{"gene":"BEX2","run_date":"2026-06-09T22:02:44","timeline":{"discoveries":[{"year":2005,"finding":"BEX2 physically interacts with LMO2 (a LIM-domain transcription factor), confirmed by GST pull-down and co-immunoprecipitation. BEX2 and LMO2 form part of a DNA-binding protein complex (shown by EMSA) that also includes NSCL2 and LDB1, and BEX2 enhances the transcriptional activity of LMO2 and augments LMO2-induced NSCL2-dependent transcriptional activity in vivo.","method":"GST pull-down, co-immunoprecipitation, EMSA, luciferase reporter assay, mammalian two-hybrid","journal":"Nucleic acids research","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — multiple orthogonal methods (pull-down, Co-IP, EMSA, reporter assay) in a single focused study","pmids":["16314316"],"is_preprint":false},{"year":2006,"finding":"BEX2 promoter is hypermethylated and transcriptionally silenced in malignant glioma. Viral re-expression of BEX2 increases sensitivity to chemotherapy-induced apoptosis and exerts tumor suppressor effects in vitro and in a xenograft mouse model.","method":"5-AzaC/TSA pharmacologic reversal, microarray, promoter methylation analysis, viral transduction, xenograft model","journal":"Cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (epigenetic reactivation, promoter methylation, viral re-expression, in vivo xenograft) in one study","pmids":["16818640"],"is_preprint":false},{"year":2007,"finding":"BEX2 expression is necessary and sufficient for NGF-mediated inhibition of ceramide-induced apoptosis through NF-κB activation in breast cancer cells. BEX2 also modulates apoptosis in response to estradiol and tamoxifen, defining a NGF/BEX2/NF-κB pathway.","method":"siRNA knockdown, BEX2 overexpression, NF-κB reporter assay, apoptosis assay","journal":"Cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss- and gain-of-function with defined pathway readout, single lab","pmids":["17638883"],"is_preprint":false},{"year":2009,"finding":"BEX2 expression (hypomethylated) is characteristic of MLL-translocation AML cell lines; demethylating agents and HDAC inhibitors restore BEX2 expression in MLLwt cells. Bex2 mRNA in MLL-ENL transgenic mouse cell lines requires expression of the MLL fusion gene, placing BEX2 downstream of MLL fusion proteins.","method":"MS-MLPA methylation analysis, demethylating agent treatment, transgenic mouse cell lines","journal":"Molecular cancer","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (methylation assay, pharmacologic reactivation, transgenic model) establishing genetic epistasis","pmids":["19835597"],"is_preprint":false},{"year":2010,"finding":"BEX2 downregulation induces mitochondrial apoptosis and sensitizes breast cancer cells to ceramide, doxorubicin, and staurosporine. BEX2 overexpression protects against mitochondrial apoptosis. This effect is mediated through positive regulation of Bcl-2 and negative regulation of BAD, BAK1, and PUMA. BEX2 expression is also required for normal G1 cell cycle progression through regulation of cyclin D1 and p21. BEX2 downregulation increases protein phosphatase 2A (PP2A) expression and activity.","method":"siRNA knockdown, BEX2 overexpression, apoptosis assay, Western blot for Bcl-2 family members, cell cycle analysis, PP2A activity assay","journal":"International journal of cancer","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal loss/gain of function with multiple pathway readouts, single lab","pmids":["19711341"],"is_preprint":false},{"year":2010,"finding":"c-Jun and p65/RelA directly bind and transcriptionally activate the BEX2 promoter in breast cancer cells. In turn, BEX2 is required for normal phosphorylation of p65 and IκBα (NF-κB activation), for phosphorylation of c-Jun, and for JNK kinase activity, establishing a feedback loop. BEX2 is also required for c-Jun-mediated cyclin D1 induction and cell proliferation. BEX2 downregulation increases PP2A activity in c-Jun stable lines.","method":"Luciferase reporter assay, chromatin immunoprecipitation (ChIP), Western blot, c-Jun stable lines, PP2A activity assay","journal":"Molecular cancer","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP confirms direct binding, reporter assay, multiple pathway readouts, single lab","pmids":["20482821"],"is_preprint":false},{"year":2011,"finding":"ErbB2 overexpression induces c-Jun and BEX2 expression; ErbB2-mediated BEX2 induction is abrogated by a dominant-negative c-Jun mutant. BEX2 overexpression in turn increases c-Jun-mediated ErbB2 induction and c-Jun binding to the ErbB2 promoter, establishing a positive feedback loop among ErbB2, c-Jun, and BEX2 in breast cancer cells.","method":"ErbB2 overexpression, dominant-negative c-Jun mutant, Western blot, ChIP, promoter assay","journal":"International journal of cancer","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — dominant-negative mutant and ChIP evidence for mechanism, single lab","pmids":["21384344"],"is_preprint":false},{"year":2012,"finding":"BEX2 downregulation inhibits glioma cell migration and invasion, associated with increased N-cadherin and decreased secretion of MMP-2; BEX2 overexpression promotes migration and invasion, placing BEX2 upstream of N-cadherin and MMP-2 in glioma.","method":"siRNA knockdown, overexpression, migration/invasion assays, Western blot, zymography","journal":"Journal of molecular neuroscience","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, phenotypic readouts with partial molecular follow-up, no reconstitution","pmids":["22907646"],"is_preprint":false},{"year":2012,"finding":"BEX2 downregulation promotes apoptosis and activates the JNK pathway in malignant glioma cells; the JNK-specific inhibitor SP600125 abolishes the pro-apoptotic effect of BEX2 knockdown, placing BEX2 upstream of JNK in glioma cell survival.","method":"siRNA knockdown, BEX2 overexpression, JNK inhibitor (SP600125), apoptosis assay","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — pharmacologic epistasis with inhibitor rescue confirms pathway placement, single lab","pmids":["23022184"],"is_preprint":false},{"year":2012,"finding":"BEX2 interacts with INI1/hSNF5 (a SWI/SNF chromatin remodeling complex component), confirmed by yeast two-hybrid and GST pull-down; truncated mutation analysis identified that two conserved reverse repeat sequences in INI1/hSNF5 are required for this interaction. Both proteins co-localize in the nucleus, and co-overexpression increases S-phase population, indicating BEX2 regulates cell cycle via INI1/hSNF5.","method":"Yeast two-hybrid, GST pull-down, truncated mutation analysis, subcellular localization, cell cycle analysis","journal":"Yi chuan = Hereditas","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple binding confirmation methods with truncation mapping and functional cell cycle readout, single lab","pmids":["22698742"],"is_preprint":false},{"year":2014,"finding":"BEX2 promotes proliferation of glioblastoma cells through NF-κB signaling: BEX2 downregulation decreases NF-κB p65 expression; BEX2 overexpression-induced proliferation is abolished by p65 downregulation. Critically, BEX2 with a nuclear localization signal deletion no longer promotes p65 expression, demonstrating that BEX2 nuclear localization is required for this function.","method":"siRNA knockdown, overexpression, nuclear localization signal deletion mutant, proliferation assay, Western blot","journal":"Journal of molecular neuroscience","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — deletion mutant establishes functional requirement for nuclear localization, epistasis via p65 co-knockdown, single lab","pmids":["24390962"],"is_preprint":false},{"year":2014,"finding":"BEX2 downregulation inhibits glioma cell migration and invasion by reducing β-catenin protein levels (nuclear and cytoplasmic, not membrane-associated); β-catenin overexpression rescues the migration/invasion defect caused by BEX2 knockdown, placing BEX2 upstream of β-catenin in glioma cell invasiveness.","method":"siRNA knockdown, β-catenin overexpression rescue, Western blot, migration/invasion assay","journal":"Biochemical and biophysical research communications","confidence":"Low","confidence_rationale":"Tier 3 / Weak — rescue experiment establishes epistasis but no direct interaction shown, single lab","pmids":["25490384"],"is_preprint":false},{"year":2017,"finding":"BEX2 promotes colorectal cancer cell proliferation via the JNK/c-Jun pathway: BEX2 knockdown inhibits JNK/c-Jun phosphorylation; BEX2 overexpression activates JNK/c-Jun phosphorylation; the JNK inhibitor SP600125 abolishes BEX2 overexpression-induced proliferation, establishing BEX2 as an upstream regulator of JNK/c-Jun signaling in colorectal cancer.","method":"siRNA knockdown, BEX2 overexpression, JNK inhibitor (SP600125) pharmacologic epistasis, phosphorylation Western blot, proliferation assay, xenograft model","journal":"International journal of biological sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — pharmacologic epistasis with inhibitor rescue plus in vivo validation, single lab","pmids":["28367093"],"is_preprint":false},{"year":2017,"finding":"BEX2 is required for isoflavone-induced autophagy in SH-SY5Y neuronal cells: BEX2 siRNA abolishes isoflavone-mediated LC3-II accumulation, p62 decrease, and neuroprotection against atrazine toxicity, placing BEX2 as a necessary mediator of autophagy induction in these cells.","method":"siRNA knockdown, Western blot (LC3-II, p62), autophagy inhibitor (3-MA), cell viability assay","journal":"Cellular physiology and biochemistry","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, knockdown phenotype without direct binding or reconstitution data","pmids":["29049987"],"is_preprint":false},{"year":2020,"finding":"BEX2 knockdown in cholangiocarcinoma decreases tumorigenicity and G0 phase fraction. Starvation induces USF2 transcription factor, which transcriptionally induces BEX2. BEX2 binding partners identified include E3 ubiquitin ligase complex proteins FEM1B and CUL2 and mitochondrial protein TUFM; knockdown of BEX2 or TUFM increases mitochondrial oxygen consumption rate and decreases tumorigenicity, indicating BEX2 suppresses mitochondrial activity through TUFM interaction.","method":"Comprehensive protein binding screen, co-immunoprecipitation, siRNA knockdown, oxygen consumption assay, xenograft model, cell cycle analysis","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple binding partners identified and functionally validated with parallel knockdowns, single lab","pmids":["33299012"],"is_preprint":false},{"year":2020,"finding":"BEX2 knockout in colorectal cancer cells activates the Hedgehog signaling pathway and promotes migration/metastasis; Hedgehog inhibitors (GANT61 and GDC-0449) rescue the migratory enhancement of BEX2-knockout cells. BEX2 negatively modulates Hedgehog signaling by retaining Zic2 in the cytoplasm; BEX2 loss causes nuclear translocation of Zic2, activating Hedgehog signaling, and Zic2 knockdown abrogates the migratory phenotype of BEX2-knockout cells.","method":"CRISPR/Cas9 knockout, RNA-Seq, Hedgehog inhibitor rescue, Zic2 knockdown epistasis, subcellular fractionation/localization, migration assay, in vivo metastasis model","journal":"International journal of biological sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic KO + pharmacologic and genetic epistasis, mechanistic pathway placement, single lab","pmids":["31929751"],"is_preprint":false},{"year":2020,"finding":"BEX2 escapes X-chromosome inactivation, demonstrated by biallelic BEX2 expression in iPSCs derived from a female patient with Xq22 deletion, in the iPSC line where the wild-type allele was inactivated.","method":"iPSC derivation from patient, allele-specific expression analysis","journal":"Congenital anomalies","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — direct experimental demonstration in patient-derived cells, single case/lab","pmids":["33244819"],"is_preprint":false},{"year":2021,"finding":"BEX2 activates mitophagy via the BNIP3/NIX pathway in SH-SY5Y neurons: BEX2 knockdown inhibits soybean isoflavone-induced BNIP3/NIX upregulation, LC3-II accumulation, and mitophagy, and prevents protection against atrazine-induced mitochondrial damage, placing BEX2 upstream of BNIP3/NIX-mediated mitophagy.","method":"siRNA knockdown, Western blot (BNIP3/NIX, LC3-II, BEX2), mitophagy inhibitor (Mdivi-1), mitochondrial membrane potential assay, electron microscopy","journal":"Ecotoxicology and environmental safety","confidence":"Low","confidence_rationale":"Tier 3 / Weak — knockdown epistasis in neuronal cells, no direct interaction shown, single lab","pmids":["34673406"],"is_preprint":false},{"year":2023,"finding":"BEX2 is crotonylated at lysine 59 (K59), and this crotonylation is critical for BEX2-mediated mitophagy in lung cancer cells. Crotonylated BEX2 facilitates interaction between NDP52 and LC3B to promote mitophagy; the K59R mutation of BEX2 impairs the NDP52-LC3B interaction and inhibits mitophagy, thereby reducing resistance to chemotherapy-induced apoptosis.","method":"Site-directed mutagenesis (K59R), co-immunoprecipitation, Western blot, mitophagy assay, apoptosis assay, in vivo xenograft model","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — mutagenesis identifies critical PTM site, Co-IP establishes ternary interaction, in vivo validation, single lab","pmids":["37777549"],"is_preprint":false},{"year":2025,"finding":"BEX2 interacts with PIK3CA (the catalytic subunit of PI3K) and impairs the PIK3CA–p85 (regulatory subunit) interaction, thereby inhibiting PI3K activity and promoting autophagic flux through the PI3K/AKT/mTOR signaling pathway in non-small-cell lung cancer cells.","method":"Co-immunoprecipitation, Western blot, confocal microscopy, rapamycin treatment","journal":"Cell communication and signaling","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP demonstrates direct interaction and competition, confocal validates localization, pathway confirmed by mTOR readouts, single lab","pmids":["41398291"],"is_preprint":false},{"year":2026,"finding":"BEX2 interacts with MCL1, promotes its ubiquitination and degradation, thereby reducing MCL1 stability. Low BEX2 expression stabilizes MCL1, which enhances cancer stem cell stemness potential and Hedgehog pathway activity in colorectal cancer cells.","method":"Co-immunoprecipitation, ubiquitination assay, Western blot, functional stem cell assays (sphere formation, ELDA), xenograft model","journal":"Cancer biology & medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP and ubiquitination assay establish mechanism, functional assays confirm consequence, single lab","pmids":["41814669"],"is_preprint":false}],"current_model":"BEX2 is a nuclear and cytoplasmic/mitochondrial protein that functions as a transcriptional co-activator (forming a complex with LMO2, NSCL2, and LDB1), a regulator of apoptosis and cell cycle (via Bcl-2 family modulation, NF-κB/p65, c-Jun/JNK, and PP2A), a promoter of mitophagy through crotonylation at K59 (facilitating NDP52–LC3B interaction) and through the BNIP3/NIX pathway, an inhibitor of PI3K activity by disrupting PIK3CA–p85 interaction to induce autophagy, a suppressor of Hedgehog signaling by cytoplasmic retention of Zic2, a promoter of MCL1 ubiquitination and degradation, and a suppressor of mitochondrial activity through interaction with TUFM; its transcription is driven by c-Jun and NF-κB p65, it is regulated by crotonylation and epigenetic (promoter methylation/histone deacetylation) mechanisms, and it escapes X-chromosome inactivation."},"narrative":{"mechanistic_narrative":"BEX2 is a small adaptor-type protein that integrates transcriptional, apoptotic, autophagic, and signaling programs in cancer cells, with a context-dependent role that spans tumor-suppressive and tumor-promoting functions [PMID:16314316, PMID:19711341, PMID:33299012]. In the nucleus, it acts as a transcriptional co-activator, joining an LMO2–NSCL2–LDB1 DNA-binding complex and enhancing LMO2- and NSCL2-dependent transcription [PMID:16314316], and it interacts with the SWI/SNF subunit INI1/hSNF5 to drive S-phase entry [PMID:22698742]. BEX2 sits within reciprocal transcriptional feedback loops: its promoter is directly bound and activated by c-Jun and NF-κB p65, and in turn BEX2 is required for p65/IκBα and c-Jun phosphorylation, JNK activity, and c-Jun-driven cyclin D1 induction and ErbB2 expression [PMID:20482821, PMID:21384344, PMID:28367093], with nuclear localization being required for its promotion of p65 [PMID:24390962]. BEX2 controls mitochondrial apoptosis by upregulating Bcl-2 and repressing BAD, BAK1, and PUMA, governs G1 progression through cyclin D1 and p21, and restrains PP2A activity [PMID:19711341]. It promotes autophagy and mitophagy through multiple routes: lysine-59 crotonylation enables crotonylated BEX2 to bridge the NDP52–LC3B interaction [PMID:37777549], it inhibits PI3K by displacing the PIK3CA–p85 interaction to activate autophagic flux via PI3K/AKT/mTOR [PMID:41398291], and it acts through the BNIP3/NIX pathway in neuronal cells [PMID:34673406]. BEX2 also suppresses mitochondrial oxygen consumption through interaction with TUFM [PMID:33299012], promotes MCL1 ubiquitination and degradation [PMID:41814669], and restrains Hedgehog signaling by retaining Zic2 in the cytoplasm [PMID:31929751]. Its expression is governed by promoter methylation and histone deacetylation [PMID:16818640, PMID:19835597] and it escapes X-chromosome inactivation [PMID:33244819].","teleology":[{"year":2005,"claim":"Established BEX2 as a nuclear transcriptional co-activator by placing it within a defined DNA-binding complex, answering what molecular role this otherwise uncharacterized protein plays.","evidence":"GST pull-down, Co-IP, EMSA, and reporter assays identifying an LMO2–NSCL2–LDB1 complex","pmids":["16314316"],"confidence":"High","gaps":["No structure of the complex or DNA-binding element defined","Does not address BEX2's cytoplasmic functions"]},{"year":2006,"claim":"Showed BEX2 can act as an epigenetically silenced tumor suppressor, addressing whether its loss contributes to cancer.","evidence":"Promoter methylation analysis, pharmacologic reactivation, viral re-expression, and xenografts in glioma","pmids":["16818640"],"confidence":"Medium","gaps":["Mechanism of tumor suppression not resolved","Apparent contradiction with later pro-proliferative roles unexplained"]},{"year":2007,"claim":"Connected BEX2 to apoptosis regulation by defining an NGF/BEX2/NF-κB anti-apoptotic axis in breast cancer.","evidence":"siRNA knockdown, overexpression, NF-κB reporter and apoptosis assays","pmids":["17638883"],"confidence":"Medium","gaps":["Direct molecular link between BEX2 and NF-κB not defined","Mechanism upstream of NF-κB activation unclear"]},{"year":2009,"claim":"Placed BEX2 genetically downstream of MLL fusion proteins and reinforced epigenetic control of its expression.","evidence":"MS-MLPA methylation analysis, demethylating agents/HDAC inhibitors, MLL-ENL transgenic cell lines","pmids":["19835597"],"confidence":"Medium","gaps":["Direct transcriptional regulation by MLL fusions not shown","Functional role of BEX2 in AML not tested"]},{"year":2010,"claim":"Defined the apoptotic and cell-cycle effector mechanism of BEX2 through Bcl-2 family modulation, cyclin D1/p21, and PP2A.","evidence":"Reciprocal knockdown/overexpression with Bcl-2 family and PP2A activity readouts in breast cancer cells","pmids":["19711341"],"confidence":"Medium","gaps":["Whether BEX2 directly binds Bcl-2 members or acts transcriptionally not resolved","PP2A regulation mechanism unknown"]},{"year":2010,"claim":"Established a transcriptional feedback loop in which c-Jun and p65 drive BEX2, which in turn sustains NF-κB and JNK/c-Jun activity, explaining its self-reinforcing pro-proliferative role.","evidence":"ChIP, luciferase reporter, and phosphorylation Western blots in c-Jun stable lines","pmids":["20482821"],"confidence":"Medium","gaps":["Molecular mechanism by which BEX2 promotes kinase phosphorylation not defined"]},{"year":2011,"claim":"Extended the feedback circuit to ErbB2, showing a positive ErbB2–c-Jun–BEX2 loop in breast cancer.","evidence":"ErbB2 overexpression, dominant-negative c-Jun, ChIP, promoter assays","pmids":["21384344"],"confidence":"Medium","gaps":["Direct BEX2 contribution to ErbB2 promoter occupancy not separated from c-Jun"]},{"year":2012,"claim":"Identified BEX2 as an upstream regulator of JNK-mediated glioma cell survival and migration, broadening its role beyond breast cancer.","evidence":"siRNA/overexpression with SP600125 epistasis, migration/invasion assays, N-cadherin and MMP-2 readouts","pmids":["23022184","22907646"],"confidence":"Medium","gaps":["Direct JNK pathway target of BEX2 unknown","Migration findings of lower confidence"]},{"year":2012,"claim":"Identified a physical interaction with the SWI/SNF subunit INI1/hSNF5, providing a chromatin-remodeling route to BEX2 cell-cycle control.","evidence":"Yeast two-hybrid, GST pull-down, truncation mapping, co-localization, cell cycle analysis","pmids":["22698742"],"confidence":"Medium","gaps":["Functional consequence for SWI/SNF activity not defined","Target genes affected unknown"]},{"year":2014,"claim":"Demonstrated that BEX2 nuclear localization is required for its NF-κB-dependent proliferative function and that it acts via β-catenin in glioma invasion.","evidence":"NLS-deletion mutant, p65 co-knockdown epistasis, β-catenin rescue, proliferation/migration assays","pmids":["24390962","25490384"],"confidence":"Medium","gaps":["How BEX2 raises p65 levels mechanistically unclear","β-catenin link is indirect, no binding shown"]},{"year":2017,"claim":"Confirmed BEX2 as an upstream activator of JNK/c-Jun signaling driving proliferation in colorectal cancer and as a mediator of induced autophagy in neurons.","evidence":"Knockdown/overexpression with SP600125 epistasis and xenografts; isoflavone-induced LC3-II/p62 autophagy in SH-SY5Y cells","pmids":["28367093","29049987"],"confidence":"Medium","gaps":["Direct kinase substrate or adaptor function not defined","Autophagy role established only by knockdown phenotype"]},{"year":2020,"claim":"Revealed BEX2's mitochondrial and Hedgehog-suppressive functions, identifying TUFM, FEM1B/CUL2, and cytoplasmic Zic2 retention as new mechanistic nodes.","evidence":"Protein binding screen, Co-IP, oxygen consumption, CRISPR knockout with Hedgehog inhibitor and Zic2 epistasis, metastasis models","pmids":["33299012","31929751"],"confidence":"Medium","gaps":["Functional role of FEM1B/CUL2 interaction unresolved","Mechanism of Zic2 cytoplasmic retention not defined"]},{"year":2020,"claim":"Showed BEX2 escapes X-chromosome inactivation, establishing biallelic dosage potential.","evidence":"Allele-specific expression in patient-derived iPSCs with Xq22 deletion","pmids":["33244819"],"confidence":"Medium","gaps":["Single patient/case","Functional consequence of escape not tested"]},{"year":2023,"claim":"Identified lysine-59 crotonylation as the modification that enables BEX2 to bridge NDP52 and LC3B for mitophagy and chemoresistance.","evidence":"K59R mutagenesis, Co-IP, mitophagy and apoptosis assays, xenografts in lung cancer","pmids":["37777549"],"confidence":"Medium","gaps":["Crotonyltransferase responsible for K59 modification not identified","Structural basis of NDP52–LC3B bridging unknown"]},{"year":2025,"claim":"Established BEX2 as a direct PI3K inhibitor that disrupts the PIK3CA–p85 interaction to promote autophagy via PI3K/AKT/mTOR.","evidence":"Co-IP, confocal microscopy, rapamycin treatment in NSCLC cells","pmids":["41398291"],"confidence":"Medium","gaps":["Binding interface on PIK3CA not mapped","Relationship to crotonylation-dependent mitophagy unresolved"]},{"year":2026,"claim":"Defined BEX2 as a promoter of MCL1 ubiquitination and degradation, linking its loss to cancer stem cell stemness and Hedgehog activity.","evidence":"Co-IP, ubiquitination assay, sphere formation/ELDA, xenografts in colorectal cancer","pmids":["41814669"],"confidence":"Medium","gaps":["E3 ligase recruited by BEX2 for MCL1 not identified","Connection to FEM1B/CUL2 interaction not tested"]},{"year":null,"claim":"How BEX2's diverse nuclear (transcriptional co-activation, SWI/SNF) and cytoplasmic/mitochondrial (PI3K inhibition, mitophagy, MCL1 degradation, TUFM) activities are coordinated, and whether its context-dependent tumor-suppressor versus oncogenic behavior reflects distinct PTM states or partner availability, remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unifying structural or biochemical model integrating BEX2's many partners","Determinants of tumor-suppressive versus pro-tumor outcomes undefined"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[0]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[0,18,19]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[19,20,14]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[0,9,10]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[15,19]},{"term_id":"GO:0005739","term_label":"mitochondrion","supporting_discovery_ids":[14,17,18]}],"pathway":[{"term_id":"R-HSA-9612973","term_label":"Autophagy","supporting_discovery_ids":[17,18,19]},{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[4,8]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[5,15,19]},{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[0,5]},{"term_id":"R-HSA-1640170","term_label":"Cell Cycle","supporting_discovery_ids":[4,9]}],"complexes":["LMO2–NSCL2–LDB1 transcriptional complex"],"partners":["LMO2","LDB1","SMARCB1","TUFM","FEM1B","CUL2","PIK3CA","MCL1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9BXY8","full_name":"Protein BEX2","aliases":["Brain-expressed X-linked protein 2","hBex2"],"length_aa":128,"mass_kda":15.3,"function":"Regulator of mitochondrial apoptosis and G1 cell cycle in breast cancer (PubMed:19711341). Protects the breast cancer cells against mitochondrial apoptosis and this effect is mediated through the modulation of BCL2 protein family, which involves the positive regulation of anti-apoptotic member BCL2 and the negative regulation of pro-apoptotic members BAD, BAK1 and PUMA (PubMed:19711341). Required for the normal cell cycle progression during G1 in breast cancer cells through the regulation of CCND1 and CDKN1A (PubMed:19711341). Regulates the level of PP2A regulatory subunit B and PP2A phosphatase activity (PubMed:19711341). 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":"Cytoplasm; Nucleus","url":"https://www.uniprot.org/uniprotkb/Q9BXY8/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/BEX2","classification":"Not Classified","n_dependent_lines":7,"n_total_lines":1208,"dependency_fraction":0.005794701986754967},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/BEX2","total_profiled":1310},"omim":[{"mim_id":"603451","title":"LIM DOMAIN-BINDING 1; LDB1","url":"https://www.omim.org/entry/603451"},{"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"},{"mim_id":"162361","title":"NESCIENT HELIX LOOP HELIX 2; NHLH2","url":"https://www.omim.org/entry/162361"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Uncertain","locations":[{"location":"Cytosol","reliability":"Uncertain"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in all","driving_tissues":[{"tissue":"brain","ntpm":301.2},{"tissue":"pituitary gland","ntpm":199.0}],"url":"https://www.proteinatlas.org/search/BEX2"},"hgnc":{"alias_symbol":["DJ79P11.1"],"prev_symbol":[]},"alphafold":{"accession":"Q9BXY8","domains":[{"cath_id":"1.20.5","chopping":"64-110","consensus_level":"medium","plddt":77.6513,"start":64,"end":110}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9BXY8","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9BXY8-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9BXY8-F1-predicted_aligned_error_v6.png","plddt_mean":68.5},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=BEX2","jax_strain_url":"https://www.jax.org/strain/search?query=BEX2"},"sequence":{"accession":"Q9BXY8","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9BXY8.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9BXY8/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9BXY8"}},"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":"17638883","id":"PMC_17638883","title":"BEX2 is overexpressed in a subset of primary breast cancers and mediates nerve growth factor/nuclear factor-kappaB inhibition of apoptosis in breast cancer cell lines.","date":"2007","source":"Cancer research","url":"https://pubmed.ncbi.nlm.nih.gov/17638883","citation_count":81,"is_preprint":false},{"pmid":"19412433","id":"PMC_19412433","title":"Galectin 1 proangiogenic and promigratory effects in the Hs683 oligodendroglioma model are partly mediated through the control of BEX2 expression.","date":"2009","source":"Neoplasia (New York, N.Y.)","url":"https://pubmed.ncbi.nlm.nih.gov/19412433","citation_count":58,"is_preprint":false},{"pmid":"19711341","id":"PMC_19711341","title":"BEX2 regulates mitochondrial apoptosis and G1 cell cycle in breast cancer.","date":"2010","source":"International journal of cancer","url":"https://pubmed.ncbi.nlm.nih.gov/19711341","citation_count":47,"is_preprint":false},{"pmid":"37777549","id":"PMC_37777549","title":"Crotonylated BEX2 interacts with NDP52 and enhances mitophagy to modulate chemotherapeutic agent-induced apoptosis in non-small-cell lung cancer cells.","date":"2023","source":"Cell death & disease","url":"https://pubmed.ncbi.nlm.nih.gov/37777549","citation_count":43,"is_preprint":false},{"pmid":"16314316","id":"PMC_16314316","title":"Human Bex2 interacts with LMO2 and regulates the transcriptional activity of a novel DNA-binding complex.","date":"2005","source":"Nucleic acids research","url":"https://pubmed.ncbi.nlm.nih.gov/16314316","citation_count":35,"is_preprint":false},{"pmid":"20482821","id":"PMC_20482821","title":"BEX2 has a functional interplay with c-Jun/JNK and p65/RelA in breast cancer.","date":"2010","source":"Molecular cancer","url":"https://pubmed.ncbi.nlm.nih.gov/20482821","citation_count":33,"is_preprint":false},{"pmid":"33299012","id":"PMC_33299012","title":"BEX2 suppresses mitochondrial activity and is required for dormant cancer stem cell maintenance in intrahepatic cholangiocarcinoma.","date":"2020","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/33299012","citation_count":28,"is_preprint":false},{"pmid":"19835597","id":"PMC_19835597","title":"Hypomethylation and expression of BEX2, IGSF4 and TIMP3 indicative of MLL translocations in acute myeloid leukemia.","date":"2009","source":"Molecular cancer","url":"https://pubmed.ncbi.nlm.nih.gov/19835597","citation_count":27,"is_preprint":false},{"pmid":"29049987","id":"PMC_29049987","title":"Isoflavones Induce BEX2-Dependent Autophagy to Prevent ATR-Induced Neurotoxicity in SH-SY5Y Cells.","date":"2017","source":"Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/29049987","citation_count":27,"is_preprint":false},{"pmid":"31929751","id":"PMC_31929751","title":"Silencing of brain-expressed X-linked 2 (BEX2) promotes colorectal cancer metastasis through the Hedgehog signaling pathway.","date":"2020","source":"International journal of biological sciences","url":"https://pubmed.ncbi.nlm.nih.gov/31929751","citation_count":26,"is_preprint":false},{"pmid":"22907646","id":"PMC_22907646","title":"Bex2 is critical for migration and invasion in malignant glioma cells.","date":"2012","source":"Journal of molecular neuroscience : MN","url":"https://pubmed.ncbi.nlm.nih.gov/22907646","citation_count":23,"is_preprint":false},{"pmid":"23022184","id":"PMC_23022184","title":"Bex2 regulates cell proliferation and apoptosis in malignant glioma cells via the c-Jun NH2-terminal kinase pathway.","date":"2012","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/23022184","citation_count":23,"is_preprint":false},{"pmid":"24390962","id":"PMC_24390962","title":"Bex2 controls proliferation of human glioblastoma cells through NF-κB signaling pathway.","date":"2014","source":"Journal of molecular neuroscience : MN","url":"https://pubmed.ncbi.nlm.nih.gov/24390962","citation_count":23,"is_preprint":false},{"pmid":"34673406","id":"PMC_34673406","title":"Soybean isoflavones protect SH-SY5Y neurons from atrazine-induced toxicity by activating mitophagy through stimulation of the BEX2/BNIP3/NIX pathway.","date":"2021","source":"Ecotoxicology and environmental safety","url":"https://pubmed.ncbi.nlm.nih.gov/34673406","citation_count":21,"is_preprint":false},{"pmid":"36451866","id":"PMC_36451866","title":"Mutant Kras and mTOR crosstalk drives hepatocellular carcinoma development via PEG3/STAT3/BEX2 signaling.","date":"2022","source":"Theranostics","url":"https://pubmed.ncbi.nlm.nih.gov/36451866","citation_count":20,"is_preprint":false},{"pmid":"28367093","id":"PMC_28367093","title":"BEX2 promotes tumor proliferation in colorectal cancer.","date":"2017","source":"International journal of biological sciences","url":"https://pubmed.ncbi.nlm.nih.gov/28367093","citation_count":18,"is_preprint":false},{"pmid":"30779920","id":"PMC_30779920","title":"Molecular functions of brain expressed X-linked 2 (BEX2) in malignancies.","date":"2019","source":"Experimental cell research","url":"https://pubmed.ncbi.nlm.nih.gov/30779920","citation_count":17,"is_preprint":false},{"pmid":"34424582","id":"PMC_34424582","title":"BEX2 is required for maintaining dormant cancer stem cell in hepatocellular carcinoma.","date":"2021","source":"Cancer science","url":"https://pubmed.ncbi.nlm.nih.gov/34424582","citation_count":17,"is_preprint":false},{"pmid":"25490384","id":"PMC_25490384","title":"Β-catenin is involved in Bex2 down-regulation induced glioma cell invasion/migration inhibition.","date":"2014","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/25490384","citation_count":15,"is_preprint":false},{"pmid":"21384344","id":"PMC_21384344","title":"A feedback loop between BEX2 and ErbB2 mediated by c-Jun signaling in breast cancer.","date":"2011","source":"International journal of cancer","url":"https://pubmed.ncbi.nlm.nih.gov/21384344","citation_count":15,"is_preprint":false},{"pmid":"31530937","id":"PMC_31530937","title":"MicroRNA-370 functions as a tumor suppressor in hepatocellular carcinoma via inhibition of the MAPK/JNK signaling pathway by targeting BEX2.","date":"2019","source":"Journal of human genetics","url":"https://pubmed.ncbi.nlm.nih.gov/31530937","citation_count":9,"is_preprint":false},{"pmid":"33412384","id":"PMC_33412384","title":"Discovery of a chemical compound that suppresses expression of BEX2, a dormant cancer stem cell-related protein.","date":"2021","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/33412384","citation_count":7,"is_preprint":false},{"pmid":"34803456","id":"PMC_34803456","title":"Analyzing differentially expressed genes and pathways of Bex2-deficient mouse lung via RNA-Seq.","date":"2021","source":"Turkish journal of biology = Turk biyoloji dergisi","url":"https://pubmed.ncbi.nlm.nih.gov/34803456","citation_count":4,"is_preprint":false},{"pmid":"22698742","id":"PMC_22698742","title":"[BEX2 regulates cell cycle through the interaction with INI1/hSNF5].","date":"2012","source":"Yi chuan = Hereditas","url":"https://pubmed.ncbi.nlm.nih.gov/22698742","citation_count":4,"is_preprint":false},{"pmid":"33244819","id":"PMC_33244819","title":"Induced pluripotent stem cells established from a female patient with Xq22 deletion confirm that BEX2 escapes from X-chromosome inactivation.","date":"2020","source":"Congenital anomalies","url":"https://pubmed.ncbi.nlm.nih.gov/33244819","citation_count":4,"is_preprint":false},{"pmid":"37864534","id":"PMC_37864534","title":"JNK/MAPK pathway regulation by BEX2 gene silencing in alcoholic hepatitis mice: Effects on oxidative stress.","date":"2023","source":"Alcohol, clinical & experimental research","url":"https://pubmed.ncbi.nlm.nih.gov/37864534","citation_count":2,"is_preprint":false},{"pmid":"41398291","id":"PMC_41398291","title":"BEX2 regulates autophagy by inhibiting PIK3CA-p85 interaction in non-small-cell lung cancer cells.","date":"2025","source":"Cell communication and signaling : CCS","url":"https://pubmed.ncbi.nlm.nih.gov/41398291","citation_count":1,"is_preprint":false},{"pmid":"41814669","id":"PMC_41814669","title":"BEX2 influences the MCL1-Hedgehog signaling axis to regulate the potential of stemness characterization in colorectal cancer.","date":"2026","source":"Cancer biology & medicine","url":"https://pubmed.ncbi.nlm.nih.gov/41814669","citation_count":1,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":16194,"output_tokens":5364,"usd":0.064521,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":13786,"output_tokens":4846,"usd":0.09504,"stage2_stop_reason":"end_turn"},"total_usd":0.159561,"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\": 2005,\n      \"finding\": \"BEX2 physically interacts with LMO2 (a LIM-domain transcription factor), confirmed by GST pull-down and co-immunoprecipitation. BEX2 and LMO2 form part of a DNA-binding protein complex (shown by EMSA) that also includes NSCL2 and LDB1, and BEX2 enhances the transcriptional activity of LMO2 and augments LMO2-induced NSCL2-dependent transcriptional activity in vivo.\",\n      \"method\": \"GST pull-down, co-immunoprecipitation, EMSA, luciferase reporter assay, mammalian two-hybrid\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — multiple orthogonal methods (pull-down, Co-IP, EMSA, reporter assay) in a single focused study\",\n      \"pmids\": [\"16314316\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"BEX2 promoter is hypermethylated and transcriptionally silenced in malignant glioma. Viral re-expression of BEX2 increases sensitivity to chemotherapy-induced apoptosis and exerts tumor suppressor effects in vitro and in a xenograft mouse model.\",\n      \"method\": \"5-AzaC/TSA pharmacologic reversal, microarray, promoter methylation analysis, viral transduction, xenograft model\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (epigenetic reactivation, promoter methylation, viral re-expression, in vivo xenograft) in one study\",\n      \"pmids\": [\"16818640\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"BEX2 expression is necessary and sufficient for NGF-mediated inhibition of ceramide-induced apoptosis through NF-κB activation in breast cancer cells. BEX2 also modulates apoptosis in response to estradiol and tamoxifen, defining a NGF/BEX2/NF-κB pathway.\",\n      \"method\": \"siRNA knockdown, BEX2 overexpression, NF-κB reporter assay, apoptosis assay\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss- and gain-of-function with defined pathway readout, single lab\",\n      \"pmids\": [\"17638883\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"BEX2 expression (hypomethylated) is characteristic of MLL-translocation AML cell lines; demethylating agents and HDAC inhibitors restore BEX2 expression in MLLwt cells. Bex2 mRNA in MLL-ENL transgenic mouse cell lines requires expression of the MLL fusion gene, placing BEX2 downstream of MLL fusion proteins.\",\n      \"method\": \"MS-MLPA methylation analysis, demethylating agent treatment, transgenic mouse cell lines\",\n      \"journal\": \"Molecular cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (methylation assay, pharmacologic reactivation, transgenic model) establishing genetic epistasis\",\n      \"pmids\": [\"19835597\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"BEX2 downregulation induces mitochondrial apoptosis and sensitizes breast cancer cells to ceramide, doxorubicin, and staurosporine. BEX2 overexpression protects against mitochondrial apoptosis. This effect is mediated through positive regulation of Bcl-2 and negative regulation of BAD, BAK1, and PUMA. BEX2 expression is also required for normal G1 cell cycle progression through regulation of cyclin D1 and p21. BEX2 downregulation increases protein phosphatase 2A (PP2A) expression and activity.\",\n      \"method\": \"siRNA knockdown, BEX2 overexpression, apoptosis assay, Western blot for Bcl-2 family members, cell cycle analysis, PP2A activity assay\",\n      \"journal\": \"International journal of cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal loss/gain of function with multiple pathway readouts, single lab\",\n      \"pmids\": [\"19711341\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"c-Jun and p65/RelA directly bind and transcriptionally activate the BEX2 promoter in breast cancer cells. In turn, BEX2 is required for normal phosphorylation of p65 and IκBα (NF-κB activation), for phosphorylation of c-Jun, and for JNK kinase activity, establishing a feedback loop. BEX2 is also required for c-Jun-mediated cyclin D1 induction and cell proliferation. BEX2 downregulation increases PP2A activity in c-Jun stable lines.\",\n      \"method\": \"Luciferase reporter assay, chromatin immunoprecipitation (ChIP), Western blot, c-Jun stable lines, PP2A activity assay\",\n      \"journal\": \"Molecular cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP confirms direct binding, reporter assay, multiple pathway readouts, single lab\",\n      \"pmids\": [\"20482821\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"ErbB2 overexpression induces c-Jun and BEX2 expression; ErbB2-mediated BEX2 induction is abrogated by a dominant-negative c-Jun mutant. BEX2 overexpression in turn increases c-Jun-mediated ErbB2 induction and c-Jun binding to the ErbB2 promoter, establishing a positive feedback loop among ErbB2, c-Jun, and BEX2 in breast cancer cells.\",\n      \"method\": \"ErbB2 overexpression, dominant-negative c-Jun mutant, Western blot, ChIP, promoter assay\",\n      \"journal\": \"International journal of cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — dominant-negative mutant and ChIP evidence for mechanism, single lab\",\n      \"pmids\": [\"21384344\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"BEX2 downregulation inhibits glioma cell migration and invasion, associated with increased N-cadherin and decreased secretion of MMP-2; BEX2 overexpression promotes migration and invasion, placing BEX2 upstream of N-cadherin and MMP-2 in glioma.\",\n      \"method\": \"siRNA knockdown, overexpression, migration/invasion assays, Western blot, zymography\",\n      \"journal\": \"Journal of molecular neuroscience\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, phenotypic readouts with partial molecular follow-up, no reconstitution\",\n      \"pmids\": [\"22907646\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"BEX2 downregulation promotes apoptosis and activates the JNK pathway in malignant glioma cells; the JNK-specific inhibitor SP600125 abolishes the pro-apoptotic effect of BEX2 knockdown, placing BEX2 upstream of JNK in glioma cell survival.\",\n      \"method\": \"siRNA knockdown, BEX2 overexpression, JNK inhibitor (SP600125), apoptosis assay\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — pharmacologic epistasis with inhibitor rescue confirms pathway placement, single lab\",\n      \"pmids\": [\"23022184\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"BEX2 interacts with INI1/hSNF5 (a SWI/SNF chromatin remodeling complex component), confirmed by yeast two-hybrid and GST pull-down; truncated mutation analysis identified that two conserved reverse repeat sequences in INI1/hSNF5 are required for this interaction. Both proteins co-localize in the nucleus, and co-overexpression increases S-phase population, indicating BEX2 regulates cell cycle via INI1/hSNF5.\",\n      \"method\": \"Yeast two-hybrid, GST pull-down, truncated mutation analysis, subcellular localization, cell cycle analysis\",\n      \"journal\": \"Yi chuan = Hereditas\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple binding confirmation methods with truncation mapping and functional cell cycle readout, single lab\",\n      \"pmids\": [\"22698742\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"BEX2 promotes proliferation of glioblastoma cells through NF-κB signaling: BEX2 downregulation decreases NF-κB p65 expression; BEX2 overexpression-induced proliferation is abolished by p65 downregulation. Critically, BEX2 with a nuclear localization signal deletion no longer promotes p65 expression, demonstrating that BEX2 nuclear localization is required for this function.\",\n      \"method\": \"siRNA knockdown, overexpression, nuclear localization signal deletion mutant, proliferation assay, Western blot\",\n      \"journal\": \"Journal of molecular neuroscience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — deletion mutant establishes functional requirement for nuclear localization, epistasis via p65 co-knockdown, single lab\",\n      \"pmids\": [\"24390962\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"BEX2 downregulation inhibits glioma cell migration and invasion by reducing β-catenin protein levels (nuclear and cytoplasmic, not membrane-associated); β-catenin overexpression rescues the migration/invasion defect caused by BEX2 knockdown, placing BEX2 upstream of β-catenin in glioma cell invasiveness.\",\n      \"method\": \"siRNA knockdown, β-catenin overexpression rescue, Western blot, migration/invasion assay\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — rescue experiment establishes epistasis but no direct interaction shown, single lab\",\n      \"pmids\": [\"25490384\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"BEX2 promotes colorectal cancer cell proliferation via the JNK/c-Jun pathway: BEX2 knockdown inhibits JNK/c-Jun phosphorylation; BEX2 overexpression activates JNK/c-Jun phosphorylation; the JNK inhibitor SP600125 abolishes BEX2 overexpression-induced proliferation, establishing BEX2 as an upstream regulator of JNK/c-Jun signaling in colorectal cancer.\",\n      \"method\": \"siRNA knockdown, BEX2 overexpression, JNK inhibitor (SP600125) pharmacologic epistasis, phosphorylation Western blot, proliferation assay, xenograft model\",\n      \"journal\": \"International journal of biological sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — pharmacologic epistasis with inhibitor rescue plus in vivo validation, single lab\",\n      \"pmids\": [\"28367093\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"BEX2 is required for isoflavone-induced autophagy in SH-SY5Y neuronal cells: BEX2 siRNA abolishes isoflavone-mediated LC3-II accumulation, p62 decrease, and neuroprotection against atrazine toxicity, placing BEX2 as a necessary mediator of autophagy induction in these cells.\",\n      \"method\": \"siRNA knockdown, Western blot (LC3-II, p62), autophagy inhibitor (3-MA), cell viability assay\",\n      \"journal\": \"Cellular physiology and biochemistry\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, knockdown phenotype without direct binding or reconstitution data\",\n      \"pmids\": [\"29049987\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"BEX2 knockdown in cholangiocarcinoma decreases tumorigenicity and G0 phase fraction. Starvation induces USF2 transcription factor, which transcriptionally induces BEX2. BEX2 binding partners identified include E3 ubiquitin ligase complex proteins FEM1B and CUL2 and mitochondrial protein TUFM; knockdown of BEX2 or TUFM increases mitochondrial oxygen consumption rate and decreases tumorigenicity, indicating BEX2 suppresses mitochondrial activity through TUFM interaction.\",\n      \"method\": \"Comprehensive protein binding screen, co-immunoprecipitation, siRNA knockdown, oxygen consumption assay, xenograft model, cell cycle analysis\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple binding partners identified and functionally validated with parallel knockdowns, single lab\",\n      \"pmids\": [\"33299012\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"BEX2 knockout in colorectal cancer cells activates the Hedgehog signaling pathway and promotes migration/metastasis; Hedgehog inhibitors (GANT61 and GDC-0449) rescue the migratory enhancement of BEX2-knockout cells. BEX2 negatively modulates Hedgehog signaling by retaining Zic2 in the cytoplasm; BEX2 loss causes nuclear translocation of Zic2, activating Hedgehog signaling, and Zic2 knockdown abrogates the migratory phenotype of BEX2-knockout cells.\",\n      \"method\": \"CRISPR/Cas9 knockout, RNA-Seq, Hedgehog inhibitor rescue, Zic2 knockdown epistasis, subcellular fractionation/localization, migration assay, in vivo metastasis model\",\n      \"journal\": \"International journal of biological sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic KO + pharmacologic and genetic epistasis, mechanistic pathway placement, single lab\",\n      \"pmids\": [\"31929751\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"BEX2 escapes X-chromosome inactivation, demonstrated by biallelic BEX2 expression in iPSCs derived from a female patient with Xq22 deletion, in the iPSC line where the wild-type allele was inactivated.\",\n      \"method\": \"iPSC derivation from patient, allele-specific expression analysis\",\n      \"journal\": \"Congenital anomalies\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — direct experimental demonstration in patient-derived cells, single case/lab\",\n      \"pmids\": [\"33244819\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"BEX2 activates mitophagy via the BNIP3/NIX pathway in SH-SY5Y neurons: BEX2 knockdown inhibits soybean isoflavone-induced BNIP3/NIX upregulation, LC3-II accumulation, and mitophagy, and prevents protection against atrazine-induced mitochondrial damage, placing BEX2 upstream of BNIP3/NIX-mediated mitophagy.\",\n      \"method\": \"siRNA knockdown, Western blot (BNIP3/NIX, LC3-II, BEX2), mitophagy inhibitor (Mdivi-1), mitochondrial membrane potential assay, electron microscopy\",\n      \"journal\": \"Ecotoxicology and environmental safety\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — knockdown epistasis in neuronal cells, no direct interaction shown, single lab\",\n      \"pmids\": [\"34673406\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"BEX2 is crotonylated at lysine 59 (K59), and this crotonylation is critical for BEX2-mediated mitophagy in lung cancer cells. Crotonylated BEX2 facilitates interaction between NDP52 and LC3B to promote mitophagy; the K59R mutation of BEX2 impairs the NDP52-LC3B interaction and inhibits mitophagy, thereby reducing resistance to chemotherapy-induced apoptosis.\",\n      \"method\": \"Site-directed mutagenesis (K59R), co-immunoprecipitation, Western blot, mitophagy assay, apoptosis assay, in vivo xenograft model\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — mutagenesis identifies critical PTM site, Co-IP establishes ternary interaction, in vivo validation, single lab\",\n      \"pmids\": [\"37777549\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"BEX2 interacts with PIK3CA (the catalytic subunit of PI3K) and impairs the PIK3CA–p85 (regulatory subunit) interaction, thereby inhibiting PI3K activity and promoting autophagic flux through the PI3K/AKT/mTOR signaling pathway in non-small-cell lung cancer cells.\",\n      \"method\": \"Co-immunoprecipitation, Western blot, confocal microscopy, rapamycin treatment\",\n      \"journal\": \"Cell communication and signaling\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP demonstrates direct interaction and competition, confocal validates localization, pathway confirmed by mTOR readouts, single lab\",\n      \"pmids\": [\"41398291\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"BEX2 interacts with MCL1, promotes its ubiquitination and degradation, thereby reducing MCL1 stability. Low BEX2 expression stabilizes MCL1, which enhances cancer stem cell stemness potential and Hedgehog pathway activity in colorectal cancer cells.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay, Western blot, functional stem cell assays (sphere formation, ELDA), xenograft model\",\n      \"journal\": \"Cancer biology & medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP and ubiquitination assay establish mechanism, functional assays confirm consequence, single lab\",\n      \"pmids\": [\"41814669\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"BEX2 is a nuclear and cytoplasmic/mitochondrial protein that functions as a transcriptional co-activator (forming a complex with LMO2, NSCL2, and LDB1), a regulator of apoptosis and cell cycle (via Bcl-2 family modulation, NF-κB/p65, c-Jun/JNK, and PP2A), a promoter of mitophagy through crotonylation at K59 (facilitating NDP52–LC3B interaction) and through the BNIP3/NIX pathway, an inhibitor of PI3K activity by disrupting PIK3CA–p85 interaction to induce autophagy, a suppressor of Hedgehog signaling by cytoplasmic retention of Zic2, a promoter of MCL1 ubiquitination and degradation, and a suppressor of mitochondrial activity through interaction with TUFM; its transcription is driven by c-Jun and NF-κB p65, it is regulated by crotonylation and epigenetic (promoter methylation/histone deacetylation) mechanisms, and it escapes X-chromosome inactivation.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"BEX2 is a small adaptor-type protein that integrates transcriptional, apoptotic, autophagic, and signaling programs in cancer cells, with a context-dependent role that spans tumor-suppressive and tumor-promoting functions [#0, #4, #14]. In the nucleus, it acts as a transcriptional co-activator, joining an LMO2–NSCL2–LDB1 DNA-binding complex and enhancing LMO2- and NSCL2-dependent transcription [#0], and it interacts with the SWI/SNF subunit INI1/hSNF5 to drive S-phase entry [#9]. BEX2 sits within reciprocal transcriptional feedback loops: its promoter is directly bound and activated by c-Jun and NF-κB p65, and in turn BEX2 is required for p65/IκBα and c-Jun phosphorylation, JNK activity, and c-Jun-driven cyclin D1 induction and ErbB2 expression [#5, #6, #12], with nuclear localization being required for its promotion of p65 [#10]. BEX2 controls mitochondrial apoptosis by upregulating Bcl-2 and repressing BAD, BAK1, and PUMA, governs G1 progression through cyclin D1 and p21, and restrains PP2A activity [#4]. It promotes autophagy and mitophagy through multiple routes: lysine-59 crotonylation enables crotonylated BEX2 to bridge the NDP52–LC3B interaction [#18], it inhibits PI3K by displacing the PIK3CA–p85 interaction to activate autophagic flux via PI3K/AKT/mTOR [#19], and it acts through the BNIP3/NIX pathway in neuronal cells [#17]. BEX2 also suppresses mitochondrial oxygen consumption through interaction with TUFM [#14], promotes MCL1 ubiquitination and degradation [#20], and restrains Hedgehog signaling by retaining Zic2 in the cytoplasm [#15]. Its expression is governed by promoter methylation and histone deacetylation [#1, #3] and it escapes X-chromosome inactivation [#16].\",\n  \"teleology\": [\n    {\n      \"year\": 2005,\n      \"claim\": \"Established BEX2 as a nuclear transcriptional co-activator by placing it within a defined DNA-binding complex, answering what molecular role this otherwise uncharacterized protein plays.\",\n      \"evidence\": \"GST pull-down, Co-IP, EMSA, and reporter assays identifying an LMO2–NSCL2–LDB1 complex\",\n      \"pmids\": [\"16314316\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No structure of the complex or DNA-binding element defined\", \"Does not address BEX2's cytoplasmic functions\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Showed BEX2 can act as an epigenetically silenced tumor suppressor, addressing whether its loss contributes to cancer.\",\n      \"evidence\": \"Promoter methylation analysis, pharmacologic reactivation, viral re-expression, and xenografts in glioma\",\n      \"pmids\": [\"16818640\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism of tumor suppression not resolved\", \"Apparent contradiction with later pro-proliferative roles unexplained\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Connected BEX2 to apoptosis regulation by defining an NGF/BEX2/NF-κB anti-apoptotic axis in breast cancer.\",\n      \"evidence\": \"siRNA knockdown, overexpression, NF-κB reporter and apoptosis assays\",\n      \"pmids\": [\"17638883\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct molecular link between BEX2 and NF-κB not defined\", \"Mechanism upstream of NF-κB activation unclear\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Placed BEX2 genetically downstream of MLL fusion proteins and reinforced epigenetic control of its expression.\",\n      \"evidence\": \"MS-MLPA methylation analysis, demethylating agents/HDAC inhibitors, MLL-ENL transgenic cell lines\",\n      \"pmids\": [\"19835597\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct transcriptional regulation by MLL fusions not shown\", \"Functional role of BEX2 in AML not tested\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Defined the apoptotic and cell-cycle effector mechanism of BEX2 through Bcl-2 family modulation, cyclin D1/p21, and PP2A.\",\n      \"evidence\": \"Reciprocal knockdown/overexpression with Bcl-2 family and PP2A activity readouts in breast cancer cells\",\n      \"pmids\": [\"19711341\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether BEX2 directly binds Bcl-2 members or acts transcriptionally not resolved\", \"PP2A regulation mechanism unknown\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Established a transcriptional feedback loop in which c-Jun and p65 drive BEX2, which in turn sustains NF-κB and JNK/c-Jun activity, explaining its self-reinforcing pro-proliferative role.\",\n      \"evidence\": \"ChIP, luciferase reporter, and phosphorylation Western blots in c-Jun stable lines\",\n      \"pmids\": [\"20482821\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular mechanism by which BEX2 promotes kinase phosphorylation not defined\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Extended the feedback circuit to ErbB2, showing a positive ErbB2–c-Jun–BEX2 loop in breast cancer.\",\n      \"evidence\": \"ErbB2 overexpression, dominant-negative c-Jun, ChIP, promoter assays\",\n      \"pmids\": [\"21384344\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct BEX2 contribution to ErbB2 promoter occupancy not separated from c-Jun\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Identified BEX2 as an upstream regulator of JNK-mediated glioma cell survival and migration, broadening its role beyond breast cancer.\",\n      \"evidence\": \"siRNA/overexpression with SP600125 epistasis, migration/invasion assays, N-cadherin and MMP-2 readouts\",\n      \"pmids\": [\"23022184\", \"22907646\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct JNK pathway target of BEX2 unknown\", \"Migration findings of lower confidence\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Identified a physical interaction with the SWI/SNF subunit INI1/hSNF5, providing a chromatin-remodeling route to BEX2 cell-cycle control.\",\n      \"evidence\": \"Yeast two-hybrid, GST pull-down, truncation mapping, co-localization, cell cycle analysis\",\n      \"pmids\": [\"22698742\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional consequence for SWI/SNF activity not defined\", \"Target genes affected unknown\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Demonstrated that BEX2 nuclear localization is required for its NF-κB-dependent proliferative function and that it acts via β-catenin in glioma invasion.\",\n      \"evidence\": \"NLS-deletion mutant, p65 co-knockdown epistasis, β-catenin rescue, proliferation/migration assays\",\n      \"pmids\": [\"24390962\", \"25490384\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"How BEX2 raises p65 levels mechanistically unclear\", \"β-catenin link is indirect, no binding shown\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Confirmed BEX2 as an upstream activator of JNK/c-Jun signaling driving proliferation in colorectal cancer and as a mediator of induced autophagy in neurons.\",\n      \"evidence\": \"Knockdown/overexpression with SP600125 epistasis and xenografts; isoflavone-induced LC3-II/p62 autophagy in SH-SY5Y cells\",\n      \"pmids\": [\"28367093\", \"29049987\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct kinase substrate or adaptor function not defined\", \"Autophagy role established only by knockdown phenotype\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Revealed BEX2's mitochondrial and Hedgehog-suppressive functions, identifying TUFM, FEM1B/CUL2, and cytoplasmic Zic2 retention as new mechanistic nodes.\",\n      \"evidence\": \"Protein binding screen, Co-IP, oxygen consumption, CRISPR knockout with Hedgehog inhibitor and Zic2 epistasis, metastasis models\",\n      \"pmids\": [\"33299012\", \"31929751\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional role of FEM1B/CUL2 interaction unresolved\", \"Mechanism of Zic2 cytoplasmic retention not defined\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Showed BEX2 escapes X-chromosome inactivation, establishing biallelic dosage potential.\",\n      \"evidence\": \"Allele-specific expression in patient-derived iPSCs with Xq22 deletion\",\n      \"pmids\": [\"33244819\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single patient/case\", \"Functional consequence of escape not tested\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Identified lysine-59 crotonylation as the modification that enables BEX2 to bridge NDP52 and LC3B for mitophagy and chemoresistance.\",\n      \"evidence\": \"K59R mutagenesis, Co-IP, mitophagy and apoptosis assays, xenografts in lung cancer\",\n      \"pmids\": [\"37777549\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Crotonyltransferase responsible for K59 modification not identified\", \"Structural basis of NDP52–LC3B bridging unknown\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Established BEX2 as a direct PI3K inhibitor that disrupts the PIK3CA–p85 interaction to promote autophagy via PI3K/AKT/mTOR.\",\n      \"evidence\": \"Co-IP, confocal microscopy, rapamycin treatment in NSCLC cells\",\n      \"pmids\": [\"41398291\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Binding interface on PIK3CA not mapped\", \"Relationship to crotonylation-dependent mitophagy unresolved\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Defined BEX2 as a promoter of MCL1 ubiquitination and degradation, linking its loss to cancer stem cell stemness and Hedgehog activity.\",\n      \"evidence\": \"Co-IP, ubiquitination assay, sphere formation/ELDA, xenografts in colorectal cancer\",\n      \"pmids\": [\"41814669\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"E3 ligase recruited by BEX2 for MCL1 not identified\", \"Connection to FEM1B/CUL2 interaction not tested\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How BEX2's diverse nuclear (transcriptional co-activation, SWI/SNF) and cytoplasmic/mitochondrial (PI3K inhibition, mitophagy, MCL1 degradation, TUFM) activities are coordinated, and whether its context-dependent tumor-suppressor versus oncogenic behavior reflects distinct PTM states or partner availability, remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unifying structural or biochemical model integrating BEX2's many partners\", \"Determinants of tumor-suppressive versus pro-tumor outcomes undefined\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [0, 18, 19]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [19, 20, 14]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [0, 9, 10]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [15, 19]},\n      {\"term_id\": \"GO:0005739\", \"supporting_discovery_ids\": [14, 17, 18]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [17, 18, 19]},\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [4, 8]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [5, 15, 19]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [0, 5]},\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [4, 9]}\n    ],\n    \"complexes\": [\"LMO2–NSCL2–LDB1 transcriptional complex\"],\n    \"partners\": [\"LMO2\", \"LDB1\", \"SMARCB1\", \"TUFM\", \"FEM1B\", \"CUL2\", \"PIK3CA\", \"MCL1\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}