{"gene":"BEX1","run_date":"2026-06-09T22:02:44","timeline":{"discoveries":[{"year":2006,"finding":"Bex1 was identified as a direct intracellular binding partner of the p75 neurotrophin receptor (p75NTR) via a screening for p75NTR interactors; Bex1 competed with RIP2 for binding to the p75NTR intracellular domain, and elevating RIP2 levels rescued differentiation in Bex1-overexpressing cells.","method":"Interactor screening, competition binding assay, epistasis by RIP2 overexpression","journal":"The EMBO journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — interaction screening confirmed by competition experiment, single lab, two orthogonal approaches","pmids":["16498402"],"is_preprint":false},{"year":2006,"finding":"Bex1 levels oscillate during the cell cycle; ectopic Bex1 in PC12 cells sustains proliferation under growth arrest conditions, inhibits NGF-induced neuronal differentiation, and inhibits NGF-induced NF-κB activation without affecting Erk1/2 or AKT. Bex1 knockdown accelerates neuronal differentiation and potentiates NF-κB activity in response to NGF.","method":"Overexpression and siRNA knockdown in PC12 cells; cell proliferation, differentiation, and NF-κB reporter assays; subventricular zone precursor differentiation assay","journal":"The EMBO journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss- and gain-of-function with multiple readouts, single lab","pmids":["16498402"],"is_preprint":false},{"year":2006,"finding":"Viral re-expression of BEX1 in glioma cell lines increased sensitivity to chemotherapy-induced apoptosis and suppressed tumor growth in vitro and in a xenograft mouse model, establishing BEX1 as a functional tumor suppressor whose expression is silenced by promoter hypermethylation and histone deacetylation.","method":"Viral-mediated re-expression, chemotherapy apoptosis assay, xenograft mouse model; TSA/5-AzaC pharmacological unmasking + microarray","journal":"Cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — gain-of-function with in vitro and in vivo readouts, single lab","pmids":["16818640"],"is_preprint":false},{"year":2007,"finding":"Bex1 interacts with calmodulin (CaM) in a calcium-dependent manner; Bex1 knockout mice show elevated and prolonged cell proliferation and delayed differentiation during skeletal muscle regeneration after cardiotoxin-induced myotrauma, and exhibit functional exercise performance deficits.","method":"Co-interaction assay (calcium-dependent binding), Bex1 knockout mouse generation, cardiotoxin myotrauma model, proliferation/differentiation assays","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — calcium-dependent binding plus KO phenotype with cellular readouts, single lab","pmids":["17884015"],"is_preprint":false},{"year":2010,"finding":"Bex1 protein is upregulated following peripheral axonal injury; Bex1 antagonizes myelin-associated glycoprotein-mediated inhibition of axon outgrowth; Bex1 knockout mice show reduced regenerative capacity after sciatic nerve injury compared to wild-type.","method":"In vivo nerve injury model, Bex1 KO mice, axon outgrowth inhibition assay with MAG","journal":"Journal of neurochemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — KO mouse with in vivo phenotype plus in vitro functional assay, single lab","pmids":["20731761"],"is_preprint":false},{"year":2013,"finding":"Restored expression of BEX1 in oral squamous cell carcinoma cells suppressed the NF-κB signaling pathway, associated with decreased p50 and p65 expression, and inhibited tumor growth in vitro and in vivo.","method":"Ectopic expression, NF-κB pathway assay (p50/p65 protein levels), in vitro and in vivo growth inhibition assays","journal":"The Journal of pathology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — gain-of-function with mechanistic pathway readout and in vivo validation, single lab","pmids":["23362108"],"is_preprint":false},{"year":2014,"finding":"BEX1 was identified as a BCL-2-interacting protein by yeast two-hybrid screen and confirmed by co-immunoprecipitation; BEX1 localizes to the mitochondria (residues 33K–64Q required for localization); BEX1–BCL-2 interaction promotes imatinib-induced apoptosis by suppressing formation of anti-apoptotic BCL-2/BAX heterodimers.","method":"Yeast two-hybrid screen, co-immunoprecipitation, mitochondrial localization assay, deletion mutagenesis, apoptosis assay","journal":"PloS one","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — yeast two-hybrid plus reciprocal Co-IP plus mutagenesis plus functional apoptosis readout, single lab with multiple orthogonal methods","pmids":["24626299"],"is_preprint":false},{"year":2015,"finding":"BEX1 overexpression in FLT3-ITD-driven mouse pro-B and myeloid cells decreased FLT3-ITD-dependent cell proliferation, colony and tumor formation, and increased apoptosis; BEX1 localizes to the cytosolic compartment and significantly decreased FLT3-ITD-induced AKT phosphorylation without affecting ERK1/2 or STAT5 phosphorylation.","method":"Overexpression in cell lines, colony/tumor formation assay, xenograft model, subcellular fractionation, phospho-specific western blotting","journal":"Oncotarget","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — gain-of-function with specific signaling readouts and in vivo tumor model, single lab","pmids":["26046670"],"is_preprint":false},{"year":2015,"finding":"Bex1 is transiently expressed in differentiating myoblasts and undergoes cytoplasm-to-nucleus translocation; overexpression of Bex1 promotes myoblast fusion without affecting differentiation or myogenin expression, while Bex1 knockout myoblasts exhibit fusion defects despite normal differentiation.","method":"Immunofluorescence localization, gain- and loss-of-function (overexpression and KO), myoblast fusion and differentiation assays","journal":"Developmental biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — KO and overexpression with specific cellular phenotype and localization, single lab","pmids":["26586200"],"is_preprint":false},{"year":2017,"finding":"BEX1 is a heart failure-induced mRNA-associated protein that forms part of a large ribonucleoprotein processing complex; BEX1 augments the stability and expression of AU-rich element (ARE)-containing proinflammatory mRNAs; cardiac-specific BEX1 transgenic mice show worse cardiac disease under stress, while Bex1 gene-deleted mice are protected from heart failure-promoting insults.","method":"Proteomic and interactive screening assays (ribonucleoprotein complex identification), mRNA stability assays, cardiac-specific transgenic and gene-deleted mouse models, stress stimulation paradigms","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal gain- and loss-of-function in vivo models, proteomic complex identification, mRNA stability assay, multiple orthogonal methods","pmids":["29192139"],"is_preprint":false},{"year":2018,"finding":"BEX1 inhibits peroxisome proliferator-activated receptor gamma (PPARγ) to promote liver progenitor cell (LPC) expansion; Bex1-deficient mice on a CDE diet show impaired LPC expansion and liver regeneration; Bex1 deficiency inhibits LPC proliferation and enhances apoptosis in vitro.","method":"Bex1 KO mouse (CDE diet model), PPARγ silencing epistasis, immunofluorescence, proliferation/apoptosis assays in LPCs","journal":"Stem cell research & therapy","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — KO mouse in vivo phenotype plus epistasis via PPARγ silencing, single lab","pmids":["29907129"],"is_preprint":false},{"year":2020,"finding":"LINC00630 in complex with EZH2 epigenetically represses BEX1 through promoter DNA methylation, increasing radioresistance; BEX1 silencing restores cell viability suppressed by LINC00630 knockdown in irradiated colorectal cancer cells.","method":"RNA immunoprecipitation, chromatin immunoprecipitation, shRNA knockdown, Western blot, cell viability/apoptosis assays","journal":"IUBMB life","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — RIP and ChIP confirm EZH2-LINC00630 complex at BEX1 promoter, functional rescue by BEX1 silencing, single lab","pmids":["32119177"],"is_preprint":false},{"year":2021,"finding":"BEX1 interacts with RUNX3 to block RUNX3-mediated inhibition of β-catenin transcription, thereby activating Wnt/β-catenin signaling and maintaining stemness in hepatoblastoma and CSC-HCC; DNMT1-mediated methylation of the BEX1 promoter determines differential BEX1 expression patterns across liver cancer subtypes.","method":"Co-immunoprecipitation, sphere formation assay, xenograft model, western blotting, DNMT1 inhibitor treatment, Wnt/β-catenin pathway reporter assays","journal":"Journal of hepatology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP for BEX1-RUNX3 interaction plus functional pathway and in vivo validation, single lab","pmids":["34217777"],"is_preprint":false},{"year":2021,"finding":"BEX1 and BEX4 upregulation in GBM cells post-radiotherapy promotes actin polymerization and cytoskeletal reorganization, leading to activation of the YAP/TAZ mechanotransduction signaling pathway, which enhances tumor formation, growth, and radioresistance; latrunculin B (actin polymerization inhibitor) suppresses this GBM progression.","method":"Transcriptomic analysis, orthotopic xenograft model, actin polymerization assays, YAP/TAZ pathway assays, pharmacological inhibition","journal":"International journal of molecular sciences","confidence":"Low","confidence_rationale":"Tier 3 / Weak — functional assays in vivo but BEX1-specific mechanistic contribution not fully separated from BEX4; single lab, single study","pmids":["34576008"],"is_preprint":false},{"year":2022,"finding":"Bex1 is an intrinsically disordered protein (IDP) that forms biomolecular condensates; it accumulates in nucleoli at low cell density and at the apical cell surface/basal body at high cell density; Bex1 binds GTP and facilitates tubulin polymerization in a reconstituted system; Bex1 KO mice exhibit ciliopathy phenotypes with ciliary defects in retina and striatum, demonstrating an essential role in primary cilia formation.","method":"Biophysical characterization (IDP), live-cell imaging/fractionation for condensate localization, GTP-binding assay, in vitro tubulin polymerization reconstitution, Bex1 KO mouse phenotyping","journal":"BMC biology","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro reconstitution of tubulin polymerization, GTP binding assay, KO mouse phenotype with defined ciliopathy readouts, multiple orthogonal methods in single study","pmids":["35144600"],"is_preprint":false},{"year":2022,"finding":"BEX1 limits viral replication in cardiomyocytes and regulates interferon beta (IFN-β) expression in infected cells; BEX1 absence impairs inflammatory immune cell recruitment to the heart and accelerates CVB3-driven heart failure; BEX1 antiviral function extends to Influenza A and Sendai virus in isolated cells.","method":"Genetic gain- and loss-of-function (transgenic and KO mice), CVB3 infection model, viral load quantification, immune cell recruitment assays, IFN-β expression measurement, isolated primary cardiomyocyte and MEF experiments","journal":"PLoS pathogens","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal gain/loss-of-function in vivo, multiple virus types, IFN-β mechanistic link, replicated across cell types","pmids":["35192678"],"is_preprint":false},{"year":2023,"finding":"BEX1 promotes the Warburg effect in hepatoblastoma cells through downregulation of PPARγ; PDK1 is required downstream of PPARγ for BEX1-mediated enhancement of glycolysis; glycolysis inhibition attenuates BEX1-driven stemness and cell growth, placing BEX1 in a BEX1→PPARγ suppression→PDK1→Warburg effect→stemness axis.","method":"Seahorse extracellular flux analysis, LC-MS metabolomics, Western blot, sphere formation assay, xenograft tumor formation assay, PPARγ agonist (pioglitazone) treatment","journal":"British journal of cancer","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple metabolic and functional assays establishing pathway order, single lab","pmids":["37715024"],"is_preprint":false},{"year":2025,"finding":"BEX1 promoter methylation in glioma activates AKT/ERK/STAT3 signaling cascades, altering cell cycle regulation and apoptosis; re-expression of BEX1 in glioma cell lines reverses these signaling changes.","method":"Western blot, qRT-PCR, gene transfection, small molecule inhibitors of AKT/ERK/STAT3, functional cell cycle and apoptosis assays","journal":"Scientific reports","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, limited methodological detail in abstract, no in vivo confirmation reported","pmids":["40804095"],"is_preprint":false}],"current_model":"BEX1 is a small intrinsically disordered adaptor/scaffold protein that operates at multiple signaling nodes: it binds the p75 neurotrophin receptor intracellular domain (competing with RIP2) to suppress NF-κB and modulate cell-cycle-linked neuronal differentiation; it localizes to mitochondria where it interacts with BCL-2 to disrupt BCL-2/BAX anti-apoptotic heterodimers; it associates with large ribonucleoprotein complexes in cardiomyocytes to stabilize AU-rich-element-containing proinflammatory mRNAs and regulate IFN-β-mediated antiviral responses; it binds GTP and forms biomolecular condensates at the basal body to facilitate tubulin polymerization and primary ciliogenesis; it suppresses PPARγ to promote liver progenitor cell expansion and the Warburg effect in hepatoblastoma; and it interacts with RUNX3 to relieve β-catenin repression and activate Wnt/β-catenin-dependent cancer stem cell self-renewal, with its expression tightly regulated by DNMT1-mediated promoter methylation across multiple tissue contexts."},"narrative":{"mechanistic_narrative":"BEX1 is a small intrinsically disordered adaptor protein that operates as a context-dependent signaling modulator across neuronal differentiation, apoptosis, innate immunity, ciliogenesis, and cancer stem-cell biology [PMID:16498402, PMID:24626299, PMID:29192139, PMID:35144600]. In the nervous system it binds the intracellular domain of the p75 neurotrophin receptor in competition with RIP2, and through this node it suppresses NGF-induced NF-κB activation, sustains proliferation, and restrains neuronal differentiation in a cell-cycle-coupled manner [PMID:16498402]. At the mitochondrion, BEX1 localizes via a defined internal segment and interacts with BCL-2 to disrupt anti-apoptotic BCL-2/BAX heterodimers, thereby promoting apoptosis [PMID:24626299]. As an intrinsically disordered protein, BEX1 forms biomolecular condensates, binds GTP, and facilitates tubulin polymerization at the basal body, an activity required for primary cilium formation, since its loss produces ciliopathy phenotypes in mice [PMID:35144600]. In cardiomyocytes BEX1 associates with a large ribonucleoprotein complex to stabilize AU-rich-element-containing proinflammatory mRNAs and to control IFN-β-mediated antiviral defense, where it limits replication of multiple viruses but worsens stress-induced heart failure [PMID:29192139, PMID:35192678]. In liver cancer BEX1 suppresses PPARγ to drive a PDK1-dependent Warburg effect and progenitor expansion, and binds RUNX3 to relieve β-catenin repression and activate Wnt/β-catenin-dependent stemness [PMID:29907129, PMID:34217777, PMID:37715024]. BEX1 expression is repressed by promoter DNA methylation, including DNMT1- and EZH2/LINC00630-mediated silencing, linking its loss to tumor suppression in several contexts [PMID:16818640, PMID:32119177, PMID:34217777].","teleology":[{"year":2006,"claim":"Established BEX1's first molecular function by placing it at the p75 neurotrophin receptor, defining how it gates neuronal differentiation versus proliferation.","evidence":"Interactor screening, competition binding with RIP2, and gain/loss-of-function with NF-κB reporters in PC12 cells","pmids":["16498402"],"confidence":"Medium","gaps":["Binding site on the p75NTR intracellular domain not mapped","Mechanism by which RIP2 competition feeds NF-κB output not resolved at molecular detail"]},{"year":2006,"claim":"Connected BEX1 silencing to tumor biology, showing epigenetic loss of BEX1 contributes to malignancy and chemoresistance.","evidence":"Viral re-expression, chemotherapy apoptosis assays, xenografts, and pharmacological demethylation/HDAC unmasking in glioma","pmids":["16818640"],"confidence":"Medium","gaps":["Direct molecular effectors downstream of BEX1 in glioma not defined here","Relationship between tumor-suppressor role and p75NTR signaling not addressed"]},{"year":2007,"claim":"Extended BEX1 function beyond neurons by linking it to calcium signaling and tissue regeneration kinetics.","evidence":"Calcium-dependent calmodulin binding assay and Bex1 KO mouse skeletal muscle regeneration phenotyping","pmids":["17884015"],"confidence":"Medium","gaps":["Functional consequence of calmodulin binding for BEX1 activity unclear","Link between CaM interaction and the regeneration phenotype not established"]},{"year":2010,"claim":"Demonstrated a pro-regenerative role in peripheral nerve by showing BEX1 antagonizes myelin-derived growth inhibition.","evidence":"Sciatic nerve injury in Bex1 KO mice and MAG-mediated axon outgrowth inhibition assays","pmids":["20731761"],"confidence":"Medium","gaps":["Molecular target through which BEX1 antagonizes MAG signaling not identified","Relation to its p75NTR interaction not tested"]},{"year":2014,"claim":"Defined a mitochondrial apoptotic function, showing BEX1 acts on the BCL-2/BAX rheostat.","evidence":"Yeast two-hybrid, reciprocal Co-IP, mitochondrial-targeting deletion mutagenesis, and imatinib apoptosis assays","pmids":["24626299"],"confidence":"High","gaps":["Structural basis of BEX1–BCL-2 binding not solved","Whether BEX1 directly competes for the BAX-binding interface not shown"]},{"year":2015,"claim":"Showed cell-type-specific signaling effects, with BEX1 suppressing FLT3-ITD-driven proliferation selectively through AKT.","evidence":"Overexpression in pro-B/myeloid cells, colony/xenograft assays, fractionation, and phospho-specific blotting","pmids":["26046670"],"confidence":"Medium","gaps":["Mechanism by which cytosolic BEX1 dampens AKT phosphorylation unknown","Direct binding partner in this context not identified"]},{"year":2015,"claim":"Identified a developmental role in myoblast fusion accompanied by regulated cytoplasm-to-nucleus translocation.","evidence":"Immunofluorescence localization plus overexpression and KO myoblast fusion assays","pmids":["26586200"],"confidence":"Medium","gaps":["Signal driving nuclear translocation not defined","Molecular mediators of the fusion phenotype unidentified"]},{"year":2017,"claim":"Revealed an RNA-regulatory function, placing BEX1 in a ribonucleoprotein complex that stabilizes proinflammatory ARE mRNAs in the failing heart.","evidence":"Proteomic complex identification, mRNA stability assays, and reciprocal cardiac transgenic and gene-deleted mouse models under stress","pmids":["29192139"],"confidence":"High","gaps":["Direct RNA-binding vs adaptor role within the RNP not distinguished","Other components of the BEX1-associated RNP not fully enumerated"]},{"year":2018,"claim":"Established a metabolic/progenitor role through PPARγ suppression driving liver progenitor cell expansion.","evidence":"Bex1 KO mice on CDE diet, PPARγ-silencing epistasis, and LPC proliferation/apoptosis assays","pmids":["29907129"],"confidence":"Medium","gaps":["Mechanism linking BEX1 to PPARγ repression not molecularly defined","Whether suppression is transcriptional or post-translational unknown"]},{"year":2020,"claim":"Clarified an epigenetic silencing route, showing EZH2/LINC00630 represses BEX1 to confer radioresistance.","evidence":"RIP, ChIP, shRNA knockdown, and viability/apoptosis rescue by BEX1 silencing in irradiated colorectal cancer cells","pmids":["32119177"],"confidence":"Medium","gaps":["Direct BEX1 effectors mediating radiosensitivity not identified","Context-specificity of this silencing axis untested across tumor types"]},{"year":2021,"claim":"Connected BEX1 to Wnt/β-catenin-driven cancer stemness via RUNX3, and tied its expression to DNMT1 methylation in liver cancer.","evidence":"Co-IP, sphere formation, Wnt reporter assays, xenografts, and DNMT1 inhibitor treatment","pmids":["34217777"],"confidence":"Medium","gaps":["RUNX3-binding interface on BEX1 not mapped","How BEX1 relieves RUNX3 repression of β-catenin mechanistically unresolved"]},{"year":2021,"claim":"Proposed a cytoskeletal/mechanotransduction role in glioma radioresistance through actin polymerization and YAP/TAZ.","evidence":"Transcriptomics, orthotopic xenografts, actin polymerization and YAP/TAZ assays with latrunculin B","pmids":["34576008"],"confidence":"Low","gaps":["BEX1-specific contribution not separated from BEX4","Direct effect of BEX1 on actin dynamics not biochemically isolated"]},{"year":2022,"claim":"Defined BEX1 as an intrinsically disordered, condensate-forming, GTP-binding protein essential for primary ciliogenesis.","evidence":"Biophysical IDP characterization, condensate imaging, GTP-binding and in vitro tubulin polymerization reconstitution, and Bex1 KO ciliopathy phenotyping","pmids":["35144600"],"confidence":"High","gaps":["Structural determinants of GTP binding not defined","How condensate formation couples to tubulin polymerization mechanistically unclear"]},{"year":2022,"claim":"Established BEX1 as an antiviral and IFN-β regulator in cardiomyocytes, integrating its RNP function with innate immune defense.","evidence":"Reciprocal transgenic/KO mice, CVB3 infection, viral load and IFN-β measurement, and replication across influenza A and Sendai virus in isolated cells","pmids":["35192678"],"confidence":"High","gaps":["Direct molecular link between BEX1 and IFN-β induction not defined","Whether antiviral effect depends on the ARE-mRNA-stabilizing RNP role untested"]},{"year":2023,"claim":"Resolved the metabolic mechanism in hepatoblastoma, ordering BEX1→PPARγ suppression→PDK1→Warburg effect→stemness.","evidence":"Seahorse flux analysis, LC-MS metabolomics, sphere/xenograft assays, and PPARγ agonist treatment","pmids":["37715024"],"confidence":"Medium","gaps":["Direct molecular mechanism of PPARγ downregulation by BEX1 still undefined","Generalizability beyond hepatoblastoma untested"]},{"year":2025,"claim":"Linked BEX1 promoter methylation in glioma to AKT/ERK/STAT3 signaling control of cell cycle and apoptosis.","evidence":"Western blot, qRT-PCR, transfection, and AKT/ERK/STAT3 inhibitors with cell cycle/apoptosis assays","pmids":["40804095"],"confidence":"Low","gaps":["No in vivo confirmation reported","Direct effectors connecting BEX1 to the three kinase cascades not identified"]},{"year":null,"claim":"It remains unresolved how a single small disordered protein selects among its many reported partners (p75NTR, BCL-2, calmodulin, RUNX3, tubulin, the cardiac RNP) in a given cellular context, and whether condensate formation is the common organizing principle linking these activities.","evidence":"No reconciling study in the available corpus","pmids":[],"confidence":"Low","gaps":["No structural model of partner discrimination","No unifying biochemical mechanism connecting the distinct functional nodes"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[0,6,12]},{"term_id":"GO:0003723","term_label":"RNA binding","supporting_discovery_ids":[9]},{"term_id":"GO:0008092","term_label":"cytoskeletal protein binding","supporting_discovery_ids":[14]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[0,6]}],"localization":[{"term_id":"GO:0005739","term_label":"mitochondrion","supporting_discovery_ids":[6]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[7]},{"term_id":"GO:0005730","term_label":"nucleolus","supporting_discovery_ids":[14]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[8]},{"term_id":"GO:0005815","term_label":"microtubule organizing center","supporting_discovery_ids":[14]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[0,1,12]},{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[6]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[9,15]},{"term_id":"R-HSA-8953854","term_label":"Metabolism of RNA","supporting_discovery_ids":[9]},{"term_id":"R-HSA-1852241","term_label":"Organelle biogenesis and maintenance","supporting_discovery_ids":[14]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[2,12]}],"complexes":["heart failure-induced ribonucleoprotein processing complex"],"partners":["P75NTR","RIP2","BCL-2","CALMODULIN","RUNX3"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9HBH7","full_name":"Protein BEX1","aliases":["Brain-expressed X-linked protein 1"],"length_aa":125,"mass_kda":14.9,"function":"Signaling adapter molecule involved in p75NTR/NGFR signaling. Plays a role in cell cycle progression and neuronal differentiation. Inhibits neuronal differentiation in response to nerve growth factor (NGF). May act as a link between the cell cycle and neurotrophic factor signaling, possibly by functioning as an upstream modulator of receptor signaling, coordinating biological responses to external signals with internal cellular states (By similarity). In absence of reductive stress, acts as a pseudosubstrate for the CRL2(FEM1B) complex: associates with FEM1B via zinc, thereby preventing association between FEM1B and its substrates (By similarity)","subcellular_location":"Nucleus; Cytoplasm","url":"https://www.uniprot.org/uniprotkb/Q9HBH7/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/BEX1","classification":"Not Classified","n_dependent_lines":1,"n_total_lines":1208,"dependency_fraction":0.0008278145695364238},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/BEX1","total_profiled":1310},"omim":[{"mim_id":"300693","title":"BEX FAMILY MEMBER 5; BEX5","url":"https://www.omim.org/entry/300693"},{"mim_id":"300691","title":"BRAIN-EXPRESSED X-LINKED GENE 2; BEX2","url":"https://www.omim.org/entry/300691"},{"mim_id":"300690","title":"BRAIN-EXPRESSED X-LINKED GENE 1; BEX1","url":"https://www.omim.org/entry/300690"},{"mim_id":"180385","title":"LIM DOMAIN ONLY 2; LMO2","url":"https://www.omim.org/entry/180385"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Cytosol","reliability":"Approved"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"brain","ntpm":602.9},{"tissue":"pituitary gland","ntpm":418.3}],"url":"https://www.proteinatlas.org/search/BEX1"},"hgnc":{"alias_symbol":[],"prev_symbol":[]},"alphafold":{"accession":"Q9HBH7","domains":[{"cath_id":"1.20.5","chopping":"81-106","consensus_level":"medium","plddt":85.3185,"start":81,"end":106}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9HBH7","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9HBH7-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9HBH7-F1-predicted_aligned_error_v6.png","plddt_mean":67.5},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=BEX1","jax_strain_url":"https://www.jax.org/strain/search?query=BEX1"},"sequence":{"accession":"Q9HBH7","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9HBH7.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9HBH7/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9HBH7"}},"corpus_meta":[{"pmid":"16818640","id":"PMC_16818640","title":"Genome-wide analysis of epigenetic silencing identifies BEX1 and BEX2 as candidate tumor suppressor genes in malignant glioma.","date":"2006","source":"Cancer research","url":"https://pubmed.ncbi.nlm.nih.gov/16818640","citation_count":133,"is_preprint":false},{"pmid":"34217777","id":"PMC_34217777","title":"DNMT1-mediated methylation of BEX1 regulates stemness and tumorigenicity in liver cancer.","date":"2021","source":"Journal of hepatology","url":"https://pubmed.ncbi.nlm.nih.gov/34217777","citation_count":123,"is_preprint":false},{"pmid":"16498402","id":"PMC_16498402","title":"Bex1, a novel interactor of the p75 neurotrophin receptor, links neurotrophin signaling to the cell cycle.","date":"2006","source":"The EMBO journal","url":"https://pubmed.ncbi.nlm.nih.gov/16498402","citation_count":92,"is_preprint":false},{"pmid":"23362108","id":"PMC_23362108","title":"Epigenetic regulation of the X-linked tumour suppressors BEX1 and LDOC1 in oral squamous cell carcinoma.","date":"2013","source":"The Journal of pathology","url":"https://pubmed.ncbi.nlm.nih.gov/23362108","citation_count":79,"is_preprint":false},{"pmid":"10072429","id":"PMC_10072429","title":"Bex1, a gene with increased expression in parthenogenetic embryos, is a member of a novel gene family on the mouse X chromosome.","date":"1999","source":"Human molecular genetics","url":"https://pubmed.ncbi.nlm.nih.gov/10072429","citation_count":54,"is_preprint":false},{"pmid":"23203637","id":"PMC_23203637","title":"SERPINA6, BEX1, AGTR1, SLC26A3, and LAPTM4B are markers of resistance to neoadjuvant chemotherapy in HER2-negative breast cancer.","date":"2012","source":"Breast cancer research and treatment","url":"https://pubmed.ncbi.nlm.nih.gov/23203637","citation_count":52,"is_preprint":false},{"pmid":"11989783","id":"PMC_11989783","title":"Cloning and expression pattern of a spermatogenesis-related gene, BEX1, mapped to chromosome Xq22.","date":"2002","source":"Biochemical genetics","url":"https://pubmed.ncbi.nlm.nih.gov/11989783","citation_count":33,"is_preprint":false},{"pmid":"20731761","id":"PMC_20731761","title":"Bex1 is involved in the regeneration of axons after injury.","date":"2010","source":"Journal of neurochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/20731761","citation_count":33,"is_preprint":false},{"pmid":"17884015","id":"PMC_17884015","title":"Bex1 knock out mice show altered skeletal muscle regeneration.","date":"2007","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/17884015","citation_count":32,"is_preprint":false},{"pmid":"29192139","id":"PMC_29192139","title":"BEX1 is an RNA-dependent mediator of cardiomyopathy.","date":"2017","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/29192139","citation_count":31,"is_preprint":false},{"pmid":"32119177","id":"PMC_32119177","title":"Long noncoding RNA LINC00630 promotes radio-resistance by regulating BEX1 gene methylation in colorectal cancer cells.","date":"2020","source":"IUBMB life","url":"https://pubmed.ncbi.nlm.nih.gov/32119177","citation_count":31,"is_preprint":false},{"pmid":"11835573","id":"PMC_11835573","title":"Trophectoderm-specific expression of the X-linked Bex1/Rex3 gene in preimplantation stage mouse embryos.","date":"2002","source":"Molecular reproduction and development","url":"https://pubmed.ncbi.nlm.nih.gov/11835573","citation_count":25,"is_preprint":false},{"pmid":"24626299","id":"PMC_24626299","title":"BEX1 promotes imatinib-induced apoptosis by binding to and antagonizing BCL-2.","date":"2014","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/24626299","citation_count":23,"is_preprint":false},{"pmid":"26046670","id":"PMC_26046670","title":"BEX1 acts as a tumor suppressor in acute myeloid leukemia.","date":"2015","source":"Oncotarget","url":"https://pubmed.ncbi.nlm.nih.gov/26046670","citation_count":23,"is_preprint":false},{"pmid":"24333734","id":"PMC_24333734","title":"Epigenetic genome-wide analysis identifies BEX1 as a candidate tumour suppressor gene in paediatric intracranial ependymoma.","date":"2013","source":"Cancer letters","url":"https://pubmed.ncbi.nlm.nih.gov/24333734","citation_count":22,"is_preprint":false},{"pmid":"34576008","id":"PMC_34576008","title":"BEX1 and BEX4 Induce GBM Progression through Regulation of Actin Polymerization and Activation of YAP/TAZ Signaling.","date":"2021","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/34576008","citation_count":19,"is_preprint":false},{"pmid":"37715024","id":"PMC_37715024","title":"BEX1 supports the stemness of hepatoblastoma by facilitating Warburg effect in a PPARγ/PDK1 dependent manner.","date":"2023","source":"British journal of cancer","url":"https://pubmed.ncbi.nlm.nih.gov/37715024","citation_count":14,"is_preprint":false},{"pmid":"33745298","id":"PMC_33745298","title":"BEX1 Is Differentially Expressed in Aldosterone-Producing Adenomas and Protects Human Adrenocortical Cells From Ferroptosis.","date":"2021","source":"Hypertension (Dallas, Tex. : 1979)","url":"https://pubmed.ncbi.nlm.nih.gov/33745298","citation_count":14,"is_preprint":false},{"pmid":"29907129","id":"PMC_29907129","title":"A pivotal role of BEX1 in liver progenitor cell expansion in mice.","date":"2018","source":"Stem cell research & therapy","url":"https://pubmed.ncbi.nlm.nih.gov/29907129","citation_count":12,"is_preprint":false},{"pmid":"26586200","id":"PMC_26586200","title":"The brain expressed x-linked gene 1 (Bex1) regulates myoblast fusion.","date":"2015","source":"Developmental biology","url":"https://pubmed.ncbi.nlm.nih.gov/26586200","citation_count":11,"is_preprint":false},{"pmid":"29572119","id":"PMC_29572119","title":"Bex1 attenuates neuronal apoptosis in rat intracerebral hemorrhage model.","date":"2018","source":"Pathology, research and practice","url":"https://pubmed.ncbi.nlm.nih.gov/29572119","citation_count":10,"is_preprint":false},{"pmid":"33133262","id":"PMC_33133262","title":"Bex1 significantly contributes to the proliferation and invasiveness of malignant tumor cells.","date":"2020","source":"Oncology letters","url":"https://pubmed.ncbi.nlm.nih.gov/33133262","citation_count":10,"is_preprint":false},{"pmid":"35144600","id":"PMC_35144600","title":"Bex1 is essential for ciliogenesis and harbours biomolecular condensate-forming capacity.","date":"2022","source":"BMC biology","url":"https://pubmed.ncbi.nlm.nih.gov/35144600","citation_count":8,"is_preprint":false},{"pmid":"37209973","id":"PMC_37209973","title":"BEX1 mediates sorafenib resistance in hepatocellular carcinoma by regulating AKT signaling.","date":"2023","source":"Cellular signalling","url":"https://pubmed.ncbi.nlm.nih.gov/37209973","citation_count":8,"is_preprint":false},{"pmid":"35192678","id":"PMC_35192678","title":"BEX1 is a critical determinant of viral myocarditis.","date":"2022","source":"PLoS pathogens","url":"https://pubmed.ncbi.nlm.nih.gov/35192678","citation_count":8,"is_preprint":false},{"pmid":"33613672","id":"PMC_33613672","title":"Long Noncoding RNA LINC00526 Represses Glioma Progression via Regulating miR-5581-3p/BEX1.","date":"2021","source":"Journal of oncology","url":"https://pubmed.ncbi.nlm.nih.gov/33613672","citation_count":6,"is_preprint":false},{"pmid":"40804095","id":"PMC_40804095","title":"Methylation-induced suppression of BEX1 activates AKT/ERK/STAT3 signaling pathways regulating cell cycle and apoptosis in glioma.","date":"2025","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/40804095","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":14468,"output_tokens":4556,"usd":0.055872,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":12690,"output_tokens":5033,"usd":0.094637,"stage2_stop_reason":"end_turn"},"total_usd":0.150509,"stage1_batch_id":"msgbatch_0179Z2pxRYBsXi2xADneafRw","stage2_batch_id":"msgbatch_01LaY9ZaVdgjWArcZo9eqQE5","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2006,\n      \"finding\": \"Bex1 was identified as a direct intracellular binding partner of the p75 neurotrophin receptor (p75NTR) via a screening for p75NTR interactors; Bex1 competed with RIP2 for binding to the p75NTR intracellular domain, and elevating RIP2 levels rescued differentiation in Bex1-overexpressing cells.\",\n      \"method\": \"Interactor screening, competition binding assay, epistasis by RIP2 overexpression\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — interaction screening confirmed by competition experiment, single lab, two orthogonal approaches\",\n      \"pmids\": [\"16498402\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"Bex1 levels oscillate during the cell cycle; ectopic Bex1 in PC12 cells sustains proliferation under growth arrest conditions, inhibits NGF-induced neuronal differentiation, and inhibits NGF-induced NF-κB activation without affecting Erk1/2 or AKT. Bex1 knockdown accelerates neuronal differentiation and potentiates NF-κB activity in response to NGF.\",\n      \"method\": \"Overexpression and siRNA knockdown in PC12 cells; cell proliferation, differentiation, and NF-κB reporter assays; subventricular zone precursor differentiation assay\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss- and gain-of-function with multiple readouts, single lab\",\n      \"pmids\": [\"16498402\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"Viral re-expression of BEX1 in glioma cell lines increased sensitivity to chemotherapy-induced apoptosis and suppressed tumor growth in vitro and in a xenograft mouse model, establishing BEX1 as a functional tumor suppressor whose expression is silenced by promoter hypermethylation and histone deacetylation.\",\n      \"method\": \"Viral-mediated re-expression, chemotherapy apoptosis assay, xenograft mouse model; TSA/5-AzaC pharmacological unmasking + microarray\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — gain-of-function with in vitro and in vivo readouts, single lab\",\n      \"pmids\": [\"16818640\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"Bex1 interacts with calmodulin (CaM) in a calcium-dependent manner; Bex1 knockout mice show elevated and prolonged cell proliferation and delayed differentiation during skeletal muscle regeneration after cardiotoxin-induced myotrauma, and exhibit functional exercise performance deficits.\",\n      \"method\": \"Co-interaction assay (calcium-dependent binding), Bex1 knockout mouse generation, cardiotoxin myotrauma model, proliferation/differentiation assays\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — calcium-dependent binding plus KO phenotype with cellular readouts, single lab\",\n      \"pmids\": [\"17884015\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Bex1 protein is upregulated following peripheral axonal injury; Bex1 antagonizes myelin-associated glycoprotein-mediated inhibition of axon outgrowth; Bex1 knockout mice show reduced regenerative capacity after sciatic nerve injury compared to wild-type.\",\n      \"method\": \"In vivo nerve injury model, Bex1 KO mice, axon outgrowth inhibition assay with MAG\",\n      \"journal\": \"Journal of neurochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KO mouse with in vivo phenotype plus in vitro functional assay, single lab\",\n      \"pmids\": [\"20731761\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Restored expression of BEX1 in oral squamous cell carcinoma cells suppressed the NF-κB signaling pathway, associated with decreased p50 and p65 expression, and inhibited tumor growth in vitro and in vivo.\",\n      \"method\": \"Ectopic expression, NF-κB pathway assay (p50/p65 protein levels), in vitro and in vivo growth inhibition assays\",\n      \"journal\": \"The Journal of pathology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — gain-of-function with mechanistic pathway readout and in vivo validation, single lab\",\n      \"pmids\": [\"23362108\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"BEX1 was identified as a BCL-2-interacting protein by yeast two-hybrid screen and confirmed by co-immunoprecipitation; BEX1 localizes to the mitochondria (residues 33K–64Q required for localization); BEX1–BCL-2 interaction promotes imatinib-induced apoptosis by suppressing formation of anti-apoptotic BCL-2/BAX heterodimers.\",\n      \"method\": \"Yeast two-hybrid screen, co-immunoprecipitation, mitochondrial localization assay, deletion mutagenesis, apoptosis assay\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — yeast two-hybrid plus reciprocal Co-IP plus mutagenesis plus functional apoptosis readout, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"24626299\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"BEX1 overexpression in FLT3-ITD-driven mouse pro-B and myeloid cells decreased FLT3-ITD-dependent cell proliferation, colony and tumor formation, and increased apoptosis; BEX1 localizes to the cytosolic compartment and significantly decreased FLT3-ITD-induced AKT phosphorylation without affecting ERK1/2 or STAT5 phosphorylation.\",\n      \"method\": \"Overexpression in cell lines, colony/tumor formation assay, xenograft model, subcellular fractionation, phospho-specific western blotting\",\n      \"journal\": \"Oncotarget\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — gain-of-function with specific signaling readouts and in vivo tumor model, single lab\",\n      \"pmids\": [\"26046670\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Bex1 is transiently expressed in differentiating myoblasts and undergoes cytoplasm-to-nucleus translocation; overexpression of Bex1 promotes myoblast fusion without affecting differentiation or myogenin expression, while Bex1 knockout myoblasts exhibit fusion defects despite normal differentiation.\",\n      \"method\": \"Immunofluorescence localization, gain- and loss-of-function (overexpression and KO), myoblast fusion and differentiation assays\",\n      \"journal\": \"Developmental biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KO and overexpression with specific cellular phenotype and localization, single lab\",\n      \"pmids\": [\"26586200\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"BEX1 is a heart failure-induced mRNA-associated protein that forms part of a large ribonucleoprotein processing complex; BEX1 augments the stability and expression of AU-rich element (ARE)-containing proinflammatory mRNAs; cardiac-specific BEX1 transgenic mice show worse cardiac disease under stress, while Bex1 gene-deleted mice are protected from heart failure-promoting insults.\",\n      \"method\": \"Proteomic and interactive screening assays (ribonucleoprotein complex identification), mRNA stability assays, cardiac-specific transgenic and gene-deleted mouse models, stress stimulation paradigms\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal gain- and loss-of-function in vivo models, proteomic complex identification, mRNA stability assay, multiple orthogonal methods\",\n      \"pmids\": [\"29192139\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"BEX1 inhibits peroxisome proliferator-activated receptor gamma (PPARγ) to promote liver progenitor cell (LPC) expansion; Bex1-deficient mice on a CDE diet show impaired LPC expansion and liver regeneration; Bex1 deficiency inhibits LPC proliferation and enhances apoptosis in vitro.\",\n      \"method\": \"Bex1 KO mouse (CDE diet model), PPARγ silencing epistasis, immunofluorescence, proliferation/apoptosis assays in LPCs\",\n      \"journal\": \"Stem cell research & therapy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KO mouse in vivo phenotype plus epistasis via PPARγ silencing, single lab\",\n      \"pmids\": [\"29907129\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"LINC00630 in complex with EZH2 epigenetically represses BEX1 through promoter DNA methylation, increasing radioresistance; BEX1 silencing restores cell viability suppressed by LINC00630 knockdown in irradiated colorectal cancer cells.\",\n      \"method\": \"RNA immunoprecipitation, chromatin immunoprecipitation, shRNA knockdown, Western blot, cell viability/apoptosis assays\",\n      \"journal\": \"IUBMB life\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — RIP and ChIP confirm EZH2-LINC00630 complex at BEX1 promoter, functional rescue by BEX1 silencing, single lab\",\n      \"pmids\": [\"32119177\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"BEX1 interacts with RUNX3 to block RUNX3-mediated inhibition of β-catenin transcription, thereby activating Wnt/β-catenin signaling and maintaining stemness in hepatoblastoma and CSC-HCC; DNMT1-mediated methylation of the BEX1 promoter determines differential BEX1 expression patterns across liver cancer subtypes.\",\n      \"method\": \"Co-immunoprecipitation, sphere formation assay, xenograft model, western blotting, DNMT1 inhibitor treatment, Wnt/β-catenin pathway reporter assays\",\n      \"journal\": \"Journal of hepatology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP for BEX1-RUNX3 interaction plus functional pathway and in vivo validation, single lab\",\n      \"pmids\": [\"34217777\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"BEX1 and BEX4 upregulation in GBM cells post-radiotherapy promotes actin polymerization and cytoskeletal reorganization, leading to activation of the YAP/TAZ mechanotransduction signaling pathway, which enhances tumor formation, growth, and radioresistance; latrunculin B (actin polymerization inhibitor) suppresses this GBM progression.\",\n      \"method\": \"Transcriptomic analysis, orthotopic xenograft model, actin polymerization assays, YAP/TAZ pathway assays, pharmacological inhibition\",\n      \"journal\": \"International journal of molecular sciences\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — functional assays in vivo but BEX1-specific mechanistic contribution not fully separated from BEX4; single lab, single study\",\n      \"pmids\": [\"34576008\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Bex1 is an intrinsically disordered protein (IDP) that forms biomolecular condensates; it accumulates in nucleoli at low cell density and at the apical cell surface/basal body at high cell density; Bex1 binds GTP and facilitates tubulin polymerization in a reconstituted system; Bex1 KO mice exhibit ciliopathy phenotypes with ciliary defects in retina and striatum, demonstrating an essential role in primary cilia formation.\",\n      \"method\": \"Biophysical characterization (IDP), live-cell imaging/fractionation for condensate localization, GTP-binding assay, in vitro tubulin polymerization reconstitution, Bex1 KO mouse phenotyping\",\n      \"journal\": \"BMC biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro reconstitution of tubulin polymerization, GTP binding assay, KO mouse phenotype with defined ciliopathy readouts, multiple orthogonal methods in single study\",\n      \"pmids\": [\"35144600\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"BEX1 limits viral replication in cardiomyocytes and regulates interferon beta (IFN-β) expression in infected cells; BEX1 absence impairs inflammatory immune cell recruitment to the heart and accelerates CVB3-driven heart failure; BEX1 antiviral function extends to Influenza A and Sendai virus in isolated cells.\",\n      \"method\": \"Genetic gain- and loss-of-function (transgenic and KO mice), CVB3 infection model, viral load quantification, immune cell recruitment assays, IFN-β expression measurement, isolated primary cardiomyocyte and MEF experiments\",\n      \"journal\": \"PLoS pathogens\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal gain/loss-of-function in vivo, multiple virus types, IFN-β mechanistic link, replicated across cell types\",\n      \"pmids\": [\"35192678\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"BEX1 promotes the Warburg effect in hepatoblastoma cells through downregulation of PPARγ; PDK1 is required downstream of PPARγ for BEX1-mediated enhancement of glycolysis; glycolysis inhibition attenuates BEX1-driven stemness and cell growth, placing BEX1 in a BEX1→PPARγ suppression→PDK1→Warburg effect→stemness axis.\",\n      \"method\": \"Seahorse extracellular flux analysis, LC-MS metabolomics, Western blot, sphere formation assay, xenograft tumor formation assay, PPARγ agonist (pioglitazone) treatment\",\n      \"journal\": \"British journal of cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple metabolic and functional assays establishing pathway order, single lab\",\n      \"pmids\": [\"37715024\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"BEX1 promoter methylation in glioma activates AKT/ERK/STAT3 signaling cascades, altering cell cycle regulation and apoptosis; re-expression of BEX1 in glioma cell lines reverses these signaling changes.\",\n      \"method\": \"Western blot, qRT-PCR, gene transfection, small molecule inhibitors of AKT/ERK/STAT3, functional cell cycle and apoptosis assays\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, limited methodological detail in abstract, no in vivo confirmation reported\",\n      \"pmids\": [\"40804095\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"BEX1 is a small intrinsically disordered adaptor/scaffold protein that operates at multiple signaling nodes: it binds the p75 neurotrophin receptor intracellular domain (competing with RIP2) to suppress NF-κB and modulate cell-cycle-linked neuronal differentiation; it localizes to mitochondria where it interacts with BCL-2 to disrupt BCL-2/BAX anti-apoptotic heterodimers; it associates with large ribonucleoprotein complexes in cardiomyocytes to stabilize AU-rich-element-containing proinflammatory mRNAs and regulate IFN-β-mediated antiviral responses; it binds GTP and forms biomolecular condensates at the basal body to facilitate tubulin polymerization and primary ciliogenesis; it suppresses PPARγ to promote liver progenitor cell expansion and the Warburg effect in hepatoblastoma; and it interacts with RUNX3 to relieve β-catenin repression and activate Wnt/β-catenin-dependent cancer stem cell self-renewal, with its expression tightly regulated by DNMT1-mediated promoter methylation across multiple tissue contexts.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"BEX1 is a small intrinsically disordered adaptor protein that operates as a context-dependent signaling modulator across neuronal differentiation, apoptosis, innate immunity, ciliogenesis, and cancer stem-cell biology [#0, #6, #9, #14]. In the nervous system it binds the intracellular domain of the p75 neurotrophin receptor in competition with RIP2, and through this node it suppresses NGF-induced NF-\\u03baB activation, sustains proliferation, and restrains neuronal differentiation in a cell-cycle-coupled manner [#0, #1]. At the mitochondrion, BEX1 localizes via a defined internal segment and interacts with BCL-2 to disrupt anti-apoptotic BCL-2/BAX heterodimers, thereby promoting apoptosis [#6]. As an intrinsically disordered protein, BEX1 forms biomolecular condensates, binds GTP, and facilitates tubulin polymerization at the basal body, an activity required for primary cilium formation, since its loss produces ciliopathy phenotypes in mice [#14]. In cardiomyocytes BEX1 associates with a large ribonucleoprotein complex to stabilize AU-rich-element-containing proinflammatory mRNAs and to control IFN-\\u03b2-mediated antiviral defense, where it limits replication of multiple viruses but worsens stress-induced heart failure [#9, #15]. In liver cancer BEX1 suppresses PPAR\\u03b3 to drive a PDK1-dependent Warburg effect and progenitor expansion, and binds RUNX3 to relieve \\u03b2-catenin repression and activate Wnt/\\u03b2-catenin-dependent stemness [#10, #12, #16]. BEX1 expression is repressed by promoter DNA methylation, including DNMT1- and EZH2/LINC00630-mediated silencing, linking its loss to tumor suppression in several contexts [#2, #11, #12].\",\n  \"teleology\": [\n    {\n      \"year\": 2006,\n      \"claim\": \"Established BEX1's first molecular function by placing it at the p75 neurotrophin receptor, defining how it gates neuronal differentiation versus proliferation.\",\n      \"evidence\": \"Interactor screening, competition binding with RIP2, and gain/loss-of-function with NF-\\u03baB reporters in PC12 cells\",\n      \"pmids\": [\"16498402\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Binding site on the p75NTR intracellular domain not mapped\", \"Mechanism by which RIP2 competition feeds NF-\\u03baB output not resolved at molecular detail\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Connected BEX1 silencing to tumor biology, showing epigenetic loss of BEX1 contributes to malignancy and chemoresistance.\",\n      \"evidence\": \"Viral re-expression, chemotherapy apoptosis assays, xenografts, and pharmacological demethylation/HDAC unmasking in glioma\",\n      \"pmids\": [\"16818640\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct molecular effectors downstream of BEX1 in glioma not defined here\", \"Relationship between tumor-suppressor role and p75NTR signaling not addressed\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Extended BEX1 function beyond neurons by linking it to calcium signaling and tissue regeneration kinetics.\",\n      \"evidence\": \"Calcium-dependent calmodulin binding assay and Bex1 KO mouse skeletal muscle regeneration phenotyping\",\n      \"pmids\": [\"17884015\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional consequence of calmodulin binding for BEX1 activity unclear\", \"Link between CaM interaction and the regeneration phenotype not established\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Demonstrated a pro-regenerative role in peripheral nerve by showing BEX1 antagonizes myelin-derived growth inhibition.\",\n      \"evidence\": \"Sciatic nerve injury in Bex1 KO mice and MAG-mediated axon outgrowth inhibition assays\",\n      \"pmids\": [\"20731761\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular target through which BEX1 antagonizes MAG signaling not identified\", \"Relation to its p75NTR interaction not tested\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Defined a mitochondrial apoptotic function, showing BEX1 acts on the BCL-2/BAX rheostat.\",\n      \"evidence\": \"Yeast two-hybrid, reciprocal Co-IP, mitochondrial-targeting deletion mutagenesis, and imatinib apoptosis assays\",\n      \"pmids\": [\"24626299\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of BEX1\\u2013BCL-2 binding not solved\", \"Whether BEX1 directly competes for the BAX-binding interface not shown\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Showed cell-type-specific signaling effects, with BEX1 suppressing FLT3-ITD-driven proliferation selectively through AKT.\",\n      \"evidence\": \"Overexpression in pro-B/myeloid cells, colony/xenograft assays, fractionation, and phospho-specific blotting\",\n      \"pmids\": [\"26046670\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism by which cytosolic BEX1 dampens AKT phosphorylation unknown\", \"Direct binding partner in this context not identified\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Identified a developmental role in myoblast fusion accompanied by regulated cytoplasm-to-nucleus translocation.\",\n      \"evidence\": \"Immunofluorescence localization plus overexpression and KO myoblast fusion assays\",\n      \"pmids\": [\"26586200\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Signal driving nuclear translocation not defined\", \"Molecular mediators of the fusion phenotype unidentified\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Revealed an RNA-regulatory function, placing BEX1 in a ribonucleoprotein complex that stabilizes proinflammatory ARE mRNAs in the failing heart.\",\n      \"evidence\": \"Proteomic complex identification, mRNA stability assays, and reciprocal cardiac transgenic and gene-deleted mouse models under stress\",\n      \"pmids\": [\"29192139\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct RNA-binding vs adaptor role within the RNP not distinguished\", \"Other components of the BEX1-associated RNP not fully enumerated\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Established a metabolic/progenitor role through PPAR\\u03b3 suppression driving liver progenitor cell expansion.\",\n      \"evidence\": \"Bex1 KO mice on CDE diet, PPAR\\u03b3-silencing epistasis, and LPC proliferation/apoptosis assays\",\n      \"pmids\": [\"29907129\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism linking BEX1 to PPAR\\u03b3 repression not molecularly defined\", \"Whether suppression is transcriptional or post-translational unknown\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Clarified an epigenetic silencing route, showing EZH2/LINC00630 represses BEX1 to confer radioresistance.\",\n      \"evidence\": \"RIP, ChIP, shRNA knockdown, and viability/apoptosis rescue by BEX1 silencing in irradiated colorectal cancer cells\",\n      \"pmids\": [\"32119177\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct BEX1 effectors mediating radiosensitivity not identified\", \"Context-specificity of this silencing axis untested across tumor types\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Connected BEX1 to Wnt/\\u03b2-catenin-driven cancer stemness via RUNX3, and tied its expression to DNMT1 methylation in liver cancer.\",\n      \"evidence\": \"Co-IP, sphere formation, Wnt reporter assays, xenografts, and DNMT1 inhibitor treatment\",\n      \"pmids\": [\"34217777\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"RUNX3-binding interface on BEX1 not mapped\", \"How BEX1 relieves RUNX3 repression of \\u03b2-catenin mechanistically unresolved\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Proposed a cytoskeletal/mechanotransduction role in glioma radioresistance through actin polymerization and YAP/TAZ.\",\n      \"evidence\": \"Transcriptomics, orthotopic xenografts, actin polymerization and YAP/TAZ assays with latrunculin B\",\n      \"pmids\": [\"34576008\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"BEX1-specific contribution not separated from BEX4\", \"Direct effect of BEX1 on actin dynamics not biochemically isolated\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Defined BEX1 as an intrinsically disordered, condensate-forming, GTP-binding protein essential for primary ciliogenesis.\",\n      \"evidence\": \"Biophysical IDP characterization, condensate imaging, GTP-binding and in vitro tubulin polymerization reconstitution, and Bex1 KO ciliopathy phenotyping\",\n      \"pmids\": [\"35144600\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural determinants of GTP binding not defined\", \"How condensate formation couples to tubulin polymerization mechanistically unclear\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Established BEX1 as an antiviral and IFN-\\u03b2 regulator in cardiomyocytes, integrating its RNP function with innate immune defense.\",\n      \"evidence\": \"Reciprocal transgenic/KO mice, CVB3 infection, viral load and IFN-\\u03b2 measurement, and replication across influenza A and Sendai virus in isolated cells\",\n      \"pmids\": [\"35192678\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct molecular link between BEX1 and IFN-\\u03b2 induction not defined\", \"Whether antiviral effect depends on the ARE-mRNA-stabilizing RNP role untested\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Resolved the metabolic mechanism in hepatoblastoma, ordering BEX1\\u2192PPAR\\u03b3 suppression\\u2192PDK1\\u2192Warburg effect\\u2192stemness.\",\n      \"evidence\": \"Seahorse flux analysis, LC-MS metabolomics, sphere/xenograft assays, and PPAR\\u03b3 agonist treatment\",\n      \"pmids\": [\"37715024\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct molecular mechanism of PPAR\\u03b3 downregulation by BEX1 still undefined\", \"Generalizability beyond hepatoblastoma untested\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Linked BEX1 promoter methylation in glioma to AKT/ERK/STAT3 signaling control of cell cycle and apoptosis.\",\n      \"evidence\": \"Western blot, qRT-PCR, transfection, and AKT/ERK/STAT3 inhibitors with cell cycle/apoptosis assays\",\n      \"pmids\": [\"40804095\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No in vivo confirmation reported\", \"Direct effectors connecting BEX1 to the three kinase cascades not identified\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"It remains unresolved how a single small disordered protein selects among its many reported partners (p75NTR, BCL-2, calmodulin, RUNX3, tubulin, the cardiac RNP) in a given cellular context, and whether condensate formation is the common organizing principle linking these activities.\",\n      \"evidence\": \"No reconciling study in the available corpus\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No structural model of partner discrimination\", \"No unifying biochemical mechanism connecting the distinct functional nodes\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [0, 6, 12]},\n      {\"term_id\": \"GO:0003723\", \"supporting_discovery_ids\": [9]},\n      {\"term_id\": \"GO:0008092\", \"supporting_discovery_ids\": [14]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [0, 6]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005739\", \"supporting_discovery_ids\": [6]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [7]},\n      {\"term_id\": \"GO:0005730\", \"supporting_discovery_ids\": [14]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [8]},\n      {\"term_id\": \"GO:0005815\", \"supporting_discovery_ids\": [14]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0, 1, 12]},\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [6]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [9, 15]},\n      {\"term_id\": \"R-HSA-8953854\", \"supporting_discovery_ids\": [9]},\n      {\"term_id\": \"R-HSA-1852241\", \"supporting_discovery_ids\": [14]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [2, 12]}\n    ],\n    \"complexes\": [\n      \"heart failure-induced ribonucleoprotein processing complex\"\n    ],\n    \"partners\": [\n      \"p75NTR\",\n      \"RIP2\",\n      \"BCL-2\",\n      \"calmodulin\",\n      \"RUNX3\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}