{"gene":"RREB1","run_date":"2026-04-28T20:42:06","timeline":{"discoveries":[{"year":1996,"finding":"RREB1 (RREB-1) was cloned as a zinc finger transcription factor that binds to the Ras-responsive element (RRE) in the human calcitonin gene promoter (consensus: CCCCAAACCACCCC) and mediates RAS/RAF-induced transcriptional activation of the calcitonin gene in medullary thyroid carcinoma cells.","method":"Affinity screening/cDNA cloning, DNase I footprinting, reporter transactivation assays with RAS/RAF overexpression","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 1 — original cloning paper with in vitro DNA-binding assay, promoter mutagenesis, and functional transactivation assay","pmids":["8816445"],"is_preprint":false},{"year":2008,"finding":"HNT (Drosophila ortholog of RREB1) regulates collective cell migration and cell-cell adhesion by modulating JNK and STAT pathways in follicle cells; siRNA knockdown of mammalian RREB1 in MCF10A cells inhibited collective migration in scratch-wound assays, suppressed surface activity, retarded cell spreading, and led to immobile, tightly adherent colonies.","method":"Drosophila genetics (loss-of-function mutants), siRNA knockdown, scratch-wound healing assay, live imaging","journal":"Current biology : CB","confidence":"High","confidence_rationale":"Tier 2 — genetic loss-of-function in two organisms with defined cellular phenotypes and pathway (JNK/STAT) placement","pmids":["18394891"],"is_preprint":false},{"year":2009,"finding":"RREB-1 represses HLA-G transcription by binding three RREs in the HLA-G promoter; in HLA-G-negative cells, RREB-1 interacts with subunits of the CtBP chromatin-remodeling complex to mediate epigenetic repression.","method":"Promoter pull-down assay followed by mass spectrometry, luciferase reporter assays, Co-IP of RREB-1 with CtBP complex subunits","journal":"Journal of immunology","confidence":"Medium","confidence_rationale":"Tier 2 — reciprocal pulldown/Co-IP with MS identification, but 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 recruits to the p53 promoter and controls apoptosis in a p53-dependent manner.","method":"ChIP, siRNA knockdown, luciferase reporter assay, apoptosis assays","journal":"The Biochemical journal","confidence":"Medium","confidence_rationale":"Tier 2 — ChIP and functional knockdown with p53-dependent readout, single lab","pmids":["19558368"],"is_preprint":false},{"year":2010,"finding":"RREB-1 binds to the hZIP1 promoter and represses hZIP1 zinc transporter transcription in prostate cancer cells; RREB-1 overexpression decreases hZIP1 membrane abundance whereas siRNA knockdown increases it.","method":"Luciferase reporter assay, site-directed mutagenesis, gel shift (EMSA), ChIP, siRNA knockdown, RREB-1 overexpression","journal":"The Prostate","confidence":"High","confidence_rationale":"Tier 1 — EMSA, ChIP, mutagenesis, and gain/loss-of-function all in one study","pmids":["19802870"],"is_preprint":false},{"year":2011,"finding":"RREB-1 overexpression in prostate cancer cells down-regulates hZIP1 zinc transporter, contributing to decreased zinc levels; inverse relationship between RREB-1 and hZIP1 confirmed in tissue microarrays.","method":"RREB-1 overexpression and siRNA knockdown in PC-3 cells, immunohistochemistry on tissue microarrays","journal":"The Prostate","confidence":"Medium","confidence_rationale":"Tier 2 — gain and loss-of-function with protein-level readout; replication of mechanism shown in 2010 paper","pmids":["21360563"],"is_preprint":false},{"year":2012,"finding":"RREB1, activated by the MAPK pathway downstream of oncogenic KRAS, negatively regulates the miR-143/145 cluster by binding two RREs in the miR-143/145 promoter in colorectal cancer; miR-143/145 in turn target KRAS and RREB1, forming a feedback loop.","method":"ChIP, luciferase reporter assay, miRNA overexpression, siRNA knockdown, MAPK pathway inhibition","journal":"Oncogene","confidence":"High","confidence_rationale":"Tier 1–2 — ChIP, promoter reporters, and epistasis with KRAS/MAPK; multiple orthogonal methods","pmids":["22751122"],"is_preprint":false},{"year":2013,"finding":"DJ-1 physically interacts with RREB1 and the DJ-1/RREB1 complex binds the RRE in the cholecystokinin (CCK) gene promoter to activate CCK transcription; DJ-1-knockout mice show reduced serum CCK levels.","method":"Co-IP, ChIP, luciferase reporter assay, siRNA knockdown, DJ-1 knockout mice","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 — Co-IP and ChIP with in vivo confirmation in knockout mice, single lab","pmids":["24348900"],"is_preprint":false},{"year":2014,"finding":"Drosophila HNT (RREB1 ortholog) and human RREB1 bind to the same DNA elements (similar to known RREB-1 sites) via the C-terminal zinc fingers; RREB-1 expressed in Drosophila rescues hnt germ-band retraction phenotypes, attenuates hnt and nervy target gene transcription, and binds identical polytene chromosome sites as HNT, demonstrating functional conservation.","method":"Drosophila genetics (loss-of-function and overexpression), in vitro DNA binding, polytene chromosome mapping, cross-species rescue experiments","journal":"Differentiation; research in biological diversity","confidence":"High","confidence_rationale":"Tier 1–2 — in vitro DNA binding, in vivo chromosomal mapping, cross-species functional rescue","pmids":["24418439"],"is_preprint":false},{"year":2014,"finding":"RREB1 is a positive regulator of ZIP3 zinc transporter expression in pancreatic cells; RREB1 and ZIP3 downregulation is an early event in pancreatic adenocarcinoma development, and zinc accumulation via ZIP3 inhibits proliferation of Panc1 cells.","method":"siRNA knockdown, zinc uptake assays, cell proliferation assays, immunohistochemistry on tissue sections","journal":"Cancer biology & therapy","confidence":"Medium","confidence_rationale":"Tier 2 — loss-of-function with functional readout, but limited mechanistic depth on how RREB1 activates ZIP3","pmids":["25050557"],"is_preprint":false},{"year":2018,"finding":"Drosophila Pebbled (RREB1 ortholog) is required in glutamatergic sensory neurons to enable normal Wallerian axon degeneration; loss of peb results in axon preservation or partial fragmentation after axotomy, and peb/RREB1 genetically interacts with dsarm, placing it in the axon death signaling cascade; human RREB1 rescues peb mutant phenotypes.","method":"Drosophila genetics (loss-of-function), axotomy assays, genetic epistasis with dsarm, cross-species rescue with human RREB1","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 — genetic epistasis, cross-species rescue, and defined cellular phenotype; multiple orthogonal approaches","pmids":["29295933"],"is_preprint":false},{"year":2018,"finding":"RREB1-MKL2 (RREB1-MRTFB) fusion gene is identified in ~90% of ectomesenchymal chondromyxoid tumors; the RREB1 (exon 8)–MKL2 (exon 11) fusion product drives increased MKL2 expression, which regulates neural and myogenic differentiation.","method":"RNA sequencing, RT-PCR, FISH, Sanger sequencing","journal":"The American journal of surgical pathology","confidence":"Medium","confidence_rationale":"Tier 2 — RNA-seq identification and FISH validation of recurrent fusion across 21 cases; functional consequence of fusion inferred from MKL2 biology","pmids":["29912715"],"is_preprint":false},{"year":2020,"finding":"RREB1 acts as a key partner of TGF-β-activated SMAD transcription factors in EMT: MAPK-activated RREB1 recruits TGF-β-activated SMADs to the SNAIL promoter, directly driving SNAIL expression and fibrogenic gene programs. In carcinoma cells, TGF-β–SMAD–RREB1 also drives intratumoral fibrosis and myofibroblast stimulation. In mouse epiblast, Nodal-SMAD and RREB1 combinatorially activate SNAIL and mesendoderm genes for gastrulation. Context-dependent chromatin accessibility determines the additional EMT gene targets activated.","method":"ChIP-seq, ATAC-seq, Co-IP of RREB1 with SMADs, reporter assays, RREB1 knockout/knockdown, mouse epiblast progenitor experiments, carcinoma cell EMT assays","journal":"Nature","confidence":"High","confidence_rationale":"Tier 1 — multiple orthogonal methods (ChIP-seq, ATAC-seq, Co-IP, KO models) in multiple biological contexts; highly cited foundational paper","pmids":["31915377"],"is_preprint":false},{"year":2020,"finding":"Rreb1 haploinsufficiency leads to sensitization of MAPK signaling; Rreb1 recruits the Sin3a corepressor and Kdm1a histone demethylase to control H3K4 methylation at MAPK pathway gene promoters, thereby acting as an epigenetic regulator of RAS-MAPK signaling. Rreb1 hemizygous mice display orbital hypertelorism and cardiac hypertrophy (Noonan-like phenotype).","method":"ChIP, Co-IP of RREB1 with Sin3a/Kdm1a, mouse knockout model, MAPK signaling assays, H3K4 methylation profiling","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1–2 — Co-IP of complex, ChIP for chromatin marks, in vivo haploinsufficiency mouse model with defined molecular and phenotypic readouts","pmids":["32938917"],"is_preprint":false},{"year":2021,"finding":"Loss of Rreb1 in mouse embryos causes upregulation of cytoskeleton-associated genes, disorganization of F-actin and adherens junctions in the epiblast epithelium, ectopic exit of epiblast cells through the basement membrane, reduction of vasculogenic factor expression, cardiovascular defects, and embryonic lethality.","method":"Rreb1 knockout mouse model, RNA-seq, immunofluorescence of F-actin/adherens junctions, histology","journal":"eLife","confidence":"High","confidence_rationale":"Tier 2 — complete KO with multiple orthogonal phenotypic readouts (transcriptomics, cytoskeletal imaging, histology) in vivo","pmids":["33929320"],"is_preprint":false},{"year":2021,"finding":"miR-26a improves deacetylation of RREB1 at Lys-60, which enables RREB1 to bind the AKT1 promoter and activate AKT transcription and downstream glycolytic signaling in colorectal cancer cells.","method":"Quantitative proteomics, ChIP, luciferase reporter assay, loss-of-function analysis, xenograft mouse model","journal":"Cancer letters","confidence":"Medium","confidence_rationale":"Tier 2 — ChIP and promoter reporter plus modification site identification; single lab","pmids":["34419497"],"is_preprint":false},{"year":2022,"finding":"RREB1 is required for RAS-mediated dissociation of medial edge epithelium (MEE) during murine palatal fusion; Rreb1 knockdown in palatal organ culture prevents MEE cell dissociation and causes palatal fusion defects, paralleling the role of RREB1 in EMT.","method":"Palatal organ culture, Rreb1 siRNA knockdown, pan-Ras inhibitor treatment, histological analysis","journal":"Disease models & mechanisms","confidence":"Medium","confidence_rationale":"Tier 2 — loss-of-function in organ culture with defined morphological phenotype; single lab","pmids":["34897389"],"is_preprint":false},{"year":2017,"finding":"RREB1 binds to the ADAMTS5 promoter and recruits the noncoding RNA linc-ADAMTS5 together with SFPQ to induce chromatin remodeling via histone deacetylases (HDACs), resulting in repression of ADAMTS5 expression in nucleus pulposus cells.","method":"RNA pull-down, RIP, ChIP, in vitro binding assays, gain- and loss-of-function studies","journal":"Clinical science","confidence":"Medium","confidence_rationale":"Tier 2 — multiple binding assays (pulldown, RIP, ChIP) supporting the mechanism; single lab","pmids":["28341660"],"is_preprint":false},{"year":2024,"finding":"A nervous system-enriched Rreb1 transcript is essential for Purkinje cell survival in mice; loss of this transcript causes progressive cerebellar degeneration and ataxia. RREB1 targets include microtubule cytoskeleton genes and endomembrane system genes. Rreb1-deficient Purkinje cells exhibit reduced dendritic complexity, fewer autophagosomes and lysosomes, and accumulation of p62- and ubiquitin-positive inclusions, indicating impaired proteostasis.","method":"Spontaneous mouse mutation model, ChIP-seq, RNA-seq, immunofluorescence, histological analysis of Purkinje cells","journal":"Science advances","confidence":"High","confidence_rationale":"Tier 1–2 — in vivo loss-of-function with ChIP-seq target identification, multiple cellular phenotypes including proteostasis and cytoskeletal readouts","pmids":["38198538"],"is_preprint":false},{"year":2024,"finding":"RREB1 interacts with KDM1A (LSD1) histone demethylase; the RREB1–KDM1A complex elevates thymidylate synthase (TS) and thymidine kinase (TK1) expression and enhances Chk1-mediated DNA damage response, conferring 5-FU resistance in colorectal cancer. SUMOylation of RREB1 is required for its interaction with KDM1A; deSUMOylation reduces this interaction and re-sensitizes cells to 5-FU.","method":"Co-IP of RREB1 with KDM1A, ChIP, siRNA knockdown of KDM1A, SUMOylation inhibitor (ML-792), cell proliferation and apoptosis assays","journal":"MedComm","confidence":"Medium","confidence_rationale":"Tier 2 — Co-IP and ChIP demonstrating RREB1–KDM1A interaction and target gene regulation; single lab","pmids":["39991628"],"is_preprint":false},{"year":2024,"finding":"RREB1 directly binds the UBC9 promoter to transcriptionally upregulate UBC9 (the sole E2 SUMO-conjugating enzyme), thereby enhancing global protein SUMOylation and conferring 5-FU resistance in colorectal cancer.","method":"ChIP, luciferase reporter assay, RREB1 overexpression and knockdown, SUMOylation inhibitor co-treatment","journal":"Frontiers in pharmacology","confidence":"Medium","confidence_rationale":"Tier 2 — ChIP and reporter assay support direct promoter binding; functional epistasis with SUMOylation inhibitor; single lab","pmids":["39108750"],"is_preprint":false},{"year":2007,"finding":"RREB-1 is identified as a transcriptional effector downstream of Ral GTPases (RalA and RalB) in bladder cancer cells; Ral depletion modulates a transcriptional program that includes RREB-1 target genes, linking Ral signaling to RREB-1-mediated transcription.","method":"siRNA depletion of RalA/RalB, microarray gene expression profiling, computational upstream sequence analysis, experimental verification of RREB-1 as Ral target","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 — computational prediction followed by experimental verification; single lab, moderate follow-up","pmids":["17496927"],"is_preprint":false},{"year":2019,"finding":"RREB1 activates transcription of the lncRNA AGAP2-AS1 in pancreatic cancer cells; AGAP2-AS1 in turn epigenetically suppresses ANKRD1 and ANGPTL4 by recruiting EZH2, promoting cell proliferation and migration.","method":"ChIP for RREB1 at AGAP2-AS1 promoter, RIP, EZH2 recruitment assay, gain/loss-of-function proliferation and invasion assays, xenograft model","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 — ChIP and RIP establishing RREB1-lncRNA-EZH2 axis; single lab","pmids":["30814490"],"is_preprint":false},{"year":2023,"finding":"In glioma stem cells, circNCAPG stabilizes RREB1 protein and promotes its nuclear translocation to activate TGF-β1 signaling; RREB1 in turn transcriptionally upregulates U2AF65, which stabilizes circNCAPG, forming a positive feedback loop.","method":"RNA pull-down, RIP, ChIP, immunofluorescence for RREB1 nuclear translocation, gain/loss-of-function assays","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 — multiple binding and ChIP assays; single lab demonstrating RREB1 nuclear translocation and transcriptional activity","pmids":["36635261"],"is_preprint":false}],"current_model":"RREB1 is a multi-zinc-finger transcription factor and RAS effector that, when activated by MAPK/ERK signaling, binds RAS-responsive elements in target gene promoters; it physically recruits TGF-β-activated SMAD complexes to drive EMT gene programs (including SNAIL), associates with chromatin-remodeling co-factors (CtBP complex, Sin3A/KDM1A, EZH2) to epigenetically repress or activate target genes (miR-143/145, hZIP1, p53, HLA-G, UBC9, ADAMTS5), regulates microtubule cytoskeleton and proteostasis genes essential for neuron survival, and controls collective cell migration and axon degeneration signaling, with its SUMOylation state modulating its interaction with chromatin-modifying partners and consequently its transcriptional output."},"narrative":{"teleology":[{"year":1996,"claim":"Establishing that RREB1 is a zinc-finger transcription factor that directly mediates RAS/RAF-induced gene activation by binding a defined RAS-responsive element (RRE) in the calcitonin promoter answered the question of how RAS signaling converges on specific promoter sequences.","evidence":"cDNA cloning, DNase I footprinting, and reporter transactivation in medullary thyroid carcinoma cells with RAS/RAF overexpression","pmids":["8816445"],"confidence":"High","gaps":["Identity of the kinase that directly phosphorylates/activates RREB1 was not determined","Full spectrum of RRE-containing target genes unknown","Structural basis of zinc-finger–RRE recognition not resolved"]},{"year":2007,"claim":"Placing RREB1 downstream of Ral GTPases in addition to RAF broadened its role as a convergence node for multiple RAS-family effector pathways.","evidence":"siRNA depletion of RalA/RalB coupled with microarray profiling and upstream motif analysis in bladder cancer cells","pmids":["17496927"],"confidence":"Medium","gaps":["Direct physical interaction between Ral pathway components and RREB1 was not shown","Whether Ral activates RREB1 independently of MAPK unclear"]},{"year":2008,"claim":"Demonstrating that RREB1 (and its Drosophila ortholog HNT) is required for collective cell migration and cell–cell adhesion remodeling via JNK and STAT pathways revealed a conserved morphogenetic function beyond simple transcriptional activation.","evidence":"Drosophila loss-of-function mutants in follicle cells and siRNA knockdown with scratch-wound assays in mammalian MCF10A cells","pmids":["18394891"],"confidence":"High","gaps":["Direct transcriptional targets mediating the migration phenotype not identified","Whether JNK/STAT regulation is direct or indirect unknown"]},{"year":2009,"claim":"Identifying RREB1 as a repressor that recruits the CtBP chromatin-remodeling complex to silence HLA-G, and as a direct transactivator of p53 under genotoxic stress, established its dual activator/repressor capacity depending on cofactor context.","evidence":"Promoter pull-down with MS, Co-IP of RREB1–CtBP subunits (HLA-G); ChIP and siRNA with apoptosis readouts (p53)","pmids":["19890057","19558368"],"confidence":"Medium","gaps":["Determinants that switch RREB1 between activation and repression not defined","CtBP complex interaction validated in single lab only"]},{"year":2010,"claim":"Showing that RREB1 directly represses the zinc transporter hZIP1 via promoter binding connected RREB1 to zinc homeostasis, a pathway later extended to ZIP3 in pancreatic cells.","evidence":"EMSA, ChIP, promoter mutagenesis, and gain/loss-of-function in prostate cancer cells; confirmed in tissue microarrays and extended to ZIP3 in pancreatic cells","pmids":["19802870","21360563","25050557"],"confidence":"High","gaps":["How RREB1 switches from repression (hZIP1) to activation (ZIP3) at different zinc transporter promoters unresolved","In vivo relevance in zinc-dependent tumor biology not fully tested"]},{"year":2012,"claim":"Elucidating that MAPK-activated RREB1 represses the miR-143/145 cluster, which in turn targets KRAS and RREB1, revealed a self-reinforcing KRAS–RREB1–miRNA feedback loop in colorectal cancer.","evidence":"ChIP, luciferase reporters, miRNA overexpression, MAPK inhibitor treatment in colorectal cancer cells","pmids":["22751122"],"confidence":"High","gaps":["Whether this feedback loop operates in normal colonic epithelium unknown","Quantitative parameters of the feedback circuit (thresholds, dynamics) not modeled"]},{"year":2014,"claim":"Cross-species rescue experiments showing human RREB1 substitutes for Drosophila HNT at identical chromosomal binding sites proved deep functional conservation of the DNA-binding and transcriptional domains.","evidence":"Polytene chromosome mapping, in vitro DNA binding, cross-species rescue of germ-band retraction in Drosophila","pmids":["24418439"],"confidence":"High","gaps":["Whether cofactor recruitment is also conserved across species not tested","Mammalian genomic binding-site repertoire not yet mapped"]},{"year":2017,"claim":"Demonstrating that RREB1 recruits a lncRNA (linc-ADAMTS5) and SFPQ to the ADAMTS5 promoter for HDAC-mediated repression expanded its mechanism to include noncoding RNA-guided chromatin remodeling.","evidence":"RNA pull-down, RIP, ChIP, and gain/loss-of-function in nucleus pulposus cells","pmids":["28341660"],"confidence":"Medium","gaps":["Generality of RREB1–lncRNA partnerships at other loci not explored","Specific HDAC isoform recruited not identified"]},{"year":2018,"claim":"Genetic epistasis placing RREB1/Pebbled upstream of dSarm in Wallerian degeneration—with cross-species rescue—established RREB1 as a transcriptional regulator of the axon death signaling pathway.","evidence":"Drosophila loss-of-function axotomy assays, genetic epistasis with dsarm, rescue with human RREB1","pmids":["29295933"],"confidence":"High","gaps":["Direct transcriptional targets through which RREB1 promotes axon degeneration not identified","Whether RREB1 acts in mammalian Wallerian degeneration in vivo unknown"]},{"year":2020,"claim":"ChIP-seq and knockout studies showing that MAPK-activated RREB1 physically recruits TGF-β-activated SMADs to the SNAIL promoter and EMT loci in carcinoma and embryonic contexts answered the long-standing question of how RAS and TGF-β pathways converge at chromatin to drive EMT.","evidence":"ChIP-seq, ATAC-seq, Co-IP of RREB1–SMADs, RREB1 KO/KD, mouse epiblast progenitors, carcinoma EMT models","pmids":["31915377"],"confidence":"High","gaps":["Structural basis of RREB1–SMAD interaction not resolved","Whether RREB1 recruits SMADs at non-EMT loci is unexplored"]},{"year":2020,"claim":"Demonstrating that RREB1 recruits the Sin3A–KDM1A corepressor to control H3K4 methylation at MAPK pathway genes, and that Rreb1 haploinsufficiency causes Noonan-like features in mice, established RREB1 as an epigenetic rheostat of RAS–MAPK signaling strength.","evidence":"Co-IP of RREB1 with Sin3A and KDM1A, ChIP for H3K4me marks, Rreb1 hemizygous mouse model with cardiac and craniofacial phenotyping","pmids":["32938917"],"confidence":"High","gaps":["Whether human RREB1 haploinsufficiency causes RASopathy-spectrum disease not established","Full set of MAPK pathway promoters regulated via this mechanism not defined"]},{"year":2021,"claim":"Rreb1-null mouse embryos revealed that RREB1 normally restrains cytoskeletal gene expression to maintain epiblast epithelial integrity, with its loss causing F-actin and adherens junction disorganization and embryonic lethality.","evidence":"Rreb1 knockout mouse, RNA-seq, immunofluorescence of F-actin/adherens junctions","pmids":["33929320"],"confidence":"High","gaps":["Whether cytoskeletal gene derepression is a direct or indirect consequence of RREB1 loss not distinguished","Relationship between this epithelial integrity role and the EMT-promoting SMAD-recruitment role is paradoxical and unresolved"]},{"year":2024,"claim":"Identification of a nervous-system-enriched Rreb1 transcript essential for Purkinje cell survival—with its loss causing defective autophagy–lysosome proteostasis, dendritic simplification, and progressive cerebellar degeneration—expanded RREB1 function to neuronal maintenance and protein quality control.","evidence":"Spontaneous mouse mutation, ChIP-seq, RNA-seq, immunofluorescence for p62/ubiquitin inclusions and autophagosomes in Purkinje cells","pmids":["38198538"],"confidence":"High","gaps":["Which specific RREB1 target genes mediate autophagy–lysosome regulation not determined","Whether human cerebellar ataxias harbor RREB1 mutations unknown"]},{"year":2024,"claim":"Showing that SUMOylation of RREB1 is required for its interaction with KDM1A and that RREB1 transcriptionally upregulates UBC9 (the SUMO E2 enzyme) revealed a SUMOylation-dependent self-amplifying loop controlling chemoresistance.","evidence":"Co-IP of RREB1–KDM1A, ChIP at TS/TK1 and UBC9 promoters, SUMOylation inhibitor rescue of 5-FU sensitivity in colorectal cancer cells","pmids":["39991628","39108750"],"confidence":"Medium","gaps":["SUMOylation site(s) on RREB1 not mapped in this context","Whether the RREB1–UBC9 loop operates outside colorectal cancer not tested","Single-lab findings awaiting independent confirmation"]},{"year":null,"claim":"Key unresolved questions include: the structural basis of RREB1 zinc-finger–DNA recognition and RREB1–SMAD interaction; the post-translational modification code (phosphorylation, acetylation, SUMOylation) that dictates cofactor choice; how RREB1 switches between activator and repressor modes at different loci; and whether human RREB1 loss-of-function mutations underlie neurodegenerative or RASopathy-spectrum diseases.","evidence":"","pmids":[],"confidence":"High","gaps":["No crystal or cryo-EM structure of RREB1 or its complexes","Genome-wide binding-site atlas in human tissues incomplete","Physiological significance of acetylation at Lys-60 in non-cancer contexts unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0003677","term_label":"DNA binding","supporting_discovery_ids":[0,4,6,8,12,17]},{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[0,3,4,6,12,13,15,18,20,22]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[13,19]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[0,3,4,12,13,18,23]}],"pathway":[{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[0,3,4,6,12,13,17,18,20]},{"term_id":"R-HSA-4839726","term_label":"Chromatin organization","supporting_discovery_ids":[2,13,17,19]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[12,14,16]},{"term_id":"R-HSA-112316","term_label":"Neuronal System","supporting_discovery_ids":[10,18]},{"term_id":"R-HSA-9612973","term_label":"Autophagy","supporting_discovery_ids":[18]}],"complexes":["Sin3A/KDM1A corepressor complex","CtBP chromatin-remodeling complex","RREB1–SMAD complex"],"partners":["SMAD2","SMAD3","KDM1A","SIN3A","CTBP1","DJ-1","SFPQ","EZH2"],"other_free_text":[]},"mechanistic_narrative":"RREB1 is a multi-zinc-finger transcription factor that functions as a RAS–MAPK effector, integrating mitogenic and morphogenetic signaling into chromatin-level transcriptional programs that control epithelial-to-mesenchymal transition (EMT), cell migration, neuronal survival, and proteostasis. RREB1 binds RAS-responsive elements in target promoters and, upon MAPK-dependent activation, recruits TGF-β-activated SMAD complexes to drive SNAIL expression and fibrogenic/mesendoderm gene programs during both carcinoma EMT and gastrulation [PMID:31915377], while also partnering with the Sin3A–KDM1A corepressor complex to modulate H3K4 methylation at MAPK pathway genes and restrain RAS signaling output [PMID:32938917, PMID:39991628]. Through additional interactions with the CtBP chromatin-remodeling complex and HDAC-containing assemblies, RREB1 epigenetically represses diverse targets including HLA-G, miR-143/145, hZIP1, and ADAMTS5 [PMID:19890057, PMID:22751122, PMID:19802870, PMID:28341660]. A nervous-system-enriched Rreb1 transcript is essential for Purkinje cell survival, with its loss causing impaired autophagy–lysosome proteostasis, cytoskeletal disorganization, and progressive cerebellar degeneration [PMID:38198538]."},"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). 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siRNA knockdown of mammalian RREB1 in MCF10A cells inhibited collective migration in scratch-wound assays, suppressed surface activity, retarded cell spreading, and led to immobile, tightly adherent colonies.\",\n      \"method\": \"Drosophila genetics (loss-of-function mutants), siRNA knockdown, scratch-wound healing assay, live imaging\",\n      \"journal\": \"Current biology : CB\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic loss-of-function in two organisms with defined cellular phenotypes and pathway (JNK/STAT) placement\",\n      \"pmids\": [\"18394891\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"RREB-1 represses HLA-G transcription by binding three RREs in the HLA-G promoter; in HLA-G-negative cells, RREB-1 interacts with subunits of the CtBP chromatin-remodeling complex to mediate epigenetic repression.\",\n      \"method\": \"Promoter pull-down assay followed by mass spectrometry, luciferase reporter assays, Co-IP of RREB-1 with CtBP complex subunits\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal pulldown/Co-IP with MS identification, but 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 recruits to the p53 promoter and controls apoptosis in a p53-dependent manner.\",\n      \"method\": \"ChIP, siRNA knockdown, luciferase reporter assay, apoptosis assays\",\n      \"journal\": \"The Biochemical journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — ChIP and functional knockdown with p53-dependent readout, single lab\",\n      \"pmids\": [\"19558368\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"RREB-1 binds to the hZIP1 promoter and represses hZIP1 zinc transporter transcription in prostate cancer cells; RREB-1 overexpression decreases hZIP1 membrane abundance whereas siRNA knockdown increases it.\",\n      \"method\": \"Luciferase reporter assay, site-directed mutagenesis, gel shift (EMSA), ChIP, siRNA knockdown, RREB-1 overexpression\",\n      \"journal\": \"The Prostate\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — EMSA, ChIP, mutagenesis, and gain/loss-of-function all in one study\",\n      \"pmids\": [\"19802870\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"RREB-1 overexpression in prostate cancer cells down-regulates hZIP1 zinc transporter, contributing to decreased zinc levels; inverse relationship between RREB-1 and hZIP1 confirmed in tissue microarrays.\",\n      \"method\": \"RREB-1 overexpression and siRNA knockdown in PC-3 cells, immunohistochemistry on tissue microarrays\",\n      \"journal\": \"The Prostate\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — gain and loss-of-function with protein-level readout; replication of mechanism shown in 2010 paper\",\n      \"pmids\": [\"21360563\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"RREB1, activated by the MAPK pathway downstream of oncogenic KRAS, negatively regulates the miR-143/145 cluster by binding two RREs in the miR-143/145 promoter in colorectal cancer; miR-143/145 in turn target KRAS and RREB1, forming a feedback loop.\",\n      \"method\": \"ChIP, luciferase reporter assay, miRNA overexpression, siRNA knockdown, MAPK pathway inhibition\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — ChIP, promoter reporters, and epistasis with KRAS/MAPK; multiple orthogonal methods\",\n      \"pmids\": [\"22751122\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"DJ-1 physically interacts with RREB1 and the DJ-1/RREB1 complex binds the RRE in the cholecystokinin (CCK) gene promoter to activate CCK transcription; DJ-1-knockout mice show reduced serum CCK levels.\",\n      \"method\": \"Co-IP, ChIP, luciferase reporter assay, siRNA knockdown, DJ-1 knockout mice\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — Co-IP and ChIP with in vivo confirmation in knockout mice, single lab\",\n      \"pmids\": [\"24348900\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Drosophila HNT (RREB1 ortholog) and human RREB1 bind to the same DNA elements (similar to known RREB-1 sites) via the C-terminal zinc fingers; RREB-1 expressed in Drosophila rescues hnt germ-band retraction phenotypes, attenuates hnt and nervy target gene transcription, and binds identical polytene chromosome sites as HNT, demonstrating functional conservation.\",\n      \"method\": \"Drosophila genetics (loss-of-function and overexpression), in vitro DNA binding, polytene chromosome mapping, cross-species rescue experiments\",\n      \"journal\": \"Differentiation; research in biological diversity\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — in vitro DNA binding, in vivo chromosomal mapping, cross-species functional rescue\",\n      \"pmids\": [\"24418439\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"RREB1 is a positive regulator of ZIP3 zinc transporter expression in pancreatic cells; RREB1 and ZIP3 downregulation is an early event in pancreatic adenocarcinoma development, and zinc accumulation via ZIP3 inhibits proliferation of Panc1 cells.\",\n      \"method\": \"siRNA knockdown, zinc uptake assays, cell proliferation assays, immunohistochemistry on tissue sections\",\n      \"journal\": \"Cancer biology & therapy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — loss-of-function with functional readout, but limited mechanistic depth on how RREB1 activates ZIP3\",\n      \"pmids\": [\"25050557\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Drosophila Pebbled (RREB1 ortholog) is required in glutamatergic sensory neurons to enable normal Wallerian axon degeneration; loss of peb results in axon preservation or partial fragmentation after axotomy, and peb/RREB1 genetically interacts with dsarm, placing it in the axon death signaling cascade; human RREB1 rescues peb mutant phenotypes.\",\n      \"method\": \"Drosophila genetics (loss-of-function), axotomy assays, genetic epistasis with dsarm, cross-species rescue with human RREB1\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic epistasis, cross-species rescue, and defined cellular phenotype; multiple orthogonal approaches\",\n      \"pmids\": [\"29295933\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"RREB1-MKL2 (RREB1-MRTFB) fusion gene is identified in ~90% of ectomesenchymal chondromyxoid tumors; the RREB1 (exon 8)–MKL2 (exon 11) fusion product drives increased MKL2 expression, which regulates neural and myogenic differentiation.\",\n      \"method\": \"RNA sequencing, RT-PCR, FISH, Sanger sequencing\",\n      \"journal\": \"The American journal of surgical pathology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — RNA-seq identification and FISH validation of recurrent fusion across 21 cases; functional consequence of fusion inferred from MKL2 biology\",\n      \"pmids\": [\"29912715\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"RREB1 acts as a key partner of TGF-β-activated SMAD transcription factors in EMT: MAPK-activated RREB1 recruits TGF-β-activated SMADs to the SNAIL promoter, directly driving SNAIL expression and fibrogenic gene programs. In carcinoma cells, TGF-β–SMAD–RREB1 also drives intratumoral fibrosis and myofibroblast stimulation. In mouse epiblast, Nodal-SMAD and RREB1 combinatorially activate SNAIL and mesendoderm genes for gastrulation. Context-dependent chromatin accessibility determines the additional EMT gene targets activated.\",\n      \"method\": \"ChIP-seq, ATAC-seq, Co-IP of RREB1 with SMADs, reporter assays, RREB1 knockout/knockdown, mouse epiblast progenitor experiments, carcinoma cell EMT assays\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — multiple orthogonal methods (ChIP-seq, ATAC-seq, Co-IP, KO models) in multiple biological contexts; highly cited foundational paper\",\n      \"pmids\": [\"31915377\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Rreb1 haploinsufficiency leads to sensitization of MAPK signaling; Rreb1 recruits the Sin3a corepressor and Kdm1a histone demethylase to control H3K4 methylation at MAPK pathway gene promoters, thereby acting as an epigenetic regulator of RAS-MAPK signaling. Rreb1 hemizygous mice display orbital hypertelorism and cardiac hypertrophy (Noonan-like phenotype).\",\n      \"method\": \"ChIP, Co-IP of RREB1 with Sin3a/Kdm1a, mouse knockout model, MAPK signaling assays, H3K4 methylation profiling\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — Co-IP of complex, ChIP for chromatin marks, in vivo haploinsufficiency mouse model with defined molecular and phenotypic readouts\",\n      \"pmids\": [\"32938917\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Loss of Rreb1 in mouse embryos causes upregulation of cytoskeleton-associated genes, disorganization of F-actin and adherens junctions in the epiblast epithelium, ectopic exit of epiblast cells through the basement membrane, reduction of vasculogenic factor expression, cardiovascular defects, and embryonic lethality.\",\n      \"method\": \"Rreb1 knockout mouse model, RNA-seq, immunofluorescence of F-actin/adherens junctions, histology\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — complete KO with multiple orthogonal phenotypic readouts (transcriptomics, cytoskeletal imaging, histology) in vivo\",\n      \"pmids\": [\"33929320\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"miR-26a improves deacetylation of RREB1 at Lys-60, which enables RREB1 to bind the AKT1 promoter and activate AKT transcription and downstream glycolytic signaling in colorectal cancer cells.\",\n      \"method\": \"Quantitative proteomics, ChIP, luciferase reporter assay, loss-of-function analysis, xenograft mouse model\",\n      \"journal\": \"Cancer letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — ChIP and promoter reporter plus modification site identification; single lab\",\n      \"pmids\": [\"34419497\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"RREB1 is required for RAS-mediated dissociation of medial edge epithelium (MEE) during murine palatal fusion; Rreb1 knockdown in palatal organ culture prevents MEE cell dissociation and causes palatal fusion defects, paralleling the role of RREB1 in EMT.\",\n      \"method\": \"Palatal organ culture, Rreb1 siRNA knockdown, pan-Ras inhibitor treatment, histological analysis\",\n      \"journal\": \"Disease models & mechanisms\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — loss-of-function in organ culture with defined morphological phenotype; single lab\",\n      \"pmids\": [\"34897389\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"RREB1 binds to the ADAMTS5 promoter and recruits the noncoding RNA linc-ADAMTS5 together with SFPQ to induce chromatin remodeling via histone deacetylases (HDACs), resulting in repression of ADAMTS5 expression in nucleus pulposus cells.\",\n      \"method\": \"RNA pull-down, RIP, ChIP, in vitro binding assays, gain- and loss-of-function studies\",\n      \"journal\": \"Clinical science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple binding assays (pulldown, RIP, ChIP) supporting the mechanism; single lab\",\n      \"pmids\": [\"28341660\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"A nervous system-enriched Rreb1 transcript is essential for Purkinje cell survival in mice; loss of this transcript causes progressive cerebellar degeneration and ataxia. RREB1 targets include microtubule cytoskeleton genes and endomembrane system genes. Rreb1-deficient Purkinje cells exhibit reduced dendritic complexity, fewer autophagosomes and lysosomes, and accumulation of p62- and ubiquitin-positive inclusions, indicating impaired proteostasis.\",\n      \"method\": \"Spontaneous mouse mutation model, ChIP-seq, RNA-seq, immunofluorescence, histological analysis of Purkinje cells\",\n      \"journal\": \"Science advances\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — in vivo loss-of-function with ChIP-seq target identification, multiple cellular phenotypes including proteostasis and cytoskeletal readouts\",\n      \"pmids\": [\"38198538\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"RREB1 interacts with KDM1A (LSD1) histone demethylase; the RREB1–KDM1A complex elevates thymidylate synthase (TS) and thymidine kinase (TK1) expression and enhances Chk1-mediated DNA damage response, conferring 5-FU resistance in colorectal cancer. SUMOylation of RREB1 is required for its interaction with KDM1A; deSUMOylation reduces this interaction and re-sensitizes cells to 5-FU.\",\n      \"method\": \"Co-IP of RREB1 with KDM1A, ChIP, siRNA knockdown of KDM1A, SUMOylation inhibitor (ML-792), cell proliferation and apoptosis assays\",\n      \"journal\": \"MedComm\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — Co-IP and ChIP demonstrating RREB1–KDM1A interaction and target gene regulation; single lab\",\n      \"pmids\": [\"39991628\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"RREB1 directly binds the UBC9 promoter to transcriptionally upregulate UBC9 (the sole E2 SUMO-conjugating enzyme), thereby enhancing global protein SUMOylation and conferring 5-FU resistance in colorectal cancer.\",\n      \"method\": \"ChIP, luciferase reporter assay, RREB1 overexpression and knockdown, SUMOylation inhibitor co-treatment\",\n      \"journal\": \"Frontiers in pharmacology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — ChIP and reporter assay support direct promoter binding; functional epistasis with SUMOylation inhibitor; single lab\",\n      \"pmids\": [\"39108750\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"RREB-1 is identified as a transcriptional effector downstream of Ral GTPases (RalA and RalB) in bladder cancer cells; Ral depletion modulates a transcriptional program that includes RREB-1 target genes, linking Ral signaling to RREB-1-mediated transcription.\",\n      \"method\": \"siRNA depletion of RalA/RalB, microarray gene expression profiling, computational upstream sequence analysis, experimental verification of RREB-1 as Ral target\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — computational prediction followed by experimental verification; single lab, moderate follow-up\",\n      \"pmids\": [\"17496927\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"RREB1 activates transcription of the lncRNA AGAP2-AS1 in pancreatic cancer cells; AGAP2-AS1 in turn epigenetically suppresses ANKRD1 and ANGPTL4 by recruiting EZH2, promoting cell proliferation and migration.\",\n      \"method\": \"ChIP for RREB1 at AGAP2-AS1 promoter, RIP, EZH2 recruitment assay, gain/loss-of-function proliferation and invasion assays, xenograft model\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — ChIP and RIP establishing RREB1-lncRNA-EZH2 axis; single lab\",\n      \"pmids\": [\"30814490\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"In glioma stem cells, circNCAPG stabilizes RREB1 protein and promotes its nuclear translocation to activate TGF-β1 signaling; RREB1 in turn transcriptionally upregulates U2AF65, which stabilizes circNCAPG, forming a positive feedback loop.\",\n      \"method\": \"RNA pull-down, RIP, ChIP, immunofluorescence for RREB1 nuclear translocation, gain/loss-of-function assays\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple binding and ChIP assays; single lab demonstrating RREB1 nuclear translocation and transcriptional activity\",\n      \"pmids\": [\"36635261\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"RREB1 is a multi-zinc-finger transcription factor and RAS effector that, when activated by MAPK/ERK signaling, binds RAS-responsive elements in target gene promoters; it physically recruits TGF-β-activated SMAD complexes to drive EMT gene programs (including SNAIL), associates with chromatin-remodeling co-factors (CtBP complex, Sin3A/KDM1A, EZH2) to epigenetically repress or activate target genes (miR-143/145, hZIP1, p53, HLA-G, UBC9, ADAMTS5), regulates microtubule cytoskeleton and proteostasis genes essential for neuron survival, and controls collective cell migration and axon degeneration signaling, with its SUMOylation state modulating its interaction with chromatin-modifying partners and consequently its transcriptional output.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"RREB1 is a multi-zinc-finger transcription factor that functions as a RAS–MAPK effector, integrating mitogenic and morphogenetic signaling into chromatin-level transcriptional programs that control epithelial-to-mesenchymal transition (EMT), cell migration, neuronal survival, and proteostasis. RREB1 binds RAS-responsive elements in target promoters and, upon MAPK-dependent activation, recruits TGF-β-activated SMAD complexes to drive SNAIL expression and fibrogenic/mesendoderm gene programs during both carcinoma EMT and gastrulation [PMID:31915377], while also partnering with the Sin3A–KDM1A corepressor complex to modulate H3K4 methylation at MAPK pathway genes and restrain RAS signaling output [PMID:32938917, PMID:39991628]. Through additional interactions with the CtBP chromatin-remodeling complex and HDAC-containing assemblies, RREB1 epigenetically represses diverse targets including HLA-G, miR-143/145, hZIP1, and ADAMTS5 [PMID:19890057, PMID:22751122, PMID:19802870, PMID:28341660]. A nervous-system-enriched Rreb1 transcript is essential for Purkinje cell survival, with its loss causing impaired autophagy–lysosome proteostasis, cytoskeletal disorganization, and progressive cerebellar degeneration [PMID:38198538].\",\n  \"teleology\": [\n    {\n      \"year\": 1996,\n      \"claim\": \"Establishing that RREB1 is a zinc-finger transcription factor that directly mediates RAS/RAF-induced gene activation by binding a defined RAS-responsive element (RRE) in the calcitonin promoter answered the question of how RAS signaling converges on specific promoter sequences.\",\n      \"evidence\": \"cDNA cloning, DNase I footprinting, and reporter transactivation in medullary thyroid carcinoma cells with RAS/RAF overexpression\",\n      \"pmids\": [\"8816445\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Identity of the kinase that directly phosphorylates/activates RREB1 was not determined\", \"Full spectrum of RRE-containing target genes unknown\", \"Structural basis of zinc-finger–RRE recognition not resolved\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Placing RREB1 downstream of Ral GTPases in addition to RAF broadened its role as a convergence node for multiple RAS-family effector pathways.\",\n      \"evidence\": \"siRNA depletion of RalA/RalB coupled with microarray profiling and upstream motif analysis in bladder cancer cells\",\n      \"pmids\": [\"17496927\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct physical interaction between Ral pathway components and RREB1 was not shown\", \"Whether Ral activates RREB1 independently of MAPK unclear\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Demonstrating that RREB1 (and its Drosophila ortholog HNT) is required for collective cell migration and cell–cell adhesion remodeling via JNK and STAT pathways revealed a conserved morphogenetic function beyond simple transcriptional activation.\",\n      \"evidence\": \"Drosophila loss-of-function mutants in follicle cells and siRNA knockdown with scratch-wound assays in mammalian MCF10A cells\",\n      \"pmids\": [\"18394891\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct transcriptional targets mediating the migration phenotype not identified\", \"Whether JNK/STAT regulation is direct or indirect unknown\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Identifying RREB1 as a repressor that recruits the CtBP chromatin-remodeling complex to silence HLA-G, and as a direct transactivator of p53 under genotoxic stress, established its dual activator/repressor capacity depending on cofactor context.\",\n      \"evidence\": \"Promoter pull-down with MS, Co-IP of RREB1–CtBP subunits (HLA-G); ChIP and siRNA with apoptosis readouts (p53)\",\n      \"pmids\": [\"19890057\", \"19558368\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Determinants that switch RREB1 between activation and repression not defined\", \"CtBP complex interaction validated in single lab only\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Showing that RREB1 directly represses the zinc transporter hZIP1 via promoter binding connected RREB1 to zinc homeostasis, a pathway later extended to ZIP3 in pancreatic cells.\",\n      \"evidence\": \"EMSA, ChIP, promoter mutagenesis, and gain/loss-of-function in prostate cancer cells; confirmed in tissue microarrays and extended to ZIP3 in pancreatic cells\",\n      \"pmids\": [\"19802870\", \"21360563\", \"25050557\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How RREB1 switches from repression (hZIP1) to activation (ZIP3) at different zinc transporter promoters unresolved\", \"In vivo relevance in zinc-dependent tumor biology not fully tested\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Elucidating that MAPK-activated RREB1 represses the miR-143/145 cluster, which in turn targets KRAS and RREB1, revealed a self-reinforcing KRAS–RREB1–miRNA feedback loop in colorectal cancer.\",\n      \"evidence\": \"ChIP, luciferase reporters, miRNA overexpression, MAPK inhibitor treatment in colorectal cancer cells\",\n      \"pmids\": [\"22751122\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether this feedback loop operates in normal colonic epithelium unknown\", \"Quantitative parameters of the feedback circuit (thresholds, dynamics) not modeled\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Cross-species rescue experiments showing human RREB1 substitutes for Drosophila HNT at identical chromosomal binding sites proved deep functional conservation of the DNA-binding and transcriptional domains.\",\n      \"evidence\": \"Polytene chromosome mapping, in vitro DNA binding, cross-species rescue of germ-band retraction in Drosophila\",\n      \"pmids\": [\"24418439\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether cofactor recruitment is also conserved across species not tested\", \"Mammalian genomic binding-site repertoire not yet mapped\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Demonstrating that RREB1 recruits a lncRNA (linc-ADAMTS5) and SFPQ to the ADAMTS5 promoter for HDAC-mediated repression expanded its mechanism to include noncoding RNA-guided chromatin remodeling.\",\n      \"evidence\": \"RNA pull-down, RIP, ChIP, and gain/loss-of-function in nucleus pulposus cells\",\n      \"pmids\": [\"28341660\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Generality of RREB1–lncRNA partnerships at other loci not explored\", \"Specific HDAC isoform recruited not identified\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Genetic epistasis placing RREB1/Pebbled upstream of dSarm in Wallerian degeneration—with cross-species rescue—established RREB1 as a transcriptional regulator of the axon death signaling pathway.\",\n      \"evidence\": \"Drosophila loss-of-function axotomy assays, genetic epistasis with dsarm, rescue with human RREB1\",\n      \"pmids\": [\"29295933\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct transcriptional targets through which RREB1 promotes axon degeneration not identified\", \"Whether RREB1 acts in mammalian Wallerian degeneration in vivo unknown\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"ChIP-seq and knockout studies showing that MAPK-activated RREB1 physically recruits TGF-β-activated SMADs to the SNAIL promoter and EMT loci in carcinoma and embryonic contexts answered the long-standing question of how RAS and TGF-β pathways converge at chromatin to drive EMT.\",\n      \"evidence\": \"ChIP-seq, ATAC-seq, Co-IP of RREB1–SMADs, RREB1 KO/KD, mouse epiblast progenitors, carcinoma EMT models\",\n      \"pmids\": [\"31915377\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of RREB1–SMAD interaction not resolved\", \"Whether RREB1 recruits SMADs at non-EMT loci is unexplored\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Demonstrating that RREB1 recruits the Sin3A–KDM1A corepressor to control H3K4 methylation at MAPK pathway genes, and that Rreb1 haploinsufficiency causes Noonan-like features in mice, established RREB1 as an epigenetic rheostat of RAS–MAPK signaling strength.\",\n      \"evidence\": \"Co-IP of RREB1 with Sin3A and KDM1A, ChIP for H3K4me marks, Rreb1 hemizygous mouse model with cardiac and craniofacial phenotyping\",\n      \"pmids\": [\"32938917\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether human RREB1 haploinsufficiency causes RASopathy-spectrum disease not established\", \"Full set of MAPK pathway promoters regulated via this mechanism not defined\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Rreb1-null mouse embryos revealed that RREB1 normally restrains cytoskeletal gene expression to maintain epiblast epithelial integrity, with its loss causing F-actin and adherens junction disorganization and embryonic lethality.\",\n      \"evidence\": \"Rreb1 knockout mouse, RNA-seq, immunofluorescence of F-actin/adherens junctions\",\n      \"pmids\": [\"33929320\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether cytoskeletal gene derepression is a direct or indirect consequence of RREB1 loss not distinguished\", \"Relationship between this epithelial integrity role and the EMT-promoting SMAD-recruitment role is paradoxical and unresolved\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Identification of a nervous-system-enriched Rreb1 transcript essential for Purkinje cell survival—with its loss causing defective autophagy–lysosome proteostasis, dendritic simplification, and progressive cerebellar degeneration—expanded RREB1 function to neuronal maintenance and protein quality control.\",\n      \"evidence\": \"Spontaneous mouse mutation, ChIP-seq, RNA-seq, immunofluorescence for p62/ubiquitin inclusions and autophagosomes in Purkinje cells\",\n      \"pmids\": [\"38198538\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Which specific RREB1 target genes mediate autophagy–lysosome regulation not determined\", \"Whether human cerebellar ataxias harbor RREB1 mutations unknown\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Showing that SUMOylation of RREB1 is required for its interaction with KDM1A and that RREB1 transcriptionally upregulates UBC9 (the SUMO E2 enzyme) revealed a SUMOylation-dependent self-amplifying loop controlling chemoresistance.\",\n      \"evidence\": \"Co-IP of RREB1–KDM1A, ChIP at TS/TK1 and UBC9 promoters, SUMOylation inhibitor rescue of 5-FU sensitivity in colorectal cancer cells\",\n      \"pmids\": [\"39991628\", \"39108750\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"SUMOylation site(s) on RREB1 not mapped in this context\", \"Whether the RREB1–UBC9 loop operates outside colorectal cancer not tested\", \"Single-lab findings awaiting independent confirmation\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Key unresolved questions include: the structural basis of RREB1 zinc-finger–DNA recognition and RREB1–SMAD interaction; the post-translational modification code (phosphorylation, acetylation, SUMOylation) that dictates cofactor choice; how RREB1 switches between activator and repressor modes at different loci; and whether human RREB1 loss-of-function mutations underlie neurodegenerative or RASopathy-spectrum diseases.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No crystal or cryo-EM structure of RREB1 or its complexes\", \"Genome-wide binding-site atlas in human tissues incomplete\", \"Physiological significance of acetylation at Lys-60 in non-cancer contexts unknown\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0003677\", \"supporting_discovery_ids\": [0, 4, 6, 8, 12, 17]},\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [0, 3, 4, 6, 12, 13, 15, 18, 20, 22]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [13, 19]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [0, 3, 4, 12, 13, 18, 23]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"GO:0162582\", \"supporting_discovery_ids\": [0, 6, 12, 13, 21]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [0, 3, 4, 6, 12, 13, 17, 18, 20]},\n      {\"term_id\": \"R-HSA-4839726\", \"supporting_discovery_ids\": [2, 13, 17, 19]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [12, 14, 16]},\n      {\"term_id\": \"R-HSA-112316\", \"supporting_discovery_ids\": [10, 18]},\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [18]}\n    ],\n    \"complexes\": [\n      \"Sin3A/KDM1A corepressor complex\",\n      \"CtBP chromatin-remodeling complex\",\n      \"RREB1–SMAD complex\"\n    ],\n    \"partners\": [\n      \"SMAD2\",\n      \"SMAD3\",\n      \"KDM1A\",\n      \"SIN3A\",\n      \"CTBP1\",\n      \"DJ-1\",\n      \"SFPQ\",\n      \"EZH2\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}