preprint":false},{"year":2024,"finding":"RREB1 directly activates transcription of UBC9 by binding its promoter, thereby elevating global protein SUMOylation (SUMO2/3) in colorectal cancer cells, which contributes to 5-fluorouracil resistance.","method":"ChIP-qPCR, luciferase reporter assay, overexpression/knockdown, Western blot for SUMOylation","journal":"Frontiers in pharmacology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP and reporter confirming direct promoter binding, functional SUMOylation assays; single lab","pmids":["39108750"],"is_preprint":false},{"year":2024,"finding":"SUMOylated RREB1 physically interacts with KDM1A; this RREB1-KDM1A complex elevates expression of thymidylate synthase (TS) and thymidine kinase (TK1) and enhances activation of Chk1-mediated DNA damage response. DeSUMOylation of RREB1 reduces the RREB1-KDM1A interaction, decreasing TS expression and attenuating DDR pathway activation.","method":"Co-immunoprecipitation, SUMOylation assay, ChIP, Western blot, KDM1A knockdown, 5-FU resistance assay","journal":"MedComm","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP of RREB1-KDM1A complex, functional SUMOylation dependency established by deSUMOylation experiments; single lab","pmids":["39991628"],"is_preprint":false},{"year":2024,"finding":"METTL3 physically interacts with RREB1 (an enriched METTL3 mRNA target), with the N-terminus of METTL3 as the primary interacting domain, revealing a novel regulatory connection between the m6A methylation machinery and RREB1.","method":"Co-immunoprecipitation, domain mapping","journal":"Biochemical and biophysical research communications","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single Co-IP with domain mapping; no functional follow-up reported in abstract","pmids":["39278095"],"is_preprint":false},{"year":2024,"finding":"Loss of RREB1 in mouse and human adipocyte precursor cells decreases adipogenic gene expression and activates transcription of genes associated with osteoblast differentiation; global Rreb1+/- mice on high-fat diet show reduced fat mass and adipocyte size, with smaller, more insulin-sensitive subcutaneous adipocytes in certain conditions.","method":"Global heterozygous Rreb1+/- mouse model, adipogenic gene expression analysis (RNA-seq), adipocyte differentiation assays in mouse and human cells, in vivo body composition","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo mouse KO model with defined phenotype, human cell validation; preprint, not yet peer-reviewed","pmids":["39131393"],"is_preprint":true},{"year":2024,"finding":"RREB1 is required for Sertoli cell maturation and spermatogenesis in mice; knockdown of Rreb1 causes defective blood-testis barrier structure, decreased expression of Sertoli cell maturity markers, and oligoasthenoteratozoospermia. Mechanistically, RREB1 directly activates the Wt1 promoter and positively regulates Fshr transcription; RREB1 knockdown destabilizes SMAD3 and reduces Wt1, Par6b, and E-cadherin expression.","method":"siRNA knockdown in mice (in vivo), promoter-reporter luciferase assay, Western blot, immunofluorescence, spermatogenesis phenotyping","journal":"Zygote","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo knockdown with defined cellular and molecular phenotypes, direct promoter activation shown by reporter assay; single lab","pmids":["38248872"],"is_preprint":false},{"year":2025,"finding":"Loss of Drosophila Peb (RREB1 ortholog) results in excessive RAS/MAPK pathway activation, causing adult-onset progressive motor axonal degeneration and NMJ degeneration; pharmacological inhibition of MEK1/2 with mirdametinib rescues peb mutant neurodegeneration, establishing that Peb/RREB1 normally functions as a transcriptional negative regulator of RAS/MAPK pathway target genes to maintain axonal integrity.","method":"Drosophila forward genetic screen, loss-of-function genetics, MAPK pathway activity assays, MEK inhibitor pharmacological rescue","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — forward genetic screen with defined pathway epistasis and pharmacological rescue; preprint, not yet peer-reviewed","pmids":[],"is_preprint":true},{"year":2007,"finding":"RREB-1 is a transcriptional effector downstream of the Ral GTPases (RalA and RalB) in bladder cancer cells; computational analysis of RRE motifs in promoters of Ral-regulated genes, verified experimentally, identified RREB-1 as a target of Ral signaling.","method":"siRNA depletion of RalA/RalB, microarray gene expression profiling, computational promoter analysis, experimental verification of RREB-1 as Ral target","journal":"Oncogene","confidence":"Low","confidence_rationale":"Tier 3 / Weak — computational identification with limited direct experimental verification of the RREB-1 node described in abstract; single lab","pmids":["17496927"],"is_preprint":false},{"year":2013,"finding":"RREB1 positively regulates ZIP3 zinc transporter expression in pancreatic cells; downregulation of RREB1 in Panc1 cells reduces ZIP3, which reduces zinc uptake and accumulation, relieving zinc cytotoxicity in developing malignant cells.","method":"RREB1 overexpression/siRNA knockdown, ZIP3 expression analysis, zinc accumulation assay, cell proliferation assay","journal":"Cancer biology & therapy","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — bidirectional manipulation with defined molecular (ZIP3, zinc) and functional (proliferation) readouts; single lab","pmids":["25050557"],"is_preprint":false},{"year":2023,"finding":"RREB1 transcriptionally activates the SNHG4 lncRNA promoter; SNHG4 in turn acts as a ceRNA sponging let-7a miRNA, which itself targets RREB1, establishing a let-7a/RREB1/SNHG4 positive feedback loop that promotes prostate cancer cell survival and enzalutamide resistance.","method":"ChIP assay, luciferase reporter assay, RNA immunoprecipitation, qRT-PCR, in vitro/in vivo functional assays","journal":"Journal of experimental & clinical cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP and reporter confirming direct RREB1-SNHG4 promoter interaction, RIP validating RNA interactions; single lab","pmids":["37596700"],"is_preprint":false},{"year":2026,"finding":"RREB1 transcriptionally activates FMR1 by directly binding the FMR1 promoter; FMR1 in turn enhances VEGFA expression and secretion, activating MAPK and PI3K signaling in endothelial cells to promote angiogenesis in colorectal cancer.","method":"ChIP-qPCR, luciferase reporter assay, HUVEC tube formation, CAM assay, siRNA knockdown, co-expression analysis in CRC tissues","journal":"Biochimica et biophysica acta. Molecular cell research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP-qPCR and reporter confirming direct promoter binding, functional angiogenesis assays; single lab","pmids":["42214628"],"is_preprint":false},{"year":2021,"finding":"RREB1 knockdown in gastric cancer cells enhances p16 expression and inhibits cell proliferation in vitro and in vivo, identifying RREB1 as a negative regulator of p16 in gastric cancer.","method":"Lentiviral RREB1 knockdown/overexpression, MTT, colony formation, cell cycle assay, xenograft mouse model, Western blot for p16","journal":"Cell cycle","confidence":"Low","confidence_rationale":"Tier 3 / Weak — functional phenotype with molecular readout (p16) but no direct promoter-binding or ChIP evidence linking RREB1 to p16 regulation; single lab","pmids":["34666611"],"is_preprint":false},{"year":2026,"finding":"In glioma stem cells, NIBAN2 directly binds FLII and enhances the FLII-RREB1 interaction, promoting RREB1 nuclear translocation; the NIBAN2-FLII-RREB1 complex activates TLR3 signaling. RREB1 also transcriptionally upregulates NIBAN2 and CD44 and promotes LDHA expression, establishing a feed-forward signaling-transcription-metabolism axis.","method":"Co-immunoprecipitation, nuclear fractionation, ChIP, RNA-seq, metabolomics, in vitro and in vivo tumor models","journal":"Advanced science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP establishing protein-protein interactions, nuclear translocation by fractionation, ChIP for transcriptional targets; single lab","pmids":["41736673"],"is_preprint":false}],"current_model":"RREB1 is a multi-zinc-finger transcription factor activated by MAPK/RAS signaling (via ERK-mediated phosphorylation) that functions both as a transcriptional activator and repressor: as an activator, it recruits TGF-β/SMAD complexes to drive EMT gene programs (including SNAIL), activates p53, ZIP3, calcitonin, AKT1, and other target gene promoters, and cooperates with co-factors including DJ-1, KDM1A, and the NIBAN2-FLII complex; as a repressor, it silences hZIP1, HLA-G, and miR-143/145 through interaction with CtBP co-repressor complexes and by recruiting histone-modifying machinery (Sin3a-KDM1A, HDACs); in the nervous system it negatively regulates RAS/MAPK pathway target genes to maintain axonal integrity; and its haploinsufficiency causes epigenetic derepression of RAS-MAPK genes leading to Noonan-like RASopathy."},"narrative":{"mechanistic_narrative":"RREB1 (Ras-responsive element binding protein 1) is a multi-zinc-finger transcription factor that serves as a downstream effector of RAS/MAPK signaling, binding Ras-responsive elements (RREs; consensus CCCCAAACCACCCC) to control gene programs governing epithelial cell behavior, development, and neuronal maintenance [PMID:8816445, PMID:24418439]. It acts bidirectionally: as an activator it transactivates promoters including calcitonin, p53, ZIP3, AKT1, and others [PMID:8816445, PMID:19558368, PMID:25050557, PMID:34419497], and as a repressor it silences targets such as HLA-G, hZIP1, and miR-143/145 through interaction with the CtBP co-repressor complex and chromatin-remodeling/histone-deacetylase machinery [PMID:19890057, PMID:19802870, PMID:22751122]. A central role is the coordination of EMT: RREB1 physically recruits TGF-β/Nodal-activated SMAD transcription factors to the SNAIL promoter to drive both carcinoma fibrogenic EMT and developmental EMT during gastrulation, and its loss in mouse embryos perturbs F-actin and adherens-junction organization, causing aberrant epithelial cell exit reminiscent of metastasis [PMID:31915377, PMID:33929320]. RREB1 also recruits a Sin3a–KDM1A complex to MAPK pathway gene promoters to set H3K4 methylation, and Rreb1 haploinsufficiency in mice epigenetically derepresses RAS-MAPK targets and phenocopies Noonan syndrome features such as hypertelorism and cardiac hypertrophy [PMID:32938917]. In the nervous system, RREB1/orthologs act as negative regulators of RAS/MAPK target genes required for axonal integrity and neuronal survival, with loss causing Purkinje cell degeneration, defective autophagy, and accumulation of P62/ubiquitin inclusions [PMID:38198538, PMID:29295933]. Functional conservation is demonstrated by human RREB1 rescuing Drosophila Hindsight/Pebbled mutant phenotypes [PMID:24418439, PMID:29295933].","teleology":[{"year":1996,"claim":"Established the founding molecular identity of RREB1 as a zinc-finger transcription factor that binds the Ras-responsive element and couples RAS/RAF signaling to target gene transactivation.","evidence":"cDNA cloning, DNase I footprinting, and reporter transactivation in medullary thyroid cancer cells","pmids":["8816445"],"confidence":"High","gaps":["Did not define the full repertoire of target genes","No structure of the DNA-binding zinc fingers","Mechanism of RAS-dependent activation not resolved"]},{"year":2008,"claim":"Linked RREB1 to a cellular phenotype — collective epithelial cell migration via modulation of cell-cell adhesion — connecting its transcriptional role to morphogenetic behavior.","evidence":"siRNA knockdown and scratch-wound/live-imaging in MCF10A cells with orthologous Drosophila hnt genetics","pmids":["18394891"],"confidence":"High","gaps":["Adhesion target genes not identified","Did not connect phenotype to specific promoters"]},{"year":2009,"claim":"Defined RREB1's dual activator/repressor mode: it represses HLA-G via the CtBP co-repressor complex while activating p53 under genotoxic stress to control apoptosis.","evidence":"Promoter pull-down/MS, Co-IP with CtBP subunits, ChIP and reporter assays in human cells","pmids":["19890057","19558368"],"confidence":"Medium","gaps":["Single-lab findings","Determinants of activator-vs-repressor switching not defined","CtBP recruitment mechanism not mapped at residue level"]},{"year":2010,"claim":"Demonstrated direct, mutation-sensitive promoter binding underlying repression of the zinc transporter hZIP1 in prostate cancer, establishing RREB1 as a regulator of cellular zinc handling.","evidence":"EMSA, ChIP, site-directed mutagenesis, and reporter/overexpression-knockdown in prostate cancer cells","pmids":["19802870","21360563"],"confidence":"High","gaps":["Co-repressor for hZIP1 silencing not defined","Physiological consequence of zinc dysregulation in vivo untested"]},{"year":2012,"claim":"Positioned RREB1 within a RAS feedback circuit by showing it is MAPK-activated and represses miR-143/145, which in turn target KRAS and RREB1.","evidence":"ChIP, reporter assays, and MAPK pathway inhibition in cancer cells","pmids":["22751122"],"confidence":"Medium","gaps":["Single lab","Repressive chromatin machinery at miR-143/145 not detailed"]},{"year":2013,"claim":"Identified co-activators and additional target genes (DJ-1 cooperation at the CCK promoter; positive regulation of ZIP3), broadening the activator repertoire and demonstrating in vivo relevance.","evidence":"Co-IP, reporter/promoter binding, and DJ-1-knockout mouse serum CCK; ZIP3/zinc assays in pancreatic cells","pmids":["24348900","25050557"],"confidence":"Medium","gaps":["Single-lab studies","Structural basis of DJ-1/RREB1 cooperation unknown"]},{"year":2014,"claim":"Established evolutionary conservation of RREB1 DNA-binding and transcriptional-attenuation function through cross-species rescue of the Drosophila Hindsight ortholog.","evidence":"In vitro DNA binding, polytene chromosome mapping, and human RREB1 rescue of hnt germ band retraction phenotype","pmids":["24418439"],"confidence":"High","gaps":["Conserved mammalian target genes not enumerated","Functional role of individual zinc fingers not dissected"]},{"year":2018,"claim":"Revealed a neuronal function: the RREB1 ortholog Pebbled is required for injury-induced axon death and acts within the dSarm/SARM1 axon-degeneration cascade, rescuable by human RREB1.","evidence":"Drosophila loss-of-function genetics, axotomy assays, genetic epistasis with dsarm, and human RREB1 rescue","pmids":["29295933"],"confidence":"High","gaps":["Mammalian transcriptional targets in axon death not defined","Mechanistic link to SARM1 signaling unresolved"]},{"year":2020,"claim":"Defined the central EMT mechanism and a chromatin-modifying mode: RREB1 recruits SMAD factors to the SNAIL promoter to drive EMT, and recruits a Sin3a–KDM1A complex to MAPK gene promoters, with haploinsufficiency causing a Noonan-like RASopathy.","evidence":"Co-IP, ChIP-seq, biochemical reconstitution of RREB1-SMAD, CRISPR/KO, and Rreb1 hemizygous mouse modeling with H3K4 methylation analysis","pmids":["31915377","32938917"],"confidence":"High","gaps":["Determinants directing RREB1 to activator vs repressor complexes not resolved","Full set of co-occupied SMAD/RREB1 genomic loci not exhaustively defined"]},{"year":2021,"claim":"Extended the developmental role in vivo: Rreb1 loss disrupts vasculogenesis, cytoskeletal/adherens-junction organization, and causes ectopic epithelial cell exit, linking embryonic and metastatic cell behaviors.","evidence":"Rreb1 knockout mouse embryos with RNA-seq, immunofluorescence (F-actin, E-cadherin), and histology","pmids":["33929320"],"confidence":"High","gaps":["Direct cytoskeletal target genes not all validated by binding","Tissue-specific contributions not separated from systemic effects"]},{"year":2021,"claim":"Identified post-translational regulation of RREB1: miR-26a-driven deacetylation at Lys-60 enables AKT1 promoter binding and glycolytic signaling in colorectal cancer.","evidence":"Quantitative proteomics, Lys-60 mutagenesis, ChIP, reporter, and xenograft assays","pmids":["34419497"],"confidence":"Medium","gaps":["Acetyltransferase/deacetylase enzymes acting on Lys-60 not identified","Single lab"]},{"year":2024,"claim":"Established RREB1 as essential for mammalian neuronal survival, regulating microtubule-cytoskeleton and endomembrane/autophagy genes whose loss causes Purkinje degeneration and proteostatic inclusions.","evidence":"Spontaneous Rreb1 mouse mutant with ChIP-seq, RNA-seq, dendritic morphology, and P62/ubiquitin immunofluorescence","pmids":["38198538"],"confidence":"High","gaps":["Causal target gene driving autophagy defect not pinpointed","Relationship to RAS/MAPK regulation in neurons not directly tested"]},{"year":2024,"claim":"Connected RREB1 to SUMOylation biology and chemoresistance: it activates UBC9 to elevate global SUMOylation, and SUMOylated RREB1 binds KDM1A to drive thymidylate synthase/TK1 and Chk1-mediated DDR.","evidence":"ChIP, reporter, SUMOylation/deSUMOylation assays, Co-IP, and 5-FU resistance assays in colorectal cancer cells","pmids":["39108750","39991628"],"confidence":"Medium","gaps":["SUMO acceptor sites on RREB1 not mapped","Single-lab findings without independent replication"]},{"year":2024,"claim":"Implicated RREB1 in additional tissue programs — adipocyte/osteoblast lineage balance and Sertoli cell maturation/spermatogenesis via Wt1 and Fshr regulation.","evidence":"Rreb1+/- mouse and human adipocyte differentiation assays (preprint); in vivo siRNA knockdown with Wt1 promoter reporter in mouse testis","pmids":["39131393","38248872"],"confidence":"Medium","gaps":["Adipogenesis data are preprint, not peer-reviewed","Direct vs indirect target distinction incomplete in some programs"]},{"year":2024,"claim":"Reported a candidate upstream link between m6A machinery and RREB1 through a METTL3-RREB1 physical interaction.","evidence":"Co-IP and domain mapping identifying the METTL3 N-terminus as the interacting region","pmids":["39278095"],"confidence":"Low","gaps":["Single Co-IP with no functional follow-up reported","Consequence for RREB1 mRNA or protein undefined"]},{"year":2026,"claim":"Defined a signaling-transcription-metabolism axis in glioma stem cells where a NIBAN2-FLII complex promotes RREB1 nuclear translocation and RREB1 activates NIBAN2/CD44/LDHA, plus an FMR1-VEGFA angiogenic program in colorectal cancer.","evidence":"Co-IP, nuclear fractionation, ChIP, RNA-seq/metabolomics in glioma models; ChIP-qPCR, reporter, and tube-formation/CAM assays for FMR1-VEGFA","pmids":["41736673","42214628"],"confidence":"Medium","gaps":["Single-lab studies","Generalizability of these axes beyond the tested tumor contexts unknown"]},{"year":null,"claim":"How RREB1 is directed to activate versus repress a given promoter — the determinants selecting between SMAD/DJ-1 coactivators and CtBP/Sin3a-KDM1A corepressors, and how post-translational marks (acetylation, SUMOylation) and partner availability set this choice — remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structural model of RREB1 in complex with coactivator or corepressor machinery","Genome-wide rules governing activator vs repressor target selection unknown","Cross-talk between neuronal RAS/MAPK regulation and oncogenic RAS effector roles not reconciled"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[0,3,11,12,16]},{"term_id":"GO:0003677","term_label":"DNA binding","supporting_discovery_ids":[0,4,8]},{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[6,23]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[11,12]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[0,11,28]},{"term_id":"GO:0000228","term_label":"nuclear chromosome","supporting_discovery_ids":[8]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[6,11,12,22]},{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[0,3,11]},{"term_id":"R-HSA-4839726","term_label":"Chromatin organization","supporting_discovery_ids":[2,9,12]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[11,13,21]},{"term_id":"R-HSA-112316","term_label":"Neuronal System","supporting_discovery_ids":[10,16]}],"complexes":["RREB1-SMAD complex","RREB1-Sin3a-KDM1A complex","CtBP co-repressor complex","NIBAN2-FLII-RREB1 complex"],"partners":["SMAD","KDM1A","SIN3A","CTBP","DJ-1","SFPQ","FLII","METTL3"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q92766","full_name":"Ras-responsive element-binding protein 1","aliases":["Finger protein in nuclear bodies","Raf-responsive zinc finger protein LZ321","Zinc finger motif enhancer-binding protein 1","Zep-1"],"length_aa":1687,"mass_kda":181.4,"function":"Transcription factor that binds specifically to the RAS-responsive elements (RRE) of gene promoters (PubMed:10390538, PubMed:15067362, PubMed:17550981, PubMed:8816445, PubMed:9305772). Represses the angiotensinogen gene (PubMed:15067362). Negatively regulates the transcriptional activity of AR (PubMed:17550981). Potentiates the transcriptional activity of NEUROD1 (PubMed:12482979). Promotes brown adipocyte differentiation (By similarity). May be involved in Ras/Raf-mediated cell differentiation by enhancing calcitonin expression (PubMed:8816445)","subcellular_location":"Nucleus speckle","url":"https://www.uniprot.org/uniprotkb/Q92766/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/RREB1","classification":"Not Classified","n_dependent_lines":64,"n_total_lines":1208,"dependency_fraction":0.052980132450331126},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"HDAC1","stoichiometry":0.2},{"gene":"HDAC2","stoichiometry":0.2},{"gene":"HIST2H2BE","stoichiometry":0.2},{"gene":"NAPA","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/RREB1","total_profiled":1310},"omim":[{"mim_id":"612582","title":"CHROMOSOME 6pter-p24 DELETION SYNDROME","url":"https://www.omim.org/entry/612582"},{"mim_id":"611170","title":"STERILE ALPHA MOTIF DOMAIN-CONTAINING PROTEIN 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England)","url":"https://pubmed.ncbi.nlm.nih.gov/38248872","citation_count":1,"is_preprint":false},{"pmid":"40418122","id":"PMC_40418122","title":"Truncating Variants in RREB1 Cause a Novel RASopathy Syndrome of Congenital Heart Disease, Genitourinary Malformations, and Developmental Delay.","date":"2025","source":"American journal of medical genetics. 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siRNA knockdown of RREB1 in MCF10A mammary epithelial cells inhibited collective migration in scratch-wound assays, suppressed surface activity, retarded cell spreading, and caused formation of immobile, tightly adherent colonies, indicating RREB1 reduces cell-cell adhesion to enable dynamic epithelial cell movements.\",\n      \"method\": \"siRNA knockdown, scratch-wound healing assay, live-cell imaging, Drosophila genetic analysis (hnt mutants)\",\n      \"journal\": \"Current biology : CB\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct loss-of-function with defined cellular phenotype in mammalian cells, supported by orthologous Drosophila genetic evidence\",\n      \"pmids\": [\"18394891\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"RREB-1 represses HLA-G transcriptional activity by binding three Ras-response elements within the HLA-G promoter; in HLA-G-negative cells, RREB-1 interacts with subunits of the CtBP co-repressor complex implicated in chromatin remodeling.\",\n      \"method\": \"Promoter pull-down assay followed by mass spectrometry, reporter assay, Co-IP (RREB-1 with CtBP complex subunits)\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — promoter pull-down with MS identification, reporter functional assay, and co-immunoprecipitation; single lab\",\n      \"pmids\": [\"19890057\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"RREB-1 binds the p53 core promoter element and transactivates p53 expression; upon genotoxic stress, RREB-1 recruitment to the p53 promoter increases, and RREB-1 silencing reduces p53 mRNA and protein levels and suppresses downstream p53 target gene expression, controlling apoptosis in a p53-dependent manner.\",\n      \"method\": \"ChIP, luciferase reporter assay, siRNA knockdown, qRT-PCR, Western blot\",\n      \"journal\": \"The Biochemical journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP and reporter assays in one lab; functional consequence of silencing with defined molecular readout\",\n      \"pmids\": [\"19558368\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"RREB-1 binds to a specific RRE site in the hZIP1 promoter and represses hZIP1 zinc transporter transcription in prostate cancer cells; this binding was demonstrated by gel shift and ChIP, and site-directed mutagenesis of the binding site relieved repression.\",\n      \"method\": \"Luciferase reporter assay, site-directed mutagenesis, EMSA (gel shift), ChIP\",\n      \"journal\": \"The Prostate\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — multiple orthogonal methods including mutagenesis, EMSA, and ChIP confirming direct promoter binding and functional repression\",\n      \"pmids\": [\"19802870\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Overexpression of RREB-1 decreases hZIP1 abundance at the plasma membrane of PC-3 prostate cancer cells, while siRNA knockdown of RREB-1 significantly increases hZIP1 expression, establishing RREB-1 as a transcriptional repressor of hZIP1 in vivo.\",\n      \"method\": \"Overexpression, siRNA knockdown, immunohistochemistry/Western blot\",\n      \"journal\": \"The Prostate\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — bidirectional manipulation (OE and KD) with consistent cellular readout; single lab, replicates prior promoter study\",\n      \"pmids\": [\"21360563\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"RREB1 is activated by the MAPK pathway downstream of oncogenic KRAS and negatively represses the miR-143/145 promoter through interaction with two RREs, constituting a regulatory feedback loop where miR-143/145 in turn targets KRAS and RREB1.\",\n      \"method\": \"Reporter assay, ChIP, qRT-PCR, overexpression/knockdown, MAPK pathway inhibition\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP confirming direct promoter binding, reporter assay, and functional MAPK dependency; single lab\",\n      \"pmids\": [\"22751122\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"DJ-1 acts as a coactivator by physically interacting with RREB1; the DJ-1/RREB1 complex (but not a DJ-1/Sp1 complex) binds to the RRE in the cholecystokinin (CCK) gene promoter, stimulating CCK transcription. DJ-1 knockout mice show reduced serum CCK levels.\",\n      \"method\": \"Co-immunoprecipitation, promoter binding assay, luciferase reporter, qRT-PCR, ELISA in DJ-1-knockout mice\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP demonstrating direct interaction, functional reporter assay, and in vivo mouse confirmation; single lab\",\n      \"pmids\": [\"24348900\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"The Drosophila HNT C-terminal region (containing the last five zinc fingers) binds DNA elements similar to those of human RREB-1; human RREB-1 expressed in Drosophila binds the same polytene chromosome sites as HNT, attenuates expression of hnt and nvy target genes, and rescues the germ band retraction phenotype, demonstrating functional conservation of DNA binding and transcriptional attenuation.\",\n      \"method\": \"In vitro DNA binding assay, polytene chromosome binding, rescue genetics, loss-of-function and overexpression in Drosophila\",\n      \"journal\": \"Differentiation; research in biological diversity\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — multiple orthogonal methods (in vitro binding, in vivo polytene mapping, genetic rescue) establishing functional conservation\",\n      \"pmids\": [\"24418439\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"RREB1 cooperates with the lncRNA linc-ADAMTS5 to repress ADAMTS5 expression in nucleus pulposus cells; RREB1 is recruited to the ADAMTS5 promoter via a physical interaction with splicing factor SFPQ (facilitated by linc-ADAMTS5 binding to SFPQ), and this complex induces chromatin remodeling involving histone deacetylases to suppress ADAMTS5 transcription.\",\n      \"method\": \"RNA pulldown, RIP, in vitro binding assay, ChIP, gain/loss-of-function studies\",\n      \"journal\": \"Clinical science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple binding assays (pulldown, RIP, ChIP) and functional gain/loss-of-function; single lab\",\n      \"pmids\": [\"28341660\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"The Drosophila RREB1 ortholog Pebbled (Peb) is required in glutamatergic sensory neurons for axon death after injury; loss of peb results in preservation or incomplete fragmentation of severed axons, and human RREB1 rescues peb mutant phenotypes. Dominant genetic interactions between peb and dsarm place peb/RREB1 in the axon death signaling cascade.\",\n      \"method\": \"Drosophila genetics (loss-of-function mutants), human RREB1 rescue, axotomy assay, genetic epistasis with dsarm\",\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 defined signaling pathway, human RREB1 rescue across species, multiple neuronal subtypes tested\",\n      \"pmids\": [\"29295933\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"RREB1 is a MAPK-activated RAS transcriptional effector that physically recruits TGF-β-activated SMAD transcription factors to the SNAIL promoter; RREB1 and SMAD together drive expression of SNAIL and context-dependent EMT gene programs. In carcinoma cells, RREB1-SMAD drive fibrogenic EMT; in mouse epiblast progenitors, RREB1-Nodal-SMAD drive developmental EMT/gastrulation.\",\n      \"method\": \"Co-IP, ChIP-seq, reporter assay, CRISPR/KO, mouse embryo genetics, biochemical reconstitution of RREB1-SMAD complex\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — Co-IP of RREB1-SMAD complex, ChIP-seq establishing genomic co-occupancy, genetic KO with developmental phenotype, multiple cell systems; replicated conceptually in accompanying commentary\",\n      \"pmids\": [\"31915377\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Rreb1 haploinsufficiency in mice sensitizes MAPK signaling; RREB1 recruits Sin3a and Kdm1a (KDM1A) to MAPK pathway gene promoters to control H3K4 methylation, thereby epigenetically reprogramming RAS-MAPK target gene expression. Loss of one Rreb1 allele phenocopies Noonan syndrome features (orbital hypertelorism, cardiac hypertrophy).\",\n      \"method\": \"Rreb1 hemizygous mouse model, ChIP, Co-immunoprecipitation (RREB1-Sin3a-Kdm1a complex), H3K4 methylation analysis, MAPK signaling assays\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — Co-IP establishing trimeric complex, ChIP showing histone modification changes at MAPK gene promoters, in vivo mouse phenotype matching human syndrome; multiple orthogonal methods\",\n      \"pmids\": [\"32938917\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Loss of Rreb1 in mouse embryos reduces expression of vasculogenic factors, causes cardiovascular defects and embryonic lethality; during gastrulation, absence of Rreb1 upregulates cytoskeleton-associated genes, alters F-actin and adherens junction organization in the epiblast, and causes ectopic exit of cells through the basement membrane, paralleling metastatic behavior.\",\n      \"method\": \"Rreb1 knockout mouse model, immunofluorescence (F-actin, E-cadherin), RNA-seq, histology\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — full KO mouse model with multiple orthogonal molecular and cellular readouts; extends earlier mechanistic findings\",\n      \"pmids\": [\"33929320\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"miR-26a promotes deacetylation of RREB1 at the Lys-60 residue; deacetylated RREB1 binds the AKT1 promoter to activate AKT transcription and downstream glycolytic signaling in colorectal cancer cells.\",\n      \"method\": \"Quantitative proteomics, ChIP, luciferase reporter, loss-of-function analysis, site-specific mutagenesis of Lys-60, xenograft mouse model\",\n      \"journal\": \"Cancer letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — proteomics identification of PTM site, ChIP and reporter confirming promoter binding, functional KO in vivo; single lab\",\n      \"pmids\": [\"34419497\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Ras signaling and RREB1 are required for dissociation of medial edge epithelial (MEE) cells during murine palatogenesis; siRNA knockdown of Rreb1 in palatal organ culture inhibited MEE cell dissociation and caused palatal fusion defects, placing RREB1 downstream of RAS in this EMT-like process.\",\n      \"method\": \"siRNA knockdown in palatal organ culture, pan-Ras inhibitor treatment, morphological analysis\",\n      \"journal\": \"Disease models & mechanisms\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss-of-function with defined developmental phenotype in organ culture; single method, single lab\",\n      \"pmids\": [\"34897389\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"RREB1 is essential for neuronal survival in the mammalian brain; a spontaneous mouse mutation in the nervous-system-enriched Rreb1 transcript causes progressive Purkinje cell loss and ataxia. ChIP-seq and RNA-seq reveal RREB1 regulates genes associated with the microtubule cytoskeleton and the endomembrane system; loss of RREB1 disrupts dendritic complexity, reduces autophagosomes/lysosomes, and causes accumulation of P62- and ubiquitin-positive inclusions.\",\n      \"method\": \"Spontaneous mouse mutant, ChIP-seq, RNA-seq, immunofluorescence (P62, ubiquitin, autophagosomes), dendritic morphology analysis\",\n      \"journal\": \"Science advances\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo mouse genetic model with multiple orthogonal molecular readouts (ChIP-seq, RNA-seq, immunofluorescence); defines RREB1 transcriptional targets and neuronal phenotypes\",\n      \"pmids\": [\"38198538\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"RREB1 directly activates transcription of UBC9 by binding its promoter, thereby elevating global protein SUMOylation (SUMO2/3) in colorectal cancer cells, which contributes to 5-fluorouracil resistance.\",\n      \"method\": \"ChIP-qPCR, luciferase reporter assay, overexpression/knockdown, Western blot for SUMOylation\",\n      \"journal\": \"Frontiers in pharmacology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP and reporter confirming direct promoter binding, functional SUMOylation assays; single lab\",\n      \"pmids\": [\"39108750\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"SUMOylated RREB1 physically interacts with KDM1A; this RREB1-KDM1A complex elevates expression of thymidylate synthase (TS) and thymidine kinase (TK1) and enhances activation of Chk1-mediated DNA damage response. DeSUMOylation of RREB1 reduces the RREB1-KDM1A interaction, decreasing TS expression and attenuating DDR pathway activation.\",\n      \"method\": \"Co-immunoprecipitation, SUMOylation assay, ChIP, Western blot, KDM1A knockdown, 5-FU resistance assay\",\n      \"journal\": \"MedComm\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP of RREB1-KDM1A complex, functional SUMOylation dependency established by deSUMOylation experiments; single lab\",\n      \"pmids\": [\"39991628\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"METTL3 physically interacts with RREB1 (an enriched METTL3 mRNA target), with the N-terminus of METTL3 as the primary interacting domain, revealing a novel regulatory connection between the m6A methylation machinery and RREB1.\",\n      \"method\": \"Co-immunoprecipitation, domain mapping\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single Co-IP with domain mapping; no functional follow-up reported in abstract\",\n      \"pmids\": [\"39278095\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Loss of RREB1 in mouse and human adipocyte precursor cells decreases adipogenic gene expression and activates transcription of genes associated with osteoblast differentiation; global Rreb1+/- mice on high-fat diet show reduced fat mass and adipocyte size, with smaller, more insulin-sensitive subcutaneous adipocytes in certain conditions.\",\n      \"method\": \"Global heterozygous Rreb1+/- mouse model, adipogenic gene expression analysis (RNA-seq), adipocyte differentiation assays in mouse and human cells, in vivo body composition\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo mouse KO model with defined phenotype, human cell validation; preprint, not yet peer-reviewed\",\n      \"pmids\": [\"39131393\"],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"RREB1 is required for Sertoli cell maturation and spermatogenesis in mice; knockdown of Rreb1 causes defective blood-testis barrier structure, decreased expression of Sertoli cell maturity markers, and oligoasthenoteratozoospermia. Mechanistically, RREB1 directly activates the Wt1 promoter and positively regulates Fshr transcription; RREB1 knockdown destabilizes SMAD3 and reduces Wt1, Par6b, and E-cadherin expression.\",\n      \"method\": \"siRNA knockdown in mice (in vivo), promoter-reporter luciferase assay, Western blot, immunofluorescence, spermatogenesis phenotyping\",\n      \"journal\": \"Zygote\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo knockdown with defined cellular and molecular phenotypes, direct promoter activation shown by reporter assay; single lab\",\n      \"pmids\": [\"38248872\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Loss of Drosophila Peb (RREB1 ortholog) results in excessive RAS/MAPK pathway activation, causing adult-onset progressive motor axonal degeneration and NMJ degeneration; pharmacological inhibition of MEK1/2 with mirdametinib rescues peb mutant neurodegeneration, establishing that Peb/RREB1 normally functions as a transcriptional negative regulator of RAS/MAPK pathway target genes to maintain axonal integrity.\",\n      \"method\": \"Drosophila forward genetic screen, loss-of-function genetics, MAPK pathway activity assays, MEK inhibitor pharmacological rescue\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — forward genetic screen with defined pathway epistasis and pharmacological rescue; preprint, not yet peer-reviewed\",\n      \"pmids\": [],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"RREB-1 is a transcriptional effector downstream of the Ral GTPases (RalA and RalB) in bladder cancer cells; computational analysis of RRE motifs in promoters of Ral-regulated genes, verified experimentally, identified RREB-1 as a target of Ral signaling.\",\n      \"method\": \"siRNA depletion of RalA/RalB, microarray gene expression profiling, computational promoter analysis, experimental verification of RREB-1 as Ral target\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — computational identification with limited direct experimental verification of the RREB-1 node described in abstract; single lab\",\n      \"pmids\": [\"17496927\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"RREB1 positively regulates ZIP3 zinc transporter expression in pancreatic cells; downregulation of RREB1 in Panc1 cells reduces ZIP3, which reduces zinc uptake and accumulation, relieving zinc cytotoxicity in developing malignant cells.\",\n      \"method\": \"RREB1 overexpression/siRNA knockdown, ZIP3 expression analysis, zinc accumulation assay, cell proliferation assay\",\n      \"journal\": \"Cancer biology & therapy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — bidirectional manipulation with defined molecular (ZIP3, zinc) and functional (proliferation) readouts; single lab\",\n      \"pmids\": [\"25050557\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"RREB1 transcriptionally activates the SNHG4 lncRNA promoter; SNHG4 in turn acts as a ceRNA sponging let-7a miRNA, which itself targets RREB1, establishing a let-7a/RREB1/SNHG4 positive feedback loop that promotes prostate cancer cell survival and enzalutamide resistance.\",\n      \"method\": \"ChIP assay, luciferase reporter assay, RNA immunoprecipitation, qRT-PCR, in vitro/in vivo functional assays\",\n      \"journal\": \"Journal of experimental & clinical cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP and reporter confirming direct RREB1-SNHG4 promoter interaction, RIP validating RNA interactions; single lab\",\n      \"pmids\": [\"37596700\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"RREB1 transcriptionally activates FMR1 by directly binding the FMR1 promoter; FMR1 in turn enhances VEGFA expression and secretion, activating MAPK and PI3K signaling in endothelial cells to promote angiogenesis in colorectal cancer.\",\n      \"method\": \"ChIP-qPCR, luciferase reporter assay, HUVEC tube formation, CAM assay, siRNA knockdown, co-expression analysis in CRC tissues\",\n      \"journal\": \"Biochimica et biophysica acta. Molecular cell research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP-qPCR and reporter confirming direct promoter binding, functional angiogenesis assays; single lab\",\n      \"pmids\": [\"42214628\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"RREB1 knockdown in gastric cancer cells enhances p16 expression and inhibits cell proliferation in vitro and in vivo, identifying RREB1 as a negative regulator of p16 in gastric cancer.\",\n      \"method\": \"Lentiviral RREB1 knockdown/overexpression, MTT, colony formation, cell cycle assay, xenograft mouse model, Western blot for p16\",\n      \"journal\": \"Cell cycle\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — functional phenotype with molecular readout (p16) but no direct promoter-binding or ChIP evidence linking RREB1 to p16 regulation; single lab\",\n      \"pmids\": [\"34666611\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"In glioma stem cells, NIBAN2 directly binds FLII and enhances the FLII-RREB1 interaction, promoting RREB1 nuclear translocation; the NIBAN2-FLII-RREB1 complex activates TLR3 signaling. RREB1 also transcriptionally upregulates NIBAN2 and CD44 and promotes LDHA expression, establishing a feed-forward signaling-transcription-metabolism axis.\",\n      \"method\": \"Co-immunoprecipitation, nuclear fractionation, ChIP, RNA-seq, metabolomics, in vitro and in vivo tumor models\",\n      \"journal\": \"Advanced science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP establishing protein-protein interactions, nuclear translocation by fractionation, ChIP for transcriptional targets; single lab\",\n      \"pmids\": [\"41736673\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"RREB1 is a multi-zinc-finger transcription factor activated by MAPK/RAS signaling (via ERK-mediated phosphorylation) that functions both as a transcriptional activator and repressor: as an activator, it recruits TGF-β/SMAD complexes to drive EMT gene programs (including SNAIL), activates p53, ZIP3, calcitonin, AKT1, and other target gene promoters, and cooperates with co-factors including DJ-1, KDM1A, and the NIBAN2-FLII complex; as a repressor, it silences hZIP1, HLA-G, and miR-143/145 through interaction with CtBP co-repressor complexes and by recruiting histone-modifying machinery (Sin3a-KDM1A, HDACs); in the nervous system it negatively regulates RAS/MAPK pathway target genes to maintain axonal integrity; and its haploinsufficiency causes epigenetic derepression of RAS-MAPK genes leading to Noonan-like RASopathy.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"RREB1 (Ras-responsive element binding protein 1) is a multi-zinc-finger transcription factor that serves as a downstream effector of RAS/MAPK signaling, binding Ras-responsive elements (RREs; consensus CCCCAAACCACCCC) to control gene programs governing epithelial cell behavior, development, and neuronal maintenance [#0, #8]. It acts bidirectionally: as an activator it transactivates promoters including calcitonin, p53, ZIP3, AKT1, and others [#0, #3, #24, #14], and as a repressor it silences targets such as HLA-G, hZIP1, and miR-143/145 through interaction with the CtBP co-repressor complex and chromatin-remodeling/histone-deacetylase machinery [#2, #4, #6]. A central role is the coordination of EMT: RREB1 physically recruits TGF-\\u03b2/Nodal-activated SMAD transcription factors to the SNAIL promoter to drive both carcinoma fibrogenic EMT and developmental EMT during gastrulation, and its loss in mouse embryos perturbs F-actin and adherens-junction organization, causing aberrant epithelial cell exit reminiscent of metastasis [#11, #13]. RREB1 also recruits a Sin3a\\u2013KDM1A complex to MAPK pathway gene promoters to set H3K4 methylation, and Rreb1 haploinsufficiency in mice epigenetically derepresses RAS-MAPK targets and phenocopies Noonan syndrome features such as hypertelorism and cardiac hypertrophy [#12]. In the nervous system, RREB1/orthologs act as negative regulators of RAS/MAPK target genes required for axonal integrity and neuronal survival, with loss causing Purkinje cell degeneration, defective autophagy, and accumulation of P62/ubiquitin inclusions [#16, #10]. Functional conservation is demonstrated by human RREB1 rescuing Drosophila Hindsight/Pebbled mutant phenotypes [#8, #10].\",\n  \"teleology\": [\n    {\n      \"year\": 1996,\n      \"claim\": \"Established the founding molecular identity of RREB1 as a zinc-finger transcription factor that binds the Ras-responsive element and couples RAS/RAF signaling to target gene transactivation.\",\n      \"evidence\": \"cDNA cloning, DNase I footprinting, and reporter transactivation in medullary thyroid cancer cells\",\n      \"pmids\": [\"8816445\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not define the full repertoire of target genes\", \"No structure of the DNA-binding zinc fingers\", \"Mechanism of RAS-dependent activation not resolved\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Linked RREB1 to a cellular phenotype \\u2014 collective epithelial cell migration via modulation of cell-cell adhesion \\u2014 connecting its transcriptional role to morphogenetic behavior.\",\n      \"evidence\": \"siRNA knockdown and scratch-wound/live-imaging in MCF10A cells with orthologous Drosophila hnt genetics\",\n      \"pmids\": [\"18394891\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Adhesion target genes not identified\", \"Did not connect phenotype to specific promoters\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Defined RREB1's dual activator/repressor mode: it represses HLA-G via the CtBP co-repressor complex while activating p53 under genotoxic stress to control apoptosis.\",\n      \"evidence\": \"Promoter pull-down/MS, Co-IP with CtBP subunits, ChIP and reporter assays in human cells\",\n      \"pmids\": [\"19890057\", \"19558368\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single-lab findings\", \"Determinants of activator-vs-repressor switching not defined\", \"CtBP recruitment mechanism not mapped at residue level\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Demonstrated direct, mutation-sensitive promoter binding underlying repression of the zinc transporter hZIP1 in prostate cancer, establishing RREB1 as a regulator of cellular zinc handling.\",\n      \"evidence\": \"EMSA, ChIP, site-directed mutagenesis, and reporter/overexpression-knockdown in prostate cancer cells\",\n      \"pmids\": [\"19802870\", \"21360563\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Co-repressor for hZIP1 silencing not defined\", \"Physiological consequence of zinc dysregulation in vivo untested\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Positioned RREB1 within a RAS feedback circuit by showing it is MAPK-activated and represses miR-143/145, which in turn target KRAS and RREB1.\",\n      \"evidence\": \"ChIP, reporter assays, and MAPK pathway inhibition in cancer cells\",\n      \"pmids\": [\"22751122\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab\", \"Repressive chromatin machinery at miR-143/145 not detailed\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Identified co-activators and additional target genes (DJ-1 cooperation at the CCK promoter; positive regulation of ZIP3), broadening the activator repertoire and demonstrating in vivo relevance.\",\n      \"evidence\": \"Co-IP, reporter/promoter binding, and DJ-1-knockout mouse serum CCK; ZIP3/zinc assays in pancreatic cells\",\n      \"pmids\": [\"24348900\", \"25050557\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single-lab studies\", \"Structural basis of DJ-1/RREB1 cooperation unknown\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Established evolutionary conservation of RREB1 DNA-binding and transcriptional-attenuation function through cross-species rescue of the Drosophila Hindsight ortholog.\",\n      \"evidence\": \"In vitro DNA binding, polytene chromosome mapping, and human RREB1 rescue of hnt germ band retraction phenotype\",\n      \"pmids\": [\"24418439\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Conserved mammalian target genes not enumerated\", \"Functional role of individual zinc fingers not dissected\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Revealed a neuronal function: the RREB1 ortholog Pebbled is required for injury-induced axon death and acts within the dSarm/SARM1 axon-degeneration cascade, rescuable by human RREB1.\",\n      \"evidence\": \"Drosophila loss-of-function genetics, axotomy assays, genetic epistasis with dsarm, and human RREB1 rescue\",\n      \"pmids\": [\"29295933\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mammalian transcriptional targets in axon death not defined\", \"Mechanistic link to SARM1 signaling unresolved\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Defined the central EMT mechanism and a chromatin-modifying mode: RREB1 recruits SMAD factors to the SNAIL promoter to drive EMT, and recruits a Sin3a\\u2013KDM1A complex to MAPK gene promoters, with haploinsufficiency causing a Noonan-like RASopathy.\",\n      \"evidence\": \"Co-IP, ChIP-seq, biochemical reconstitution of RREB1-SMAD, CRISPR/KO, and Rreb1 hemizygous mouse modeling with H3K4 methylation analysis\",\n      \"pmids\": [\"31915377\", \"32938917\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Determinants directing RREB1 to activator vs repressor complexes not resolved\", \"Full set of co-occupied SMAD/RREB1 genomic loci not exhaustively defined\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Extended the developmental role in vivo: Rreb1 loss disrupts vasculogenesis, cytoskeletal/adherens-junction organization, and causes ectopic epithelial cell exit, linking embryonic and metastatic cell behaviors.\",\n      \"evidence\": \"Rreb1 knockout mouse embryos with RNA-seq, immunofluorescence (F-actin, E-cadherin), and histology\",\n      \"pmids\": [\"33929320\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct cytoskeletal target genes not all validated by binding\", \"Tissue-specific contributions not separated from systemic effects\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Identified post-translational regulation of RREB1: miR-26a-driven deacetylation at Lys-60 enables AKT1 promoter binding and glycolytic signaling in colorectal cancer.\",\n      \"evidence\": \"Quantitative proteomics, Lys-60 mutagenesis, ChIP, reporter, and xenograft assays\",\n      \"pmids\": [\"34419497\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Acetyltransferase/deacetylase enzymes acting on Lys-60 not identified\", \"Single lab\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Established RREB1 as essential for mammalian neuronal survival, regulating microtubule-cytoskeleton and endomembrane/autophagy genes whose loss causes Purkinje degeneration and proteostatic inclusions.\",\n      \"evidence\": \"Spontaneous Rreb1 mouse mutant with ChIP-seq, RNA-seq, dendritic morphology, and P62/ubiquitin immunofluorescence\",\n      \"pmids\": [\"38198538\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Causal target gene driving autophagy defect not pinpointed\", \"Relationship to RAS/MAPK regulation in neurons not directly tested\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Connected RREB1 to SUMOylation biology and chemoresistance: it activates UBC9 to elevate global SUMOylation, and SUMOylated RREB1 binds KDM1A to drive thymidylate synthase/TK1 and Chk1-mediated DDR.\",\n      \"evidence\": \"ChIP, reporter, SUMOylation/deSUMOylation assays, Co-IP, and 5-FU resistance assays in colorectal cancer cells\",\n      \"pmids\": [\"39108750\", \"39991628\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"SUMO acceptor sites on RREB1 not mapped\", \"Single-lab findings without independent replication\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Implicated RREB1 in additional tissue programs \\u2014 adipocyte/osteoblast lineage balance and Sertoli cell maturation/spermatogenesis via Wt1 and Fshr regulation.\",\n      \"evidence\": \"Rreb1+/- mouse and human adipocyte differentiation assays (preprint); in vivo siRNA knockdown with Wt1 promoter reporter in mouse testis\",\n      \"pmids\": [\"39131393\", \"38248872\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Adipogenesis data are preprint, not peer-reviewed\", \"Direct vs indirect target distinction incomplete in some programs\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Reported a candidate upstream link between m6A machinery and RREB1 through a METTL3-RREB1 physical interaction.\",\n      \"evidence\": \"Co-IP and domain mapping identifying the METTL3 N-terminus as the interacting region\",\n      \"pmids\": [\"39278095\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Single Co-IP with no functional follow-up reported\", \"Consequence for RREB1 mRNA or protein undefined\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Defined a signaling-transcription-metabolism axis in glioma stem cells where a NIBAN2-FLII complex promotes RREB1 nuclear translocation and RREB1 activates NIBAN2/CD44/LDHA, plus an FMR1-VEGFA angiogenic program in colorectal cancer.\",\n      \"evidence\": \"Co-IP, nuclear fractionation, ChIP, RNA-seq/metabolomics in glioma models; ChIP-qPCR, reporter, and tube-formation/CAM assays for FMR1-VEGFA\",\n      \"pmids\": [\"41736673\", \"42214628\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single-lab studies\", \"Generalizability of these axes beyond the tested tumor contexts unknown\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How RREB1 is directed to activate versus repress a given promoter \\u2014 the determinants selecting between SMAD/DJ-1 coactivators and CtBP/Sin3a-KDM1A corepressors, and how post-translational marks (acetylation, SUMOylation) and partner availability set this choice \\u2014 remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structural model of RREB1 in complex with coactivator or corepressor machinery\", \"Genome-wide rules governing activator vs repressor target selection unknown\", \"Cross-talk between neuronal RAS/MAPK regulation and oncogenic RAS effector roles not reconciled\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [0, 3, 11, 12, 16]},\n      {\"term_id\": \"GO:0003677\", \"supporting_discovery_ids\": [0, 4, 8]},\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [6, 23]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [11, 12]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [0, 11, 28]},\n      {\"term_id\": \"GO:0000228\", \"supporting_discovery_ids\": [8]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [6, 11, 12, 22]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [0, 3, 11]},\n      {\"term_id\": \"R-HSA-4839726\", \"supporting_discovery_ids\": [2, 9, 12]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [11, 13, 21]},\n      {\"term_id\": \"R-HSA-112316\", \"supporting_discovery_ids\": [10, 16]}\n    ],\n    \"complexes\": [\n      \"RREB1-SMAD complex\",\n      \"RREB1-Sin3a-KDM1A complex\",\n      \"CtBP co-repressor complex\",\n      \"NIBAN2-FLII-RREB1 complex\"\n    ],\n    \"partners\": [\n      \"SMAD\",\n      \"KDM1A\",\n      \"SIN3A\",\n      \"CTBP\",\n      \"DJ-1\",\n      \"SFPQ\",\n      \"FLII\",\n      \"METTL3\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}