{"gene":"MXI1","run_date":"2026-06-10T05:19:52","timeline":{"discoveries":[{"year":1993,"finding":"MXI1 (Mxi1) interacts specifically with Max to form heterodimers that efficiently bind to the Myc-Max consensus recognition site (CACGTG E-box). When bound to DNA in yeast, Mxi1 does not stimulate transcription, consistent with it being a transcriptional repressor that sequesters Max and competes with Myc-Max heterodimers for target sites.","method":"Yeast two-hybrid interaction trap, DNA binding assays","journal":"Cell","confidence":"High","confidence_rationale":"Tier 1 / Strong — original biochemical characterization with yeast two-hybrid and DNA binding assays, replicated in multiple subsequent studies","pmids":["8425219"],"is_preprint":false},{"year":1995,"finding":"A short amino-terminal alpha-helical domain of Mxi1 (the SIN3-interacting domain, SID) dramatically augments its transcriptional repressive and anti-Myc suppressive potential by mediating physical association with a mammalian homolog of the yeast transcriptional repressor SIN3 (mSin3B). Mxi1 isoforms lacking this domain are functionally weaker repressors.","method":"Deletion mutagenesis, co-immunoprecipitation, rat embryo fibroblast transformation assay, transient transfection reporter assays","journal":"Cell","confidence":"High","confidence_rationale":"Tier 1 / Strong — multiple orthogonal methods including mutagenesis, co-IP, and functional transformation assay; independently replicated","pmids":["7889571"],"is_preprint":false},{"year":1994,"finding":"Mad and Mxi1 suppress Myc-induced transformation (c-Myc and N-Myc, but not E1a) in rat embryo fibroblast cooperation assays. Deletion of the basic region (DNA-binding domain) attenuates suppression, indicating that occupation of common DNA binding sites by transactivation-incompetent Mxi1-Max complexes is the dominant suppression mechanism over simple Max titration.","method":"Rat embryo fibroblast focus formation assay, basic-region deletion mutants","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 / Strong — epistasis/functional assay with mutagenesis controls, replicated by subsequent studies","pmids":["8202517"],"is_preprint":false},{"year":1996,"finding":"mSin3A physically associates with the strong-repression isoform of Mxi1 (Mxi1-SR) and both co-localize to the nucleus. A mSin3A–Mxi1 fusion protein in which the Sin3-interacting domain of Mxi1 is replaced by full-length mSin3A retains or exceeds Mxi1-SR repression activity, demonstrating that the amino-terminal domain of Mxi1-SR functions solely to recruit mSin3A (and related proteins) and that this recruitment is necessary for anti-Myc activity.","method":"Co-immunoprecipitation, nuclear localization by immunofluorescence, fusion protein rescue in REF transformation assay","journal":"Oncogene","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — co-IP plus functional rescue with fusion protein in single lab, multiple orthogonal methods","pmids":["8649810"],"is_preprint":false},{"year":1996,"finding":"Overexpression of Mxi1 inhibits Myc/Max-dependent transcriptional induction of the ornithine decarboxylase (ODC) gene in a dose-dependent manner both in vivo (transfection) and in vitro. Mxi1 protein levels are up-regulated during quiescence and down-regulated following serum stimulation.","method":"Transient transfection reporter assays, Northern blot for ODC mRNA","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo and in vitro reporter assays, single lab","pmids":["8637719"],"is_preprint":false},{"year":1998,"finding":"Mice lacking Mxi1 exhibit progressive, multisystem abnormalities including prostate epithelial hyperplasia, increased susceptibility to carcinogen-induced tumors, and enhanced tumorigenesis when also deficient in Ink4a, establishing Mxi1 as a tumor suppressor in vivo that engages the Myc network in a functionally relevant manner.","method":"Targeted gene deletion (knockout mouse), carcinogen treatment, genetic cross with Ink4a-deficient mice","journal":"Nature","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo knockout with multiple phenotypic readouts and genetic epistasis","pmids":["9624006"],"is_preprint":false},{"year":1999,"finding":"Mxi1 represses transcription from the major c-myc promoter P2 by targeting the core promoter elements and reversing activation by the constitutive transcription factor USF. This repression is independent of mSin3 binding but requires the Mxi1 leucine zipper and C-terminal sequences including putative CK2 phosphorylation sites. Zinc-inducible Mxi1 expression blocks serum-induced c-myc transcription and cell entry into S phase.","method":"Transient transfection reporter assays, stable inducible expression (metallothionein promoter), cell cycle analysis","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reporter assays with mutagenesis and inducible expression, single lab","pmids":["9872993"],"is_preprint":false},{"year":1999,"finding":"The MXI1 promoter is GC-rich, lacks a TATA box, and its activity is driven primarily by two proximal initiator sequences combined with nearby Sp1 and MED-1 sites. MXI1 promoter activity is repressed by high levels of AP2 transcription factor.","method":"Promoter cloning, deletion analysis, transient transfection reporter assays","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — promoter functional dissection with multiple deletion constructs, single lab","pmids":["10497252"],"is_preprint":false},{"year":2001,"finding":"Expression of Mxi1 in DU145 prostate carcinoma cells via adenoviral vector reduces cell proliferation, reduces soft agar colony formation, and causes G2/M phase cell cycle arrest associated with elevated cyclin B and reduced c-MYC and MDM2 protein levels.","method":"Adenoviral Mxi1 expression, MTT proliferation assay, soft agar colony formation, flow cytometry cell cycle analysis, Western blot","journal":"The Prostate","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — gain-of-function with multiple phenotypic readouts, single lab","pmids":["11351349"],"is_preprint":false},{"year":2004,"finding":"Mxi1-0, an alternatively transcribed Mxi1 isoform using an upstream exon with a unique N-terminal sequence, can bind Max and E-box DNA sites and interact with Sin3, but is predominantly localized to the cytoplasm (unlike nuclear Mxi1) and fails to repress c-Myc-dependent transcription. Its levels are higher in primary glioblastoma than normal brain, suggesting it may modulate Mxi1's Myc-inhibitory activity.","method":"RT-PCR/cloning, co-immunoprecipitation, EMSA (E-box binding), reporter assays, subcellular fractionation/immunofluorescence","journal":"Neoplasia (New York, N.Y.)","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — multiple orthogonal biochemical and cell biological methods in a single thorough study","pmids":["15548375"],"is_preprint":false},{"year":2004,"finding":"A novel Mxi1 isoform, Mxi1-SRalpha, arises from its own promoter and encodes a unique Sin3-interacting domain with greater affinity for Sin3 adapter proteins than the related Mxi1-SRbeta isoform, conferring enhanced transcriptional repression in reporter assays. Unlike Mxi1-SRbeta, Mxi1-SRalpha activates rather than represses the MYC promoter, and is a less potent suppressor of Myc-induced cellular transformation.","method":"Promoter-specific RT-PCR, co-immunoprecipitation, transient transfection reporter assays, REF transformation assay","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple methods including co-IP and functional assays, single lab","pmids":["15467743"],"is_preprint":false},{"year":2005,"finding":"Mxi1 is induced by hypoxia in a HIF-1-dependent manner (not induced in ARNT/HIF-1β-deficient cells), identifying it as a transcriptional target of the HIF-1 complex. Mxi1 induction during hypoxia contributes to downregulation of c-Myc target genes (e.g., ODC) and protects cells from c-Myc-dependent sensitization to hypoxia-induced apoptosis.","method":"Northern/Western blot in ARNT-deficient cells, reporter assays, apoptosis assays","journal":"Cancer biology & therapy","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic (ARNT-KO) and functional evidence, single lab","pmids":["16319523"],"is_preprint":false},{"year":2006,"finding":"In Xenopus, Mxi1 is positively regulated by Sox3, SoxD, and proneural genes, and negatively by the Notch pathway. Loss-of-function of Xmxi1 impairs establishment of a mature neural state, while overexpression causes ectopic Sox3 activation and transient inhibition of N-tubulin and cell cycle genes (XPak3, p27), placing Mxi1 between pan-neural and proneural gene programs in neurogenesis.","method":"Xenopus loss-of-function (antisense/dominant-negative), overexpression, in situ hybridization","journal":"Developmental biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic epistasis by loss- and gain-of-function in Xenopus model, single lab","pmids":["16457797"],"is_preprint":false},{"year":2007,"finding":"Glyceraldehyde-3-phosphate dehydrogenase (GAPDH) physically interacts with Mxi1-SRalpha and enhances its ability to activate the MYC promoter, contributing to the differential function of SRalpha versus SRbeta isoforms.","method":"Co-immunoprecipitation, transient transfection reporter assay","journal":"The FEBS journal","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single co-IP plus reporter assay, single lab","pmids":["17697116"],"is_preprint":false},{"year":2008,"finding":"Mxi1 is overexpressed in primary clear cell renal cancers bearing VHL inactivation (constitutive HIF signaling). shRNA inhibition of Mxi1 in pVHL-defective kidney cancer cells alters cell cycle parameters, inhibits Matrigel invasion, and suppresses tumor formation in vivo, establishing Mxi1 as a downstream HIF target that contributes to renal carcinoma tumorigenesis.","method":"shRNA knockdown, flow cytometry, Matrigel invasion assay, xenograft tumor formation","journal":"Cancer biology & therapy","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss-of-function with multiple readouts in vitro and in vivo, single lab","pmids":["19018165"],"is_preprint":false},{"year":2009,"finding":"HIF-1α (and HIF-2) directly binds and transactivates sequences near the MXI1-0 promoter, inducing the MXI1-0 isoform rapidly under hypoxia in neuroblastoma and breast cancer cells. Knockdown of MXI1 had limited effect on MYC/MYCN activity under hypoxia, suggesting the two MXI1 isoforms differ in their ability to antagonize MYC under hypoxic conditions.","method":"ChIP, transactivation reporter assay, siRNA knockdown, RT-PCR","journal":"Experimental cell research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP plus reporter assay demonstrating direct HIF binding and transactivation, single lab","pmids":["19254710"],"is_preprint":false},{"year":2010,"finding":"miR-191 directly targets Mxi1 (and Riok3) in erythroid cells. Knockdown of Mxi1 blocks erythroid enucleation and chromatin condensation, while miR-191 overexpression phenocopies this by suppressing Mxi1. Down-regulation of miR-191 during terminal erythroid differentiation is required to allow Mxi1 upregulation and enable enucleation.","method":"miRNA overexpression/knockdown, shRNA knockdown of Mxi1, luciferase 3′UTR reporter assay, RNA-seq","journal":"Genes & development","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal knockdown and rescue experiments with direct target validation, replicated across multiple approaches in a single rigorous study","pmids":["21196494"],"is_preprint":false},{"year":2012,"finding":"miR-24-3p and miR-27a-3p directly target the MXI1 3′UTR (validated by luciferase reporter assay) and cooperate to suppress MXI1 expression, thereby promoting glioma cell proliferation. Rescue experiments confirm that MXI1 knockdown phenocopies miRNA overexpression.","method":"3′UTR luciferase reporter assay, MTT proliferation assay, rescue experiments, bioinformatic target prediction","journal":"International journal of oncology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct 3′UTR validation plus rescue experiments, single lab","pmids":["23254855"],"is_preprint":false},{"year":2013,"finding":"miR-155 directly targets the MXI1 3′UTR (attenuates luciferase reporter activity) and decreases MXI1 mRNA and protein levels in glioma cells, promoting glioma cell proliferation. Rescue experiments confirm that miR-155-mediated proliferation promotion is through MXI1 suppression.","method":"3′UTR luciferase reporter assay, MTT assay, EdU incorporation, rescue experiments","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct 3′UTR validation and rescue, single lab","pmids":["24376632"],"is_preprint":false},{"year":2018,"finding":"S6K1 phosphorylates Mxi1 at serine 160 (S160), which enables β-TrCP E3 ubiquitin ligase to bind, ubiquitinate, and degrade Mxi1. A phosphorylation-resistant Mxi1-S160A mutant is more stable, more effective at suppressing Myc transcriptional activity, and more effective at reducing radioresistance in lung cancer cells.","method":"In vitro kinase assay (S6K1 on Mxi1), in vivo ubiquitination assay, immunoprecipitation, stable cell lines expressing WT or S160A Mxi1, tandem affinity purification/mass spectrometry","journal":"Theranostics","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro kinase assay plus mutagenesis plus in vivo ubiquitination assay, multiple orthogonal methods in single study","pmids":["29507620"],"is_preprint":false},{"year":2020,"finding":"UBE2O, an E2/E3 hybrid ubiquitin-protein ligase, physically interacts with Mxi1 and promotes its ubiquitination and degradation specifically at lysine 46 (K46). Genetic or pharmacological blockade of UBE2O impairs lung cancer tumor progression and radioresistance, effects reversed by Mxi1 inhibition.","method":"Co-immunoprecipitation, in vivo ubiquitination assay, site-directed mutagenesis (K46), genetic knockdown/knockout, rescue experiments in vitro and in vivo","journal":"Cell death and differentiation","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — co-IP, ubiquitination assay with K46 mutant, and in vivo rescue, multiple orthogonal methods","pmids":["32901121"],"is_preprint":false},{"year":2020,"finding":"MYC suppresses MXI1 expression via upregulation of miR-155 and the miR-23a~27a~24-2 cluster. In turn, MXI1 inhibits MYC expression by binding to the MYC promoter, forming a negative feedback loop. FTO (m6A RNA demethylase) regulates this loop by targeting MYC.","method":"Luciferase reporter assays, ChIP (Mxi1 binding to MYC promoter), miRNA overexpression, co-transfection rescue experiments","journal":"Cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP for Mxi1 at MYC promoter plus reporter assays plus miRNA functional studies, single lab","pmids":["32680921"],"is_preprint":false},{"year":2022,"finding":"PRMT5 arginine methyltransferase physically interacts with Mxi1 and methylates it, promoting binding of β-TrCP ubiquitin ligase to Mxi1 and thereby facilitating its ubiquitination and proteasomal degradation. Genetic or pharmacological blockade of PRMT5 increases Mxi1 stability, impairs DNA damage repair, and enhances radiosensitivity in lung cancer.","method":"Co-immunoprecipitation, in vitro methylation assay, in vivo ubiquitination assay, shRNA knockdown, pharmacological inhibition (EPZ015666), in vitro and in vivo functional assays","journal":"Cancer letters","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — in vitro methylation assay plus ubiquitination assay plus co-IP plus functional rescue, multiple orthogonal methods in single study","pmids":["35149174"],"is_preprint":false},{"year":2022,"finding":"Mxi1 inhibits lung cancer progression by directly suppressing transcription of miR-300, which in turn derepresses KLF9, and KLF9 negatively regulates GADD34 expression. ChIP and dual-luciferase assays confirm direct Mxi1 binding at the miR-300 promoter. In vivo, silencing KLF9 promotes tumor growth via GADD34-mediated MDSC immunosuppression.","method":"ChIP assay, dual luciferase reporter assay, loss- and gain-of-function studies, in vivo tumor models","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP plus reporter plus in vivo functional data, single lab","pmids":["35501353"],"is_preprint":false},{"year":2005,"finding":"A novel Mxi1 isoform (Mxi-D), lacking exon 3 (the basic region), can bind Max protein and the PAH2 region of mSin3 proteins (GST pulldown), but the Mxi-D/Max heterodimer cannot bind E-box DNA sequences (EMSA). Mxi-D represses transcription in reporter assays as strongly as full-length Mxi1, but cannot suppress c-Myc-induced clonal growth as effectively, suggesting it acts as a dominant-negative isoform.","method":"GST pulldown, EMSA, transient transfection reporter assay, colony formation assay","journal":"International journal of oncology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple biochemical methods (pulldown, EMSA, reporter, colony assay) in a single study, single lab","pmids":["15809730"],"is_preprint":false},{"year":2017,"finding":"Mxi1-0 regulates proliferation of HUVECs through ERK1/2 and IL-8 pathways. Mxi1-0 suppression decreased HUVEC proliferation, G2/M accumulation, IL-8 expression/secretion, and ERK1/2 activity; IL-8 neutralization abolished conditioned-medium-induced proliferation. ERK1/2 inhibition attenuated Mxi1-0-induced IL-8 autocrine production, indicating reciprocal activation between ERK1/2 and IL-8 downstream of Mxi1-0.","method":"siRNA knockdown, overexpression, ERK1/2 inhibitor (U0126), neutralizing antibody, flow cytometry, ELISA","journal":"PloS one","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, functional cell biology without direct biochemical mechanism for how Mxi1-0 activates ERK","pmids":["28575053"],"is_preprint":false},{"year":2025,"finding":"FUBP3 stabilizes Mxi1 protein by interacting with it, and Mxi1 in turn recruits NCOR1/2, Sin3A/B, and HDAC1 to co-repress RRAS transcription, thereby blocking RRAS-mediated ERK signaling. This FUBP3/MXI1/RRAS/MAPK axis suppresses CD8+ T cell immune escape in acute megakaryoblastic leukemia.","method":"Co-immunoprecipitation, lentiviral overexpression/knockdown, ChIP (Mxi1 at RRAS promoter with co-repressor recruitment), in vivo mouse AMKL model","journal":"Cancer immunology, immunotherapy : CII","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP plus co-IP plus in vivo functional evidence, single lab, single study","pmids":["41428087"],"is_preprint":false}],"current_model":"MXI1 (Mxi1) is a bHLH-Zip transcriptional repressor that heterodimerizes with Max via its HLH-Zip domain to bind E-box (CACGTG) sequences, competing with oncogenic Myc-Max complexes; its amino-terminal SIN3-interacting domain (SID) recruits mSin3A/B and associated HDAC complexes (including NCOR1/2 and HDAC1) to actively repress transcription of Myc target genes, while it also directly represses the c-MYC promoter through a Sin3-independent, LZ/CK2-site-dependent mechanism; its stability is regulated post-translationally by S6K1-mediated phosphorylation at S160 triggering β-TrCP-dependent ubiquitin–proteasome degradation, by UBE2O-mediated ubiquitination at K46, and by PRMT5-mediated arginine methylation that enhances β-TrCP binding, while FUBP3 counteracts degradation by stabilizing Mxi1; alternative promoter usage and splicing generate functionally distinct isoforms, notably Mxi1-0, which localizes predominantly to the cytoplasm and cannot repress Myc targets despite retaining Max and E-box binding, and the nuclear Mxi1-SRalpha, which has higher Sin3 affinity but paradoxically activates the MYC promoter, adding a layer of isoform-dependent complexity to the Myc antagonism network; in vivo, Mxi1 loss causes multi-organ hyperplasia, prostate hyperplasia, and enhanced tumorigenesis, confirming its tumor suppressor function downstream of both HIF-1 (which induces Mxi1 transcription under hypoxia) and the Myc/Max/Mad signaling network."},"narrative":{"mechanistic_narrative":"MXI1 (Mxi1) is a bHLH-Zip transcriptional repressor that antagonizes the Myc oncogenic program and acts as a tumor suppressor [PMID:8425219, PMID:9624006]. It heterodimerizes specifically with Max and binds the CACGTG E-box, occupying Myc-Max target sites as a transactivation-incompetent complex; deletion of its basic DNA-binding region attenuates suppression, establishing site occupancy rather than simple Max titration as the dominant antagonism mechanism [PMID:8425219, PMID:8202517]. Active repression is conferred by a short amino-terminal SIN3-interacting domain (SID) that recruits mSin3 and associated co-repressors, dramatically augmenting anti-Myc activity; a Sin3-fusion substituting for the SID recapitulates full repression, and Mxi1 in turn assembles NCOR1/2, Sin3A/B, and HDAC1 on target promoters [PMID:7889571, PMID:8649810, PMID:41428087]. Beyond E-box-dependent repression, Mxi1 directly represses the c-MYC P2 promoter through a Sin3-independent mechanism requiring its leucine zipper and C-terminal CK2 sites, and MYC reciprocally suppresses MXI1 via miRNA induction, forming a negative feedback loop [PMID:9872993, PMID:32680921]. Functionally, Mxi1 inhibits Myc-driven target genes such as ODC, arrests the cell cycle, suppresses transformation and tumor growth, and its loss in mice causes multi-organ and prostate hyperplasia with enhanced tumorigenesis [PMID:8202517, PMID:8637719, PMID:9624006, PMID:11351349]. Mxi1 abundance is controlled post-translationally: S6K1 phosphorylation at S160 and PRMT5-mediated arginine methylation both promote β-TrCP-dependent ubiquitin–proteasome degradation, UBE2O ubiquitinates Mxi1 at K46, and FUBP3 counteracts turnover by stabilizing the protein [PMID:29507620, PMID:32901121, PMID:35149174, PMID:41428087]. Transcriptionally, MXI1 is a hypoxia-inducible HIF-1/HIF-2 target and is repressed by multiple oncogenic miRNAs (miR-24-3p, miR-27a-3p, miR-155, miR-191), linking it to hypoxic adaptation, erythroid differentiation, and glioma proliferation [PMID:16319523, PMID:19254710, PMID:21196494, PMID:23254855, PMID:24376632]. Alternative promoter usage and splicing generate functionally distinct isoforms, notably the cytoplasmic Mxi1-0, which retains Max and E-box binding but cannot repress Myc targets, and Mxi1-SRalpha, which has higher Sin3 affinity yet paradoxically activates the MYC promoter [PMID:15548375, PMID:15467743, PMID:15809730].","teleology":[{"year":1993,"claim":"Established the founding molecular identity of Mxi1 as a Max partner that occupies Myc-Max DNA sites without activating transcription, defining it as a candidate Myc antagonist.","evidence":"Yeast two-hybrid interaction trap and E-box DNA binding assays","pmids":["8425219"],"confidence":"High","gaps":["Did not establish how repression is enforced beyond site occupancy","No in vivo functional role demonstrated"]},{"year":1994,"claim":"Distinguished between two competing suppression models, showing transactivation-incompetent Mxi1-Max site occupancy, not mere Max sequestration, drives suppression of Myc-induced transformation.","evidence":"Rat embryo fibroblast focus formation assay with basic-region deletion mutants","pmids":["8202517"],"confidence":"High","gaps":["Did not identify the repressive co-factors recruited","Transformation readout indirect for endogenous transcription"]},{"year":1995,"claim":"Identified the SID as the module that converts passive site occupancy into active repression by recruiting mSin3, explaining why SID-lacking isoforms are weak repressors.","evidence":"Deletion mutagenesis, co-IP, and REF transformation assays","pmids":["7889571","8649810"],"confidence":"High","gaps":["HDAC enzymatic activity not directly shown in these studies","Genome-wide target occupancy unmeasured"]},{"year":1998,"claim":"Provided definitive in vivo proof that Mxi1 is a tumor suppressor, with loss causing hyperplasia and accelerated tumorigenesis cooperating with Ink4a deficiency.","evidence":"Mxi1 knockout mice, carcinogen challenge, and genetic cross with Ink4a-deficient mice","pmids":["9624006"],"confidence":"High","gaps":["Did not resolve which target genes mediate the phenotype","Tissue-specific contributions not dissected"]},{"year":1999,"claim":"Revealed a second, Sin3-independent repression mode in which Mxi1 directly silences the c-myc P2 promoter via its leucine zipper and C-terminal CK2 sites, coupling Mxi1 to S-phase entry control.","evidence":"Reporter assays, inducible expression, and cell cycle analysis","pmids":["9872993"],"confidence":"Medium","gaps":["CK2 phosphorylation of Mxi1 not directly demonstrated","Mechanism of USF antagonism unresolved"]},{"year":2004,"claim":"Demonstrated isoform-dependent functional divergence, with cytoplasmic Mxi1-0 retaining Max/E-box/Sin3 binding yet failing to repress Myc, and Mxi1-SRalpha paradoxically activating the MYC promoter.","evidence":"Promoter-specific RT-PCR, co-IP, EMSA, fractionation, and reporter/REF transformation assays","pmids":["15548375","15467743"],"confidence":"High","gaps":["Mechanism of Mxi1-0 cytoplasmic retention unknown","Basis for SRalpha activation versus repression undefined"]},{"year":2005,"claim":"Identified additional isoform complexity with Mxi-D, which binds Max and Sin3 but cannot bind E-box DNA, acting as a dominant-negative.","evidence":"GST pulldown, EMSA, reporter, and colony formation assays","pmids":["15809730"],"confidence":"Medium","gaps":["Endogenous abundance and physiological relevance unclear","Dominant-negative mechanism in vivo untested"]},{"year":2006,"claim":"Placed Mxi1 in a developmental program, positioning it downstream of proneural/Sox and Notch inputs during neurogenesis.","evidence":"Xenopus loss- and gain-of-function with in situ hybridization","pmids":["16457797"],"confidence":"Medium","gaps":["Direct transcriptional targets in neural cells unidentified","Mammalian relevance not established"]},{"year":2008,"claim":"Connected Mxi1 to hypoxic signaling, showing it is a HIF-1-induced transcriptional target that downregulates Myc targets and buffers Myc-driven hypoxic apoptosis.","evidence":"Northern/Western in ARNT-deficient cells, reporter and apoptosis assays; shRNA in pVHL-defective cells with xenografts","pmids":["16319523","19018165"],"confidence":"Medium","gaps":["Context-dependent oncogenic versus suppressive roles unresolved","Direct HIF binding element on canonical MXI1 promoter not mapped here"]},{"year":2009,"claim":"Mapped direct HIF binding to the MXI1-0 promoter and showed the MXI1-0 isoform is the predominant hypoxia-induced form, with limited effect on MYC under hypoxia.","evidence":"ChIP, transactivation reporter, and siRNA/RT-PCR","pmids":["19254710"],"confidence":"Medium","gaps":["Functional consequence of MXI1-0 induction under hypoxia incompletely defined","Isoform-specific targets unknown"]},{"year":2013,"claim":"Established post-transcriptional control of MXI1 by oncogenic miRNAs, showing miR-191, miR-24-3p/miR-27a-3p, and miR-155 directly target the 3'UTR to modulate erythroid maturation and tumor cell proliferation.","evidence":"3'UTR luciferase reporters, miRNA/shRNA modulation, rescue experiments, and RNA-seq","pmids":["21196494","23254855","24376632"],"confidence":"High","gaps":["Relative contribution of each miRNA in normal tissue unclear","Downstream Myc target sets in each context not fully mapped"]},{"year":2020,"claim":"Defined the post-translational degradation machinery for Mxi1, identifying S6K1-S160 phosphorylation and UBE2O-K46 ubiquitination as drivers of β-TrCP/proteasome turnover that regulate Myc suppression and radioresistance.","evidence":"In vitro kinase/ubiquitination assays, site-directed mutagenesis, and in vivo rescue in lung cancer models","pmids":["29507620","32901121"],"confidence":"High","gaps":["Interplay between S6K1 and UBE2O pathways not resolved","Deubiquitinase counter-regulation unidentified at this stage"]},{"year":2020,"claim":"Closed the MYC-MXI1 regulatory circuit, showing MYC represses MXI1 via miRNAs while MXI1 binds and represses the MYC promoter, forming a negative feedback loop.","evidence":"ChIP at MYC promoter, reporter assays, and miRNA functional studies","pmids":["32680921"],"confidence":"Medium","gaps":["Quantitative dynamics of the feedback loop unmodeled","FTO/m6A contribution mechanistically incomplete"]},{"year":2022,"claim":"Extended Mxi1 regulation to arginine methylation, showing PRMT5 methylates Mxi1 to enhance β-TrCP binding and degradation, linking Mxi1 stability to DNA damage repair and radiosensitivity.","evidence":"In vitro methylation/ubiquitination assays, co-IP, PRMT5 inhibition (EPZ015666), and in vivo functional assays","pmids":["35149174"],"confidence":"High","gaps":["Specific methylated arginine residue(s) not pinpointed","Crosstalk with S160 phosphorylation undefined"]},{"year":2022,"claim":"Identified non-Myc target genes of Mxi1, showing direct repression of the miR-300 promoter feeds a KLF9/GADD34 axis controlling tumor immunosuppression.","evidence":"ChIP, dual-luciferase reporter, loss/gain-of-function, and in vivo tumor models","pmids":["35501353"],"confidence":"Medium","gaps":["Direct co-repressor recruitment at miR-300 promoter not shown","Generalizability beyond lung cancer untested"]},{"year":2025,"claim":"Showed Mxi1 stabilization by FUBP3 and direct co-repressor (NCOR1/2, Sin3A/B, HDAC1) recruitment to the RRAS promoter blocks ERK signaling and CD8+ T cell immune escape, integrating Mxi1 into immune regulation.","evidence":"Co-IP, lentiviral knockdown/overexpression, ChIP with co-repressor mapping, and in vivo AMKL mouse model","pmids":["41428087"],"confidence":"Medium","gaps":["FUBP3-Mxi1 interaction interface unmapped","Whether RRAS repression is E-box-dependent unclear"]},{"year":null,"claim":"How the distinct degradation inputs (S6K1, UBE2O, PRMT5, β-TrCP) and stabilizers (FUBP3) are integrated to set Mxi1 levels across tissues, and what determines isoform-specific localization and the activator-versus-repressor switch, remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structural model of the Mxi1-Max-Sin3 repressive complex","Genome-wide direct target catalog incomplete","Mechanism of cytoplasmic retention of Mxi1-0 unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[0,1,2,6,21,23,26]},{"term_id":"GO:0003677","term_label":"DNA binding","supporting_discovery_ids":[0,2,21,23]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[3,9]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[9]}],"pathway":[{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[0,1,6,21,23]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[5,8,14,26]},{"term_id":"R-HSA-8953897","term_label":"Cellular responses to stimuli","supporting_discovery_ids":[11,15]},{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[19,20,22]}],"complexes":["Mxi1-Max heterodimer","mSin3-HDAC co-repressor complex"],"partners":["MAX","SIN3A","SIN3B","NCOR1","NCOR2","HDAC1","UBE2O","PRMT5"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P50539","full_name":"Max-interacting protein 1","aliases":["Class C basic helix-loop-helix protein 11","bHLHc11"],"length_aa":228,"mass_kda":26.1,"function":"Transcriptional repressor. MXI1 binds with MAX to form a sequence-specific DNA-binding protein complex which recognizes the core sequence 5'-CAC[GA]TG-3'. 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the calcifying areas of the epiphyseal-plate cartilage matrix of growing rats.","date":"1999","source":"Bone","url":"https://pubmed.ncbi.nlm.nih.gov/10375197","citation_count":1,"is_preprint":false},{"pmid":"41428087","id":"PMC_41428087","title":"FUBP3 mediates MXI1 stability to silence RRAS and hinder MAPK signaling in acute megakaryoblastic leukemia progression.","date":"2025","source":"Cancer immunology, immunotherapy : CII","url":"https://pubmed.ncbi.nlm.nih.gov/41428087","citation_count":0,"is_preprint":false},{"pmid":"22449707","id":"PMC_22449707","title":"Mxi1 influences cyst formation in three-dimensional cell culture.","date":"2012","source":"BMB reports","url":"https://pubmed.ncbi.nlm.nih.gov/22449707","citation_count":0,"is_preprint":false},{"pmid":"18457265","id":"PMC_18457265","title":"[Expression and mutation of myc antagonist genes Mad1, Mxi1 and Rox in leukemia cells].","date":"2007","source":"Zhonghua xue ye xue za zhi = Zhonghua xueyexue zazhi","url":"https://pubmed.ncbi.nlm.nih.gov/18457265","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2025.09.11.675674","title":"Integrated Expression Analysis of C-MYC Oncogene-Associated Pathways in Gastric Adenocarcinoma and it’s Correlation with Clinicopathological Factors","date":"2025-09-16","source":"bioRxiv","url":"https://doi.org/10.1101/2025.09.11.675674","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2024.11.12.623187","title":"Unveiling epigenetic regulatory elements associated with breast cancer development","date":"2024-11-15","source":"bioRxiv","url":"https://doi.org/10.1101/2024.11.12.623187","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":38875,"output_tokens":6877,"usd":0.10989,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":15861,"output_tokens":5166,"usd":0.104228,"stage2_stop_reason":"end_turn"},"total_usd":0.214118,"stage1_batch_id":"msgbatch_013a8chtv3AWyTqv4z4sEF4C","stage2_batch_id":"msgbatch_01AHsuW63vinsvuTgzmQ3n62","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1993,\n      \"finding\": \"MXI1 (Mxi1) interacts specifically with Max to form heterodimers that efficiently bind to the Myc-Max consensus recognition site (CACGTG E-box). When bound to DNA in yeast, Mxi1 does not stimulate transcription, consistent with it being a transcriptional repressor that sequesters Max and competes with Myc-Max heterodimers for target sites.\",\n      \"method\": \"Yeast two-hybrid interaction trap, DNA binding assays\",\n      \"journal\": \"Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — original biochemical characterization with yeast two-hybrid and DNA binding assays, replicated in multiple subsequent studies\",\n      \"pmids\": [\"8425219\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1995,\n      \"finding\": \"A short amino-terminal alpha-helical domain of Mxi1 (the SIN3-interacting domain, SID) dramatically augments its transcriptional repressive and anti-Myc suppressive potential by mediating physical association with a mammalian homolog of the yeast transcriptional repressor SIN3 (mSin3B). Mxi1 isoforms lacking this domain are functionally weaker repressors.\",\n      \"method\": \"Deletion mutagenesis, co-immunoprecipitation, rat embryo fibroblast transformation assay, transient transfection reporter assays\",\n      \"journal\": \"Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — multiple orthogonal methods including mutagenesis, co-IP, and functional transformation assay; independently replicated\",\n      \"pmids\": [\"7889571\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1994,\n      \"finding\": \"Mad and Mxi1 suppress Myc-induced transformation (c-Myc and N-Myc, but not E1a) in rat embryo fibroblast cooperation assays. Deletion of the basic region (DNA-binding domain) attenuates suppression, indicating that occupation of common DNA binding sites by transactivation-incompetent Mxi1-Max complexes is the dominant suppression mechanism over simple Max titration.\",\n      \"method\": \"Rat embryo fibroblast focus formation assay, basic-region deletion mutants\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — epistasis/functional assay with mutagenesis controls, replicated by subsequent studies\",\n      \"pmids\": [\"8202517\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1996,\n      \"finding\": \"mSin3A physically associates with the strong-repression isoform of Mxi1 (Mxi1-SR) and both co-localize to the nucleus. A mSin3A–Mxi1 fusion protein in which the Sin3-interacting domain of Mxi1 is replaced by full-length mSin3A retains or exceeds Mxi1-SR repression activity, demonstrating that the amino-terminal domain of Mxi1-SR functions solely to recruit mSin3A (and related proteins) and that this recruitment is necessary for anti-Myc activity.\",\n      \"method\": \"Co-immunoprecipitation, nuclear localization by immunofluorescence, fusion protein rescue in REF transformation assay\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — co-IP plus functional rescue with fusion protein in single lab, multiple orthogonal methods\",\n      \"pmids\": [\"8649810\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1996,\n      \"finding\": \"Overexpression of Mxi1 inhibits Myc/Max-dependent transcriptional induction of the ornithine decarboxylase (ODC) gene in a dose-dependent manner both in vivo (transfection) and in vitro. Mxi1 protein levels are up-regulated during quiescence and down-regulated following serum stimulation.\",\n      \"method\": \"Transient transfection reporter assays, Northern blot for ODC mRNA\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo and in vitro reporter assays, single lab\",\n      \"pmids\": [\"8637719\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"Mice lacking Mxi1 exhibit progressive, multisystem abnormalities including prostate epithelial hyperplasia, increased susceptibility to carcinogen-induced tumors, and enhanced tumorigenesis when also deficient in Ink4a, establishing Mxi1 as a tumor suppressor in vivo that engages the Myc network in a functionally relevant manner.\",\n      \"method\": \"Targeted gene deletion (knockout mouse), carcinogen treatment, genetic cross with Ink4a-deficient mice\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo knockout with multiple phenotypic readouts and genetic epistasis\",\n      \"pmids\": [\"9624006\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"Mxi1 represses transcription from the major c-myc promoter P2 by targeting the core promoter elements and reversing activation by the constitutive transcription factor USF. This repression is independent of mSin3 binding but requires the Mxi1 leucine zipper and C-terminal sequences including putative CK2 phosphorylation sites. Zinc-inducible Mxi1 expression blocks serum-induced c-myc transcription and cell entry into S phase.\",\n      \"method\": \"Transient transfection reporter assays, stable inducible expression (metallothionein promoter), cell cycle analysis\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reporter assays with mutagenesis and inducible expression, single lab\",\n      \"pmids\": [\"9872993\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"The MXI1 promoter is GC-rich, lacks a TATA box, and its activity is driven primarily by two proximal initiator sequences combined with nearby Sp1 and MED-1 sites. MXI1 promoter activity is repressed by high levels of AP2 transcription factor.\",\n      \"method\": \"Promoter cloning, deletion analysis, transient transfection reporter assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — promoter functional dissection with multiple deletion constructs, single lab\",\n      \"pmids\": [\"10497252\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"Expression of Mxi1 in DU145 prostate carcinoma cells via adenoviral vector reduces cell proliferation, reduces soft agar colony formation, and causes G2/M phase cell cycle arrest associated with elevated cyclin B and reduced c-MYC and MDM2 protein levels.\",\n      \"method\": \"Adenoviral Mxi1 expression, MTT proliferation assay, soft agar colony formation, flow cytometry cell cycle analysis, Western blot\",\n      \"journal\": \"The Prostate\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — gain-of-function with multiple phenotypic readouts, single lab\",\n      \"pmids\": [\"11351349\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"Mxi1-0, an alternatively transcribed Mxi1 isoform using an upstream exon with a unique N-terminal sequence, can bind Max and E-box DNA sites and interact with Sin3, but is predominantly localized to the cytoplasm (unlike nuclear Mxi1) and fails to repress c-Myc-dependent transcription. Its levels are higher in primary glioblastoma than normal brain, suggesting it may modulate Mxi1's Myc-inhibitory activity.\",\n      \"method\": \"RT-PCR/cloning, co-immunoprecipitation, EMSA (E-box binding), reporter assays, subcellular fractionation/immunofluorescence\",\n      \"journal\": \"Neoplasia (New York, N.Y.)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — multiple orthogonal biochemical and cell biological methods in a single thorough study\",\n      \"pmids\": [\"15548375\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"A novel Mxi1 isoform, Mxi1-SRalpha, arises from its own promoter and encodes a unique Sin3-interacting domain with greater affinity for Sin3 adapter proteins than the related Mxi1-SRbeta isoform, conferring enhanced transcriptional repression in reporter assays. Unlike Mxi1-SRbeta, Mxi1-SRalpha activates rather than represses the MYC promoter, and is a less potent suppressor of Myc-induced cellular transformation.\",\n      \"method\": \"Promoter-specific RT-PCR, co-immunoprecipitation, transient transfection reporter assays, REF transformation assay\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple methods including co-IP and functional assays, single lab\",\n      \"pmids\": [\"15467743\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"Mxi1 is induced by hypoxia in a HIF-1-dependent manner (not induced in ARNT/HIF-1β-deficient cells), identifying it as a transcriptional target of the HIF-1 complex. Mxi1 induction during hypoxia contributes to downregulation of c-Myc target genes (e.g., ODC) and protects cells from c-Myc-dependent sensitization to hypoxia-induced apoptosis.\",\n      \"method\": \"Northern/Western blot in ARNT-deficient cells, reporter assays, apoptosis assays\",\n      \"journal\": \"Cancer biology & therapy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic (ARNT-KO) and functional evidence, single lab\",\n      \"pmids\": [\"16319523\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"In Xenopus, Mxi1 is positively regulated by Sox3, SoxD, and proneural genes, and negatively by the Notch pathway. Loss-of-function of Xmxi1 impairs establishment of a mature neural state, while overexpression causes ectopic Sox3 activation and transient inhibition of N-tubulin and cell cycle genes (XPak3, p27), placing Mxi1 between pan-neural and proneural gene programs in neurogenesis.\",\n      \"method\": \"Xenopus loss-of-function (antisense/dominant-negative), overexpression, in situ hybridization\",\n      \"journal\": \"Developmental biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic epistasis by loss- and gain-of-function in Xenopus model, single lab\",\n      \"pmids\": [\"16457797\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"Glyceraldehyde-3-phosphate dehydrogenase (GAPDH) physically interacts with Mxi1-SRalpha and enhances its ability to activate the MYC promoter, contributing to the differential function of SRalpha versus SRbeta isoforms.\",\n      \"method\": \"Co-immunoprecipitation, transient transfection reporter assay\",\n      \"journal\": \"The FEBS journal\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single co-IP plus reporter assay, single lab\",\n      \"pmids\": [\"17697116\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Mxi1 is overexpressed in primary clear cell renal cancers bearing VHL inactivation (constitutive HIF signaling). shRNA inhibition of Mxi1 in pVHL-defective kidney cancer cells alters cell cycle parameters, inhibits Matrigel invasion, and suppresses tumor formation in vivo, establishing Mxi1 as a downstream HIF target that contributes to renal carcinoma tumorigenesis.\",\n      \"method\": \"shRNA knockdown, flow cytometry, Matrigel invasion assay, xenograft tumor formation\",\n      \"journal\": \"Cancer biology & therapy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss-of-function with multiple readouts in vitro and in vivo, single lab\",\n      \"pmids\": [\"19018165\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"HIF-1α (and HIF-2) directly binds and transactivates sequences near the MXI1-0 promoter, inducing the MXI1-0 isoform rapidly under hypoxia in neuroblastoma and breast cancer cells. Knockdown of MXI1 had limited effect on MYC/MYCN activity under hypoxia, suggesting the two MXI1 isoforms differ in their ability to antagonize MYC under hypoxic conditions.\",\n      \"method\": \"ChIP, transactivation reporter assay, siRNA knockdown, RT-PCR\",\n      \"journal\": \"Experimental cell research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP plus reporter assay demonstrating direct HIF binding and transactivation, single lab\",\n      \"pmids\": [\"19254710\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"miR-191 directly targets Mxi1 (and Riok3) in erythroid cells. Knockdown of Mxi1 blocks erythroid enucleation and chromatin condensation, while miR-191 overexpression phenocopies this by suppressing Mxi1. Down-regulation of miR-191 during terminal erythroid differentiation is required to allow Mxi1 upregulation and enable enucleation.\",\n      \"method\": \"miRNA overexpression/knockdown, shRNA knockdown of Mxi1, luciferase 3′UTR reporter assay, RNA-seq\",\n      \"journal\": \"Genes & development\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal knockdown and rescue experiments with direct target validation, replicated across multiple approaches in a single rigorous study\",\n      \"pmids\": [\"21196494\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"miR-24-3p and miR-27a-3p directly target the MXI1 3′UTR (validated by luciferase reporter assay) and cooperate to suppress MXI1 expression, thereby promoting glioma cell proliferation. Rescue experiments confirm that MXI1 knockdown phenocopies miRNA overexpression.\",\n      \"method\": \"3′UTR luciferase reporter assay, MTT proliferation assay, rescue experiments, bioinformatic target prediction\",\n      \"journal\": \"International journal of oncology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct 3′UTR validation plus rescue experiments, single lab\",\n      \"pmids\": [\"23254855\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"miR-155 directly targets the MXI1 3′UTR (attenuates luciferase reporter activity) and decreases MXI1 mRNA and protein levels in glioma cells, promoting glioma cell proliferation. Rescue experiments confirm that miR-155-mediated proliferation promotion is through MXI1 suppression.\",\n      \"method\": \"3′UTR luciferase reporter assay, MTT assay, EdU incorporation, rescue experiments\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct 3′UTR validation and rescue, single lab\",\n      \"pmids\": [\"24376632\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"S6K1 phosphorylates Mxi1 at serine 160 (S160), which enables β-TrCP E3 ubiquitin ligase to bind, ubiquitinate, and degrade Mxi1. A phosphorylation-resistant Mxi1-S160A mutant is more stable, more effective at suppressing Myc transcriptional activity, and more effective at reducing radioresistance in lung cancer cells.\",\n      \"method\": \"In vitro kinase assay (S6K1 on Mxi1), in vivo ubiquitination assay, immunoprecipitation, stable cell lines expressing WT or S160A Mxi1, tandem affinity purification/mass spectrometry\",\n      \"journal\": \"Theranostics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro kinase assay plus mutagenesis plus in vivo ubiquitination assay, multiple orthogonal methods in single study\",\n      \"pmids\": [\"29507620\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"UBE2O, an E2/E3 hybrid ubiquitin-protein ligase, physically interacts with Mxi1 and promotes its ubiquitination and degradation specifically at lysine 46 (K46). Genetic or pharmacological blockade of UBE2O impairs lung cancer tumor progression and radioresistance, effects reversed by Mxi1 inhibition.\",\n      \"method\": \"Co-immunoprecipitation, in vivo ubiquitination assay, site-directed mutagenesis (K46), genetic knockdown/knockout, rescue experiments in vitro and in vivo\",\n      \"journal\": \"Cell death and differentiation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — co-IP, ubiquitination assay with K46 mutant, and in vivo rescue, multiple orthogonal methods\",\n      \"pmids\": [\"32901121\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"MYC suppresses MXI1 expression via upregulation of miR-155 and the miR-23a~27a~24-2 cluster. In turn, MXI1 inhibits MYC expression by binding to the MYC promoter, forming a negative feedback loop. FTO (m6A RNA demethylase) regulates this loop by targeting MYC.\",\n      \"method\": \"Luciferase reporter assays, ChIP (Mxi1 binding to MYC promoter), miRNA overexpression, co-transfection rescue experiments\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP for Mxi1 at MYC promoter plus reporter assays plus miRNA functional studies, single lab\",\n      \"pmids\": [\"32680921\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"PRMT5 arginine methyltransferase physically interacts with Mxi1 and methylates it, promoting binding of β-TrCP ubiquitin ligase to Mxi1 and thereby facilitating its ubiquitination and proteasomal degradation. Genetic or pharmacological blockade of PRMT5 increases Mxi1 stability, impairs DNA damage repair, and enhances radiosensitivity in lung cancer.\",\n      \"method\": \"Co-immunoprecipitation, in vitro methylation assay, in vivo ubiquitination assay, shRNA knockdown, pharmacological inhibition (EPZ015666), in vitro and in vivo functional assays\",\n      \"journal\": \"Cancer letters\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — in vitro methylation assay plus ubiquitination assay plus co-IP plus functional rescue, multiple orthogonal methods in single study\",\n      \"pmids\": [\"35149174\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Mxi1 inhibits lung cancer progression by directly suppressing transcription of miR-300, which in turn derepresses KLF9, and KLF9 negatively regulates GADD34 expression. ChIP and dual-luciferase assays confirm direct Mxi1 binding at the miR-300 promoter. In vivo, silencing KLF9 promotes tumor growth via GADD34-mediated MDSC immunosuppression.\",\n      \"method\": \"ChIP assay, dual luciferase reporter assay, loss- and gain-of-function studies, in vivo tumor models\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP plus reporter plus in vivo functional data, single lab\",\n      \"pmids\": [\"35501353\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"A novel Mxi1 isoform (Mxi-D), lacking exon 3 (the basic region), can bind Max protein and the PAH2 region of mSin3 proteins (GST pulldown), but the Mxi-D/Max heterodimer cannot bind E-box DNA sequences (EMSA). Mxi-D represses transcription in reporter assays as strongly as full-length Mxi1, but cannot suppress c-Myc-induced clonal growth as effectively, suggesting it acts as a dominant-negative isoform.\",\n      \"method\": \"GST pulldown, EMSA, transient transfection reporter assay, colony formation assay\",\n      \"journal\": \"International journal of oncology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple biochemical methods (pulldown, EMSA, reporter, colony assay) in a single study, single lab\",\n      \"pmids\": [\"15809730\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Mxi1-0 regulates proliferation of HUVECs through ERK1/2 and IL-8 pathways. Mxi1-0 suppression decreased HUVEC proliferation, G2/M accumulation, IL-8 expression/secretion, and ERK1/2 activity; IL-8 neutralization abolished conditioned-medium-induced proliferation. ERK1/2 inhibition attenuated Mxi1-0-induced IL-8 autocrine production, indicating reciprocal activation between ERK1/2 and IL-8 downstream of Mxi1-0.\",\n      \"method\": \"siRNA knockdown, overexpression, ERK1/2 inhibitor (U0126), neutralizing antibody, flow cytometry, ELISA\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, functional cell biology without direct biochemical mechanism for how Mxi1-0 activates ERK\",\n      \"pmids\": [\"28575053\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"FUBP3 stabilizes Mxi1 protein by interacting with it, and Mxi1 in turn recruits NCOR1/2, Sin3A/B, and HDAC1 to co-repress RRAS transcription, thereby blocking RRAS-mediated ERK signaling. This FUBP3/MXI1/RRAS/MAPK axis suppresses CD8+ T cell immune escape in acute megakaryoblastic leukemia.\",\n      \"method\": \"Co-immunoprecipitation, lentiviral overexpression/knockdown, ChIP (Mxi1 at RRAS promoter with co-repressor recruitment), in vivo mouse AMKL model\",\n      \"journal\": \"Cancer immunology, immunotherapy : CII\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP plus co-IP plus in vivo functional evidence, single lab, single study\",\n      \"pmids\": [\"41428087\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"MXI1 (Mxi1) is a bHLH-Zip transcriptional repressor that heterodimerizes with Max via its HLH-Zip domain to bind E-box (CACGTG) sequences, competing with oncogenic Myc-Max complexes; its amino-terminal SIN3-interacting domain (SID) recruits mSin3A/B and associated HDAC complexes (including NCOR1/2 and HDAC1) to actively repress transcription of Myc target genes, while it also directly represses the c-MYC promoter through a Sin3-independent, LZ/CK2-site-dependent mechanism; its stability is regulated post-translationally by S6K1-mediated phosphorylation at S160 triggering β-TrCP-dependent ubiquitin–proteasome degradation, by UBE2O-mediated ubiquitination at K46, and by PRMT5-mediated arginine methylation that enhances β-TrCP binding, while FUBP3 counteracts degradation by stabilizing Mxi1; alternative promoter usage and splicing generate functionally distinct isoforms, notably Mxi1-0, which localizes predominantly to the cytoplasm and cannot repress Myc targets despite retaining Max and E-box binding, and the nuclear Mxi1-SRalpha, which has higher Sin3 affinity but paradoxically activates the MYC promoter, adding a layer of isoform-dependent complexity to the Myc antagonism network; in vivo, Mxi1 loss causes multi-organ hyperplasia, prostate hyperplasia, and enhanced tumorigenesis, confirming its tumor suppressor function downstream of both HIF-1 (which induces Mxi1 transcription under hypoxia) and the Myc/Max/Mad signaling network.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"MXI1 (Mxi1) is a bHLH-Zip transcriptional repressor that antagonizes the Myc oncogenic program and acts as a tumor suppressor [#0, #5]. It heterodimerizes specifically with Max and binds the CACGTG E-box, occupying Myc-Max target sites as a transactivation-incompetent complex; deletion of its basic DNA-binding region attenuates suppression, establishing site occupancy rather than simple Max titration as the dominant antagonism mechanism [#0, #2]. Active repression is conferred by a short amino-terminal SIN3-interacting domain (SID) that recruits mSin3 and associated co-repressors, dramatically augmenting anti-Myc activity; a Sin3-fusion substituting for the SID recapitulates full repression, and Mxi1 in turn assembles NCOR1/2, Sin3A/B, and HDAC1 on target promoters [#1, #3, #26]. Beyond E-box-dependent repression, Mxi1 directly represses the c-MYC P2 promoter through a Sin3-independent mechanism requiring its leucine zipper and C-terminal CK2 sites, and MYC reciprocally suppresses MXI1 via miRNA induction, forming a negative feedback loop [#6, #21]. Functionally, Mxi1 inhibits Myc-driven target genes such as ODC, arrests the cell cycle, suppresses transformation and tumor growth, and its loss in mice causes multi-organ and prostate hyperplasia with enhanced tumorigenesis [#2, #4, #5, #8]. Mxi1 abundance is controlled post-translationally: S6K1 phosphorylation at S160 and PRMT5-mediated arginine methylation both promote \\u03b2-TrCP-dependent ubiquitin\\u2013proteasome degradation, UBE2O ubiquitinates Mxi1 at K46, and FUBP3 counteracts turnover by stabilizing the protein [#19, #20, #22, #26]. Transcriptionally, MXI1 is a hypoxia-inducible HIF-1/HIF-2 target and is repressed by multiple oncogenic miRNAs (miR-24-3p, miR-27a-3p, miR-155, miR-191), linking it to hypoxic adaptation, erythroid differentiation, and glioma proliferation [#11, #15, #16, #17, #18]. Alternative promoter usage and splicing generate functionally distinct isoforms, notably the cytoplasmic Mxi1-0, which retains Max and E-box binding but cannot repress Myc targets, and Mxi1-SRalpha, which has higher Sin3 affinity yet paradoxically activates the MYC promoter [#9, #10, #24].\",\n  \"teleology\": [\n    {\n      \"year\": 1993,\n      \"claim\": \"Established the founding molecular identity of Mxi1 as a Max partner that occupies Myc-Max DNA sites without activating transcription, defining it as a candidate Myc antagonist.\",\n      \"evidence\": \"Yeast two-hybrid interaction trap and E-box DNA binding assays\",\n      \"pmids\": [\"8425219\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not establish how repression is enforced beyond site occupancy\", \"No in vivo functional role demonstrated\"]\n    },\n    {\n      \"year\": 1994,\n      \"claim\": \"Distinguished between two competing suppression models, showing transactivation-incompetent Mxi1-Max site occupancy, not mere Max sequestration, drives suppression of Myc-induced transformation.\",\n      \"evidence\": \"Rat embryo fibroblast focus formation assay with basic-region deletion mutants\",\n      \"pmids\": [\"8202517\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not identify the repressive co-factors recruited\", \"Transformation readout indirect for endogenous transcription\"]\n    },\n    {\n      \"year\": 1995,\n      \"claim\": \"Identified the SID as the module that converts passive site occupancy into active repression by recruiting mSin3, explaining why SID-lacking isoforms are weak repressors.\",\n      \"evidence\": \"Deletion mutagenesis, co-IP, and REF transformation assays\",\n      \"pmids\": [\"7889571\", \"8649810\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"HDAC enzymatic activity not directly shown in these studies\", \"Genome-wide target occupancy unmeasured\"]\n    },\n    {\n      \"year\": 1998,\n      \"claim\": \"Provided definitive in vivo proof that Mxi1 is a tumor suppressor, with loss causing hyperplasia and accelerated tumorigenesis cooperating with Ink4a deficiency.\",\n      \"evidence\": \"Mxi1 knockout mice, carcinogen challenge, and genetic cross with Ink4a-deficient mice\",\n      \"pmids\": [\"9624006\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not resolve which target genes mediate the phenotype\", \"Tissue-specific contributions not dissected\"]\n    },\n    {\n      \"year\": 1999,\n      \"claim\": \"Revealed a second, Sin3-independent repression mode in which Mxi1 directly silences the c-myc P2 promoter via its leucine zipper and C-terminal CK2 sites, coupling Mxi1 to S-phase entry control.\",\n      \"evidence\": \"Reporter assays, inducible expression, and cell cycle analysis\",\n      \"pmids\": [\"9872993\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"CK2 phosphorylation of Mxi1 not directly demonstrated\", \"Mechanism of USF antagonism unresolved\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Demonstrated isoform-dependent functional divergence, with cytoplasmic Mxi1-0 retaining Max/E-box/Sin3 binding yet failing to repress Myc, and Mxi1-SRalpha paradoxically activating the MYC promoter.\",\n      \"evidence\": \"Promoter-specific RT-PCR, co-IP, EMSA, fractionation, and reporter/REF transformation assays\",\n      \"pmids\": [\"15548375\", \"15467743\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism of Mxi1-0 cytoplasmic retention unknown\", \"Basis for SRalpha activation versus repression undefined\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Identified additional isoform complexity with Mxi-D, which binds Max and Sin3 but cannot bind E-box DNA, acting as a dominant-negative.\",\n      \"evidence\": \"GST pulldown, EMSA, reporter, and colony formation assays\",\n      \"pmids\": [\"15809730\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Endogenous abundance and physiological relevance unclear\", \"Dominant-negative mechanism in vivo untested\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Placed Mxi1 in a developmental program, positioning it downstream of proneural/Sox and Notch inputs during neurogenesis.\",\n      \"evidence\": \"Xenopus loss- and gain-of-function with in situ hybridization\",\n      \"pmids\": [\"16457797\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct transcriptional targets in neural cells unidentified\", \"Mammalian relevance not established\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Connected Mxi1 to hypoxic signaling, showing it is a HIF-1-induced transcriptional target that downregulates Myc targets and buffers Myc-driven hypoxic apoptosis.\",\n      \"evidence\": \"Northern/Western in ARNT-deficient cells, reporter and apoptosis assays; shRNA in pVHL-defective cells with xenografts\",\n      \"pmids\": [\"16319523\", \"19018165\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Context-dependent oncogenic versus suppressive roles unresolved\", \"Direct HIF binding element on canonical MXI1 promoter not mapped here\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Mapped direct HIF binding to the MXI1-0 promoter and showed the MXI1-0 isoform is the predominant hypoxia-induced form, with limited effect on MYC under hypoxia.\",\n      \"evidence\": \"ChIP, transactivation reporter, and siRNA/RT-PCR\",\n      \"pmids\": [\"19254710\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional consequence of MXI1-0 induction under hypoxia incompletely defined\", \"Isoform-specific targets unknown\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Established post-transcriptional control of MXI1 by oncogenic miRNAs, showing miR-191, miR-24-3p/miR-27a-3p, and miR-155 directly target the 3'UTR to modulate erythroid maturation and tumor cell proliferation.\",\n      \"evidence\": \"3'UTR luciferase reporters, miRNA/shRNA modulation, rescue experiments, and RNA-seq\",\n      \"pmids\": [\"21196494\", \"23254855\", \"24376632\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Relative contribution of each miRNA in normal tissue unclear\", \"Downstream Myc target sets in each context not fully mapped\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Defined the post-translational degradation machinery for Mxi1, identifying S6K1-S160 phosphorylation and UBE2O-K46 ubiquitination as drivers of \\u03b2-TrCP/proteasome turnover that regulate Myc suppression and radioresistance.\",\n      \"evidence\": \"In vitro kinase/ubiquitination assays, site-directed mutagenesis, and in vivo rescue in lung cancer models\",\n      \"pmids\": [\"29507620\", \"32901121\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Interplay between S6K1 and UBE2O pathways not resolved\", \"Deubiquitinase counter-regulation unidentified at this stage\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Closed the MYC-MXI1 regulatory circuit, showing MYC represses MXI1 via miRNAs while MXI1 binds and represses the MYC promoter, forming a negative feedback loop.\",\n      \"evidence\": \"ChIP at MYC promoter, reporter assays, and miRNA functional studies\",\n      \"pmids\": [\"32680921\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Quantitative dynamics of the feedback loop unmodeled\", \"FTO/m6A contribution mechanistically incomplete\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Extended Mxi1 regulation to arginine methylation, showing PRMT5 methylates Mxi1 to enhance \\u03b2-TrCP binding and degradation, linking Mxi1 stability to DNA damage repair and radiosensitivity.\",\n      \"evidence\": \"In vitro methylation/ubiquitination assays, co-IP, PRMT5 inhibition (EPZ015666), and in vivo functional assays\",\n      \"pmids\": [\"35149174\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Specific methylated arginine residue(s) not pinpointed\", \"Crosstalk with S160 phosphorylation undefined\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Identified non-Myc target genes of Mxi1, showing direct repression of the miR-300 promoter feeds a KLF9/GADD34 axis controlling tumor immunosuppression.\",\n      \"evidence\": \"ChIP, dual-luciferase reporter, loss/gain-of-function, and in vivo tumor models\",\n      \"pmids\": [\"35501353\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct co-repressor recruitment at miR-300 promoter not shown\", \"Generalizability beyond lung cancer untested\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Showed Mxi1 stabilization by FUBP3 and direct co-repressor (NCOR1/2, Sin3A/B, HDAC1) recruitment to the RRAS promoter blocks ERK signaling and CD8+ T cell immune escape, integrating Mxi1 into immune regulation.\",\n      \"evidence\": \"Co-IP, lentiviral knockdown/overexpression, ChIP with co-repressor mapping, and in vivo AMKL mouse model\",\n      \"pmids\": [\"41428087\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"FUBP3-Mxi1 interaction interface unmapped\", \"Whether RRAS repression is E-box-dependent unclear\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How the distinct degradation inputs (S6K1, UBE2O, PRMT5, \\u03b2-TrCP) and stabilizers (FUBP3) are integrated to set Mxi1 levels across tissues, and what determines isoform-specific localization and the activator-versus-repressor switch, remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structural model of the Mxi1-Max-Sin3 repressive complex\", \"Genome-wide direct target catalog incomplete\", \"Mechanism of cytoplasmic retention of Mxi1-0 unknown\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [0, 1, 2, 6, 21, 23, 26]},\n      {\"term_id\": \"GO:0003677\", \"supporting_discovery_ids\": [0, 2, 21, 23]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [3, 9]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [9]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [0, 1, 6, 21, 23]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [5, 8, 14, 26]},\n      {\"term_id\": \"R-HSA-8953897\", \"supporting_discovery_ids\": [11, 15]},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [19, 20, 22]}\n    ],\n    \"complexes\": [\"Mxi1-Max heterodimer\", \"mSin3-HDAC co-repressor complex\"],\n    \"partners\": [\"MAX\", \"SIN3A\", \"SIN3B\", \"NCOR1\", \"NCOR2\", \"HDAC1\", \"UBE2O\", \"PRMT5\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":8,"faith_total":8,"faith_pct":100.0}}