{"gene":"MNT","run_date":"2026-04-28T18:30:28","timeline":{"discoveries":[{"year":1997,"finding":"MNT (Mnt) heterodimerizes with Max via its bHLHZip domain and the Mnt:Max complex acts as a transcriptional repressor at CACGTG E-box sites; repression maps to a 13-amino-acid N-terminal Sin3 interaction domain (SID) that mediates interaction with mSin3 corepressor proteins, and deletion of the SID converts Mnt from a repressor to a transcriptional activator.","method":"Interaction mating, co-immunoprecipitation, reporter gene assays, deletion mutagenesis, in vivo complex detection","journal":"Genes & development","confidence":"High","confidence_rationale":"Tier 1-2 — multiple orthogonal methods (Co-IP, reporter assays, mutagenesis) in a single study with functional validation","pmids":["9000049"],"is_preprint":false},{"year":1997,"finding":"MNT (Rox) heterodimerizes with Max and shows a novel DNA-binding specificity, preferring CACGCG over the canonical CACGTG E-box; Rox represses transcription through its N-terminus interacting with the Sin3 co-repressor; expression is high in quiescent fibroblasts and decreases upon cell cycle entry.","method":"Interaction mating, co-immunoprecipitation, bandshift/EMSA assays, reporter transcription assays in HEK293 and yeast","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 1-2 — multiple orthogonal methods (Co-IP, EMSA, reporter assays) with functional validation","pmids":["9184233"],"is_preprint":false},{"year":1997,"finding":"Mnt:Max heterodimers efficiently suppress Myc-dependent transcriptional activation from CACGTG-containing promoters; wild-type Mnt suppresses Myc+Ras co-transformation of primary cells, whereas Mnt with a SID deletion cooperates with Ras to transform cells in the absence of Myc, indicating overlapping target gene sets.","method":"Reporter gene assays, primary cell transformation assay, transgenic mouse embryo lethal phenotype","journal":"Genes & development","confidence":"High","confidence_rationale":"Tier 2 — multiple functional assays including cell transformation and in vivo transgenic data","pmids":["9000049"],"is_preprint":false},{"year":2003,"finding":"Deletion of the Mnt gene in MEFs causes premature S-phase entry, accelerated proliferation, upregulation of Cdk4 and cyclin E, increased apoptosis, escape from senescence, and transformability by oncogenic Ras alone; conditional Mnt knockout in breast epithelium leads to adenocarcinomas, demonstrating Mnt as a tumor suppressor and Myc antagonist in vivo.","method":"Mnt gene knockout in mice, MEF cell cycle analysis, BrdU incorporation, Western blot, Cre-lox conditional knockout","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 2 — clean genetic KO with multiple defined cellular phenotypes and in vivo tumor suppressor evidence","pmids":["12970171"],"is_preprint":false},{"year":2004,"finding":"In quiescent cells, the Odc E-box elements are occupied by Max:Mnt repressor complexes; upon mitogen stimulation these are displaced by Myc:Max complexes. Stable RNAi knockdown of Mnt triggers Myc target gene expression, accelerates proliferation and apoptosis, and is sufficient to transform primary fibroblasts with Ras even in the absence of c-myc.","method":"Chromatin immunoprecipitation (ChIP), stable retroviral RNAi, transformation assay, cell cycle analysis","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 2 — ChIP demonstrating occupancy switch, RNAi with multiple phenotypic readouts","pmids":["14749372"],"is_preprint":false},{"year":2005,"finding":"During G0-to-S-phase transition, c-Myc induction leads to a transient decrease in Mnt-Max complexes and a switch in the ratio of Mnt-Max to c-Myc-Max on shared target gene promoters; Mnt overexpression suppresses cell cycle entry, and simultaneous Cre-lox deletion of both Mnt and c-Myc in MEFs rescues the proliferative block caused by c-Myc ablation alone.","method":"Co-immunoprecipitation, ChIP, Cre-lox double knockout MEFs, flow cytometry","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 2 — reciprocal Co-IP, ChIP, and epistasis by double KO rescue","pmids":["15866886"],"is_preprint":false},{"year":2005,"finding":"Mnt is phosphorylated upon serum-stimulated cell cycle re-entry, and this phosphorylation disrupts the Mnt-mSin3 interaction, reducing Mnt-associated HDAC activity; Mnt binds the cyclin D2 promoter (a Myc target) in quiescent cells, and RNAi-mediated Mnt knockdown upregulates cyclin D2 in growth-arrested fibroblasts.","method":"Co-immunoprecipitation, ChIP, RNAi, HDAC activity assay, Western blot phosphorylation analysis","journal":"Oncogene","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal methods linking phosphorylation to loss of co-repressor interaction and target gene derepression","pmids":["16103876"],"is_preprint":false},{"year":2009,"finding":"miR-210 targets MNT mRNA via multiple binding sites in its 3' UTR; MNT knockdown phenocopies miR-210 overexpression (bypass of hypoxia-induced cell cycle arrest), and loss of MYC abolishes this effect, placing MNT as a key node through which miR-210 exerts a MYC-like transcriptional response in hypoxia.","method":"3' UTR reporter assays, siRNA knockdown, microarray expression analysis, cell cycle analysis","journal":"Cell cycle (Georgetown, Tex.)","confidence":"High","confidence_rationale":"Tier 2 — 3'UTR validation, phenocopy knockdown, and epistasis with MYC","pmids":["19652553"],"is_preprint":false},{"year":2009,"finding":"During cholestasis, expression of MNT decreases while c-Myc increases; nuclear E-box binding by Mnt to the p53 and cyclin D1 promoters decreases while Myc binding increases; this Mnt-to-Myc switch is responsible for p53 and cyclin D1 upregulation and hepatocyte apoptosis, as demonstrated by Myc siRNA protection experiments.","method":"ChIP/EMSA, siRNA knockdown of c-Myc, lentiviral c-Myc siRNA in vivo, promoter activity assays","journal":"Hepatology (Baltimore, Md.)","confidence":"High","confidence_rationale":"Tier 2 — ChIP, in vivo lentiviral intervention, and epistasis experiments","pmids":["19086036"],"is_preprint":false},{"year":2011,"finding":"Max-Mnt-Sin3a-HDAC complexes occupy and repress E-box-containing genes promoting cell cycle arrest and apoptosis in proliferating cells; inhibition of PI3-kinase leads to loss of Max/Mnt binding and transcriptional induction by MITF and USF1 as well as FoxO at these loci.","method":"Chromatin immunoprecipitation, siRNA knockdown, reporter gene assays","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 — ChIP and RNAi, single lab but multiple orthogonal methods","pmids":["21873430"],"is_preprint":false},{"year":2012,"finding":"Conditional deletion of Mnt in T cells reveals that Mnt does not require Myc to induce apoptosis, but ectopic Myc expression dramatically increases death of Mnt-deficient T cells; Myc-driven T-cell proliferative expansion and thymoma formation are prevented in the absence of Mnt; tumor suppression by Mnt loss is linked to increased ROS-mediated apoptosis.","method":"Cre-lox conditional KO in T cells, in vivo tumor incidence, apoptosis assays, ROS measurement","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 — clean conditional KO with multiple in vivo and in vitro functional readouts and epistasis with Myc","pmids":["23150551"],"is_preprint":false},{"year":2016,"finding":"The E3 ubiquitin ligase E6AP (UBE3A) physically associates with MNT and promotes its ubiquitin-mediated proteasomal degradation; catalytically inactive E6AP (C843A) stabilizes MNT instead; wild-type E6AP overexpression impedes ATRA-mediated myeloid differentiation whereas MNT overexpression promotes G0-G1 arrest and myeloid differentiation.","method":"Co-immunoprecipitation, proteasome inhibitor experiments, MNT overexpression/knockdown, flow cytometry, differentiation assays","journal":"Oncotarget","confidence":"Medium","confidence_rationale":"Tier 2 — Co-IP with active-site mutant validation and functional cellular phenotype, single lab","pmids":["26506232"],"is_preprint":false},{"year":2020,"finding":"MNT autoregulates its own expression: MNT-MAX dimers bind E-boxes on the MNT promoter and repress it; in MAX-deficient cells, MNT is overexpressed and redistributed to the cytoplasm, forms homodimers and MNT-MLX dimers, and supports cell proliferation by regulating genes involved in cell cycle and DNA repair independently of MAX.","method":"ChIP, RNA-sequencing, co-immunoprecipitation, siRNA knockdown, immunofluorescence localization in MAX-deficient cells","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 — ChIP demonstrating promoter autoregulation, RNA-seq, Co-IP for alternative dimers, and localization change, multiple orthogonal methods","pmids":["31919096"],"is_preprint":false},{"year":2020,"finding":"MNT synergizes with MYC in B lymphoid cells by suppressing MYC-driven apoptosis primarily through reducing pro-apoptotic BIM levels; homozygous Mnt deletion in Eμ-Myc mice greatly reduces lymphoma incidence by enhancing apoptosis; induction of Mnt deletion in fully malignant Eμ-Myc lymphoma cells extends recipient survival.","method":"Cre-lox conditional/inducible KO in Eμ-Myc mouse model, tumor incidence, apoptosis measurement, BIM protein level analysis, transplantation experiments","journal":"Blood","confidence":"High","confidence_rationale":"Tier 2 — genetic epistasis in vivo with mechanistic link to BIM-dependent apoptosis, replicated in multiple experimental settings","pmids":["31978211"],"is_preprint":false},{"year":2004,"finding":"Loss of Mnt in mice produces severely runted pups that die perinatally with reduced c-Myc and N-Myc levels and craniofacial defects including cleft palate, demonstrating essential roles in embryonic growth and linking Mnt haploinsufficiency to Miller-Dieker syndrome features.","method":"Mnt null mouse generation, genetic and histological phenotyping, Western blot","journal":"Human molecular genetics","confidence":"Medium","confidence_rationale":"Tier 2 — clean genetic KO with in vivo phenotype, single lab","pmids":["15028671"],"is_preprint":false},{"year":2006,"finding":"Conditional deletion of Mnt in T cells causes increased apoptosis of thymic T cells, disrupts T-cell development, skews toward Th1 cytokine production, enhances proliferation of activated CD4+ T cells, and ultimately leads to T-cell lymphoma, demonstrating roles in T-cell immune homeostasis and tumor suppression.","method":"Cre-lox conditional KO, FACS, cytokine profiling, histology, tumor incidence","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 2 — clean conditional KO with multiple defined in vivo phenotypes","pmids":["16507988"],"is_preprint":false},{"year":2008,"finding":"In parous mammary glands, Mnt is upregulated and forms HDAC1/c-Myc/Mnt/Max complexes on promoters of Myc target genes (ornithine decarboxylase, cyclin D2, TGFβ1); these complexes act as transcriptional repressors and are disassembled in serum-stimulated cells, providing a mechanism for parity-induced protection against carcinogenesis.","method":"Co-immunoprecipitation, ChIP, Western blot, mammary carcinogenesis rat model","journal":"Cancer science","confidence":"Medium","confidence_rationale":"Tier 2-3 — ChIP and Co-IP demonstrating complex on target promoters, single lab","pmids":["18271930"],"is_preprint":false},{"year":2006,"finding":"Mnt-deficient mammary glands show severely disrupted involution with reduced apoptosis; promoter array analysis demonstrates that Mnt and c-Myc bind similar promoters in mammary tumors, and mRNA expression patterns in Mnt-KO mammary tumors resemble those in MMTV-c-Myc transgenic tumors, confirming Mnt as a functional Myc antagonist in the mammary gland.","method":"Cre-lox conditional KO, mammary gland histology, promoter array (ChIP-chip), oligonucleotide expression arrays","journal":"Cancer research","confidence":"High","confidence_rationale":"Tier 2 — conditional KO with ChIP-chip genome-wide promoter occupancy comparison and expression arrays","pmids":["16740691"],"is_preprint":false},{"year":1998,"finding":"The human ROX/MNT gene encodes a bHLHZip protein that heterodimerizes with Max, represses transcription in an E-box reporter system, and its expression is down-regulated in proliferating cells; the gene maps to chromosome 17p13.3, a region frequently deleted in human malignancies.","method":"Co-immunoprecipitation, reporter gene assays, Northern blot cell-cycle expression analysis","journal":"Genomics","confidence":"Medium","confidence_rationale":"Tier 3 — Co-IP and reporter assays confirm binding and repressor activity, corroborating founding study","pmids":["9598315"],"is_preprint":false}],"current_model":"MNT is a bHLHZip transcriptional repressor that heterodimerizes with MAX (and can also homodimerize or partner with MLX in the absence of MAX) to bind E-box sequences (CACGTG/CACGCG) and recruit the mSin3-HDAC co-repressor complex via an N-terminal Sin3-interaction domain, thereby antagonizing MYC-MAX transcriptional activation of shared target genes; its repressive activity is regulated by phosphorylation-induced dissociation from mSin3-HDAC upon mitogen stimulation and by E6AP-mediated ubiquitin-proteasomal degradation, while miR-210 suppresses MNT expression post-transcriptionally to allow a MYC-like hypoxic response; genetic deletion studies establish MNT as a tumor suppressor whose loss phenocopies MYC overexpression in proliferation, apoptosis susceptibility, and oncogenesis, yet paradoxically MNT also supports MYC-driven lymphomagenesis by suppressing MYC-induced apoptosis through downregulation of BIM."},"narrative":{"teleology":[{"year":1997,"claim":"The founding question—how MYC-MAX transcriptional activation is counterbalanced—was answered by the identification of MNT as a MAX-interacting bHLHZip repressor that recruits mSin3 corepressors via a discrete SID to E-box elements, and whose SID deletion converts it from repressor to activator/oncoprotein.","evidence":"Interaction mating, co-immunoprecipitation, E-box reporter assays, deletion mutagenesis, and primary cell transformation assays in multiple labs","pmids":["9000049","9184233"],"confidence":"High","gaps":["No genome-wide target gene identification","Mechanism by which SID-deleted MNT activates transcription undefined","In vivo relevance as tumor suppressor not yet tested genetically"]},{"year":2003,"claim":"Whether MNT loss alone is sufficient to phenocopy MYC gain was resolved: Mnt-knockout MEFs showed premature S-phase entry, CDK4/cyclin E upregulation, apoptosis, senescence bypass, and Ras-mediated transformation, while conditional mammary knockout produced adenocarcinomas, establishing MNT as a tumor suppressor in vivo.","evidence":"Mnt gene knockout mice, MEF cell cycle and apoptosis analysis, conditional Cre-lox mammary deletion","pmids":["12970171"],"confidence":"High","gaps":["Identity of direct versus indirect MNT target genes genome-wide unknown","Whether tumor suppression requires MAX dimerization not tested"]},{"year":2004,"claim":"The dynamic occupancy model was demonstrated: ChIP showed that quiescent cells harbor MAX:MNT on E-box promoters (e.g., ODC) and mitogens trigger a switch to MYC:MAX; stable MNT RNAi alone was sufficient to transform fibroblasts with Ras even without c-Myc.","evidence":"ChIP for occupancy switch, stable retroviral RNAi, transformation assay in MEFs, Mnt-null mouse perinatal phenotyping","pmids":["14749372","15028671"],"confidence":"High","gaps":["Kinetics and signaling pathway driving the occupancy switch not defined","Whether MNT loss fully recapitulates all MYC targets unresolved"]},{"year":2005,"claim":"The mechanism by which mitogenic signals inactivate MNT repression was identified: phosphorylation of MNT upon serum stimulation disrupts the MNT-mSin3 interaction and reduces associated HDAC activity, derepressing targets such as cyclin D2; double knockout of Mnt and c-Myc rescued proliferative defects of c-Myc loss, confirming epistatic antagonism.","evidence":"Co-IP, ChIP, phosphorylation analysis, HDAC activity assays, Cre-lox double-KO MEFs","pmids":["16103876","15866886"],"confidence":"High","gaps":["Identity of the kinase(s) phosphorylating MNT unknown","Phosphorylation site mapping incomplete","Structural basis of phosphorylation-induced SID-mSin3 dissociation undefined"]},{"year":2006,"claim":"Tissue-specific consequences of MNT loss were mapped: conditional deletion in T cells caused increased apoptosis, disrupted development, Th1 skewing, and eventual T-cell lymphoma; in mammary gland, Mnt loss disrupted involution and produced tumors with expression profiles resembling MMTV-c-Myc tumors.","evidence":"Cre-lox conditional KO in T cells and mammary epithelium, FACS, ChIP-chip promoter arrays, expression arrays","pmids":["16507988","16740691"],"confidence":"High","gaps":["Cell-type-specific MNT target genes not fully catalogued","Mechanism of disrupted involution not molecularly resolved"]},{"year":2009,"claim":"Post-transcriptional regulation of MNT was established: miR-210 targets MNT mRNA via 3′UTR sites, and MNT knockdown phenocopies miR-210 overexpression in bypassing hypoxia-induced cell cycle arrest in a MYC-dependent manner; separately, a physiological MNT-to-MYC promoter occupancy switch on p53 and cyclin D1 was demonstrated during cholestasis-induced hepatocyte apoptosis.","evidence":"3′UTR reporter assays, siRNA knockdown, microarray, cell cycle analysis; ChIP/EMSA, in vivo lentiviral MYC siRNA","pmids":["19652553","19086036"],"confidence":"High","gaps":["Whether miR-210 regulation of MNT is operative in non-hypoxic physiological contexts unknown","Additional miRNAs targeting MNT not systematically explored"]},{"year":2012,"claim":"The paradox of MNT's dual role was clarified: while MNT loss alone increases apoptosis (tumor suppressor), in the context of MYC-driven T-cell expansion MNT is required to restrain MYC-induced ROS-mediated apoptosis, so MNT loss prevents MYC-driven thymoma.","evidence":"Conditional Mnt KO crossed with Myc transgenic mice, ROS measurement, apoptosis assays, tumor incidence","pmids":["23150551"],"confidence":"High","gaps":["Direct transcriptional targets mediating ROS regulation by MNT not identified","Whether this anti-apoptotic role extends to non-T-cell tumors unclear at this point"]},{"year":2016,"claim":"Proteasomal control of MNT protein levels was established: E6AP (UBE3A) physically associates with MNT and promotes its ubiquitination and degradation; a catalytically inactive E6AP mutant stabilizes MNT, and E6AP overexpression opposes MNT-dependent myeloid differentiation.","evidence":"Co-immunoprecipitation with wild-type and C843A mutant E6AP, proteasome inhibitor experiments, differentiation assays","pmids":["26506232"],"confidence":"Medium","gaps":["Ubiquitination sites on MNT not mapped","Whether E6AP regulation of MNT operates in all tissues unknown","Reciprocal validation in E6AP-knockout cells not shown"]},{"year":2020,"claim":"Two breakthroughs resolved MAX-independent functions and the in vivo apoptotic paradox: in MAX-deficient cells MNT forms homodimers and MNT-MLX heterodimers that redistribute to the cytoplasm and regulate cell cycle/DNA repair genes independently of MAX; in Eμ-Myc B-cell lymphomagenesis MNT suppresses BIM-dependent apoptosis, so its deletion prevents lymphoma by unleashing MYC-driven apoptosis.","evidence":"ChIP, RNA-seq, Co-IP and localization in MAX-null cells; Cre-lox and inducible KO in Eμ-Myc mouse model, BIM protein analysis, transplantation","pmids":["31919096","31978211"],"confidence":"High","gaps":["Genomic targets of MNT homodimers and MNT-MLX dimers not fully defined","Whether cytoplasmic MNT has non-transcriptional functions unknown","Structural basis for MNT homodimerization not resolved"]},{"year":null,"claim":"Key unresolved questions include the identity of the kinase(s) phosphorylating MNT, the structural basis of SID–mSin3 regulation by phosphorylation, the full genome-wide target repertoire specific to MNT homodimers versus MNT-MLX versus MNT-MAX, and whether MNT's context-dependent pro-survival versus tumor-suppressive functions can be therapeutically exploited.","evidence":"","pmids":[],"confidence":"Low","gaps":["No kinase responsible for MNT phosphorylation identified","No structural model of MNT or MNT-MAX complex available","Therapeutic relevance of modulating MNT in MYC-driven cancers untested"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[0,1,2,4,6,12]},{"term_id":"GO:0003677","term_label":"DNA binding","supporting_discovery_ids":[0,1,4,5,8]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[0,4,5,12]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[12]}],"pathway":[{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[0,1,4,5,6,8,12]},{"term_id":"R-HSA-4839726","term_label":"Chromatin organization","supporting_discovery_ids":[0,6,9]},{"term_id":"R-HSA-1640170","term_label":"Cell Cycle","supporting_discovery_ids":[3,4,5,6,7]},{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[3,10,13,15]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[3,15,17]}],"complexes":["MNT-MAX heterodimer","MNT-MAX-mSin3-HDAC co-repressor complex","MNT-MLX heterodimer"],"partners":["MAX","MLX","SIN3A","SIN3B","HDAC1","UBE3A","MYC"],"other_free_text":[]},"mechanistic_narrative":"MNT is a bHLHZip transcriptional repressor that functions as the principal physiological antagonist of MYC-family oncoproteins by competing for heterodimerization with MAX and occupancy of E-box elements on shared target gene promoters. MNT:MAX heterodimers recruit the mSin3-HDAC co-repressor complex through a 13-amino-acid N-terminal Sin3-interaction domain (SID), maintaining transcriptional repression of proliferative genes such as cyclin D2, CDK4, and ODC in quiescent cells; mitogenic signaling triggers MNT phosphorylation that disrupts mSin3 binding, while E6AP-mediated ubiquitin-proteasomal degradation and miR-210-dependent post-transcriptional suppression further relieve MNT repression to permit MYC-driven gene activation [PMID:9000049, PMID:16103876, PMID:26506232, PMID:19652553]. Genetic deletion of Mnt in mice phenocopies MYC overexpression—accelerating proliferation, enhancing apoptosis, bypassing senescence, and causing mammary adenocarcinomas and T-cell lymphomas—establishing MNT as a bona fide tumor suppressor; paradoxically, in MYC-driven lymphomagenesis MNT is required to suppress BIM-dependent apoptosis, so its loss prevents MYC-driven lymphoma [PMID:12970171, PMID:16507988, PMID:31978211]. In MAX-deficient contexts, MNT forms homodimers or MNT:MLX heterodimers and redistributes to the cytoplasm, where it supports proliferation through MAX-independent gene regulation [PMID:31919096]."},"prefetch_data":{"uniprot":{"accession":"Q99583","full_name":"Max-binding protein MNT","aliases":["Class D basic helix-loop-helix protein 3","bHLHd3","Myc antagonist MNT","Protein ROX"],"length_aa":582,"mass_kda":62.3,"function":"Binds DNA as a heterodimer with MAX and represses transcription. Binds to the canonical E box sequence 5'-CACGTG-3' and, with higher affinity, to 5'-CACGCG-3'","subcellular_location":"Nucleus","url":"https://www.uniprot.org/uniprotkb/Q99583/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/MNT","classification":"Not Classified","n_dependent_lines":72,"n_total_lines":1208,"dependency_fraction":0.059602649006622516},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/MNT","total_profiled":1310},"omim":[{"mim_id":"616186","title":"H19/IGF2-IMPRINTING CONTROL REGION","url":"https://www.omim.org/entry/616186"},{"mim_id":"605678","title":"MLX-INTERACTING PROTEIN-LIKE; MLXIPL","url":"https://www.omim.org/entry/605678"},{"mim_id":"603039","title":"MAX NETWORK TRANSCRIPTIONAL REPRESSOR; MNT","url":"https://www.omim.org/entry/603039"},{"mim_id":"602976","title":"MAX-LIKE PROTEIN X; MLX","url":"https://www.omim.org/entry/602976"},{"mim_id":"300808","title":"G PROTEIN-COUPLED RECEPTOR 143; GPR143","url":"https://www.omim.org/entry/300808"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Enhanced","locations":[{"location":"Nucleoplasm","reliability":"Enhanced"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/MNT"},"hgnc":{"alias_symbol":["ROX","MXD6","MAD6","bHLHd3","lncRNA-HAL"],"prev_symbol":[]},"alphafold":{"accession":"Q99583","domains":[],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q99583","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q99583-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q99583-F1-predicted_aligned_error_v6.png","plddt_mean":59.34},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=MNT","jax_strain_url":"https://www.jax.org/strain/search?query=MNT"},"sequence":{"accession":"Q99583","fasta_url":"https://rest.uniprot.org/uniprotkb/Q99583.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q99583/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q99583"}},"corpus_meta":[{"pmid":"12695332","id":"PMC_12695332","title":"Genomic binding by the Drosophila Myc, Max, Mad/Mnt transcription factor network.","date":"2003","source":"Genes & 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repression maps to a 13-amino-acid N-terminal Sin3 interaction domain (SID) that mediates interaction with mSin3 corepressor proteins, and deletion of the SID converts Mnt from a repressor to a transcriptional activator.\",\n      \"method\": \"Interaction mating, co-immunoprecipitation, reporter gene assays, deletion mutagenesis, in vivo complex detection\",\n      \"journal\": \"Genes & development\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — multiple orthogonal methods (Co-IP, reporter assays, mutagenesis) in a single study with functional validation\",\n      \"pmids\": [\"9000049\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1997,\n      \"finding\": \"MNT (Rox) heterodimerizes with Max and shows a novel DNA-binding specificity, preferring CACGCG over the canonical CACGTG E-box; Rox represses transcription through its N-terminus interacting with the Sin3 co-repressor; expression is high in quiescent fibroblasts and decreases upon cell cycle entry.\",\n      \"method\": \"Interaction mating, co-immunoprecipitation, bandshift/EMSA assays, reporter transcription assays in HEK293 and yeast\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — multiple orthogonal methods (Co-IP, EMSA, reporter assays) with functional validation\",\n      \"pmids\": [\"9184233\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1997,\n      \"finding\": \"Mnt:Max heterodimers efficiently suppress Myc-dependent transcriptional activation from CACGTG-containing promoters; wild-type Mnt suppresses Myc+Ras co-transformation of primary cells, whereas Mnt with a SID deletion cooperates with Ras to transform cells in the absence of Myc, indicating overlapping target gene sets.\",\n      \"method\": \"Reporter gene assays, primary cell transformation assay, transgenic mouse embryo lethal phenotype\",\n      \"journal\": \"Genes & development\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple functional assays including cell transformation and in vivo transgenic data\",\n      \"pmids\": [\"9000049\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"Deletion of the Mnt gene in MEFs causes premature S-phase entry, accelerated proliferation, upregulation of Cdk4 and cyclin E, increased apoptosis, escape from senescence, and transformability by oncogenic Ras alone; conditional Mnt knockout in breast epithelium leads to adenocarcinomas, demonstrating Mnt as a tumor suppressor and Myc antagonist in vivo.\",\n      \"method\": \"Mnt gene knockout in mice, MEF cell cycle analysis, BrdU incorporation, Western blot, Cre-lox conditional knockout\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — clean genetic KO with multiple defined cellular phenotypes and in vivo tumor suppressor evidence\",\n      \"pmids\": [\"12970171\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"In quiescent cells, the Odc E-box elements are occupied by Max:Mnt repressor complexes; upon mitogen stimulation these are displaced by Myc:Max complexes. Stable RNAi knockdown of Mnt triggers Myc target gene expression, accelerates proliferation and apoptosis, and is sufficient to transform primary fibroblasts with Ras even in the absence of c-myc.\",\n      \"method\": \"Chromatin immunoprecipitation (ChIP), stable retroviral RNAi, transformation assay, cell cycle analysis\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — ChIP demonstrating occupancy switch, RNAi with multiple phenotypic readouts\",\n      \"pmids\": [\"14749372\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"During G0-to-S-phase transition, c-Myc induction leads to a transient decrease in Mnt-Max complexes and a switch in the ratio of Mnt-Max to c-Myc-Max on shared target gene promoters; Mnt overexpression suppresses cell cycle entry, and simultaneous Cre-lox deletion of both Mnt and c-Myc in MEFs rescues the proliferative block caused by c-Myc ablation alone.\",\n      \"method\": \"Co-immunoprecipitation, ChIP, Cre-lox double knockout MEFs, flow cytometry\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal Co-IP, ChIP, and epistasis by double KO rescue\",\n      \"pmids\": [\"15866886\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"Mnt is phosphorylated upon serum-stimulated cell cycle re-entry, and this phosphorylation disrupts the Mnt-mSin3 interaction, reducing Mnt-associated HDAC activity; Mnt binds the cyclin D2 promoter (a Myc target) in quiescent cells, and RNAi-mediated Mnt knockdown upregulates cyclin D2 in growth-arrested fibroblasts.\",\n      \"method\": \"Co-immunoprecipitation, ChIP, RNAi, HDAC activity assay, Western blot phosphorylation analysis\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods linking phosphorylation to loss of co-repressor interaction and target gene derepression\",\n      \"pmids\": [\"16103876\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"miR-210 targets MNT mRNA via multiple binding sites in its 3' UTR; MNT knockdown phenocopies miR-210 overexpression (bypass of hypoxia-induced cell cycle arrest), and loss of MYC abolishes this effect, placing MNT as a key node through which miR-210 exerts a MYC-like transcriptional response in hypoxia.\",\n      \"method\": \"3' UTR reporter assays, siRNA knockdown, microarray expression analysis, cell cycle analysis\",\n      \"journal\": \"Cell cycle (Georgetown, Tex.)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — 3'UTR validation, phenocopy knockdown, and epistasis with MYC\",\n      \"pmids\": [\"19652553\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"During cholestasis, expression of MNT decreases while c-Myc increases; nuclear E-box binding by Mnt to the p53 and cyclin D1 promoters decreases while Myc binding increases; this Mnt-to-Myc switch is responsible for p53 and cyclin D1 upregulation and hepatocyte apoptosis, as demonstrated by Myc siRNA protection experiments.\",\n      \"method\": \"ChIP/EMSA, siRNA knockdown of c-Myc, lentiviral c-Myc siRNA in vivo, promoter activity assays\",\n      \"journal\": \"Hepatology (Baltimore, Md.)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — ChIP, in vivo lentiviral intervention, and epistasis experiments\",\n      \"pmids\": [\"19086036\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Max-Mnt-Sin3a-HDAC complexes occupy and repress E-box-containing genes promoting cell cycle arrest and apoptosis in proliferating cells; inhibition of PI3-kinase leads to loss of Max/Mnt binding and transcriptional induction by MITF and USF1 as well as FoxO at these loci.\",\n      \"method\": \"Chromatin immunoprecipitation, siRNA knockdown, reporter gene assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — ChIP and RNAi, single lab but multiple orthogonal methods\",\n      \"pmids\": [\"21873430\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Conditional deletion of Mnt in T cells reveals that Mnt does not require Myc to induce apoptosis, but ectopic Myc expression dramatically increases death of Mnt-deficient T cells; Myc-driven T-cell proliferative expansion and thymoma formation are prevented in the absence of Mnt; tumor suppression by Mnt loss is linked to increased ROS-mediated apoptosis.\",\n      \"method\": \"Cre-lox conditional KO in T cells, in vivo tumor incidence, apoptosis assays, ROS measurement\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — clean conditional KO with multiple in vivo and in vitro functional readouts and epistasis with Myc\",\n      \"pmids\": [\"23150551\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"The E3 ubiquitin ligase E6AP (UBE3A) physically associates with MNT and promotes its ubiquitin-mediated proteasomal degradation; catalytically inactive E6AP (C843A) stabilizes MNT instead; wild-type E6AP overexpression impedes ATRA-mediated myeloid differentiation whereas MNT overexpression promotes G0-G1 arrest and myeloid differentiation.\",\n      \"method\": \"Co-immunoprecipitation, proteasome inhibitor experiments, MNT overexpression/knockdown, flow cytometry, differentiation assays\",\n      \"journal\": \"Oncotarget\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — Co-IP with active-site mutant validation and functional cellular phenotype, single lab\",\n      \"pmids\": [\"26506232\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"MNT autoregulates its own expression: MNT-MAX dimers bind E-boxes on the MNT promoter and repress it; in MAX-deficient cells, MNT is overexpressed and redistributed to the cytoplasm, forms homodimers and MNT-MLX dimers, and supports cell proliferation by regulating genes involved in cell cycle and DNA repair independently of MAX.\",\n      \"method\": \"ChIP, RNA-sequencing, co-immunoprecipitation, siRNA knockdown, immunofluorescence localization in MAX-deficient cells\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — ChIP demonstrating promoter autoregulation, RNA-seq, Co-IP for alternative dimers, and localization change, multiple orthogonal methods\",\n      \"pmids\": [\"31919096\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"MNT synergizes with MYC in B lymphoid cells by suppressing MYC-driven apoptosis primarily through reducing pro-apoptotic BIM levels; homozygous Mnt deletion in Eμ-Myc mice greatly reduces lymphoma incidence by enhancing apoptosis; induction of Mnt deletion in fully malignant Eμ-Myc lymphoma cells extends recipient survival.\",\n      \"method\": \"Cre-lox conditional/inducible KO in Eμ-Myc mouse model, tumor incidence, apoptosis measurement, BIM protein level analysis, transplantation experiments\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic epistasis in vivo with mechanistic link to BIM-dependent apoptosis, replicated in multiple experimental settings\",\n      \"pmids\": [\"31978211\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"Loss of Mnt in mice produces severely runted pups that die perinatally with reduced c-Myc and N-Myc levels and craniofacial defects including cleft palate, demonstrating essential roles in embryonic growth and linking Mnt haploinsufficiency to Miller-Dieker syndrome features.\",\n      \"method\": \"Mnt null mouse generation, genetic and histological phenotyping, Western blot\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — clean genetic KO with in vivo phenotype, single lab\",\n      \"pmids\": [\"15028671\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"Conditional deletion of Mnt in T cells causes increased apoptosis of thymic T cells, disrupts T-cell development, skews toward Th1 cytokine production, enhances proliferation of activated CD4+ T cells, and ultimately leads to T-cell lymphoma, demonstrating roles in T-cell immune homeostasis and tumor suppression.\",\n      \"method\": \"Cre-lox conditional KO, FACS, cytokine profiling, histology, tumor incidence\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — clean conditional KO with multiple defined in vivo phenotypes\",\n      \"pmids\": [\"16507988\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"In parous mammary glands, Mnt is upregulated and forms HDAC1/c-Myc/Mnt/Max complexes on promoters of Myc target genes (ornithine decarboxylase, cyclin D2, TGFβ1); these complexes act as transcriptional repressors and are disassembled in serum-stimulated cells, providing a mechanism for parity-induced protection against carcinogenesis.\",\n      \"method\": \"Co-immunoprecipitation, ChIP, Western blot, mammary carcinogenesis rat model\",\n      \"journal\": \"Cancer science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — ChIP and Co-IP demonstrating complex on target promoters, single lab\",\n      \"pmids\": [\"18271930\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"Mnt-deficient mammary glands show severely disrupted involution with reduced apoptosis; promoter array analysis demonstrates that Mnt and c-Myc bind similar promoters in mammary tumors, and mRNA expression patterns in Mnt-KO mammary tumors resemble those in MMTV-c-Myc transgenic tumors, confirming Mnt as a functional Myc antagonist in the mammary gland.\",\n      \"method\": \"Cre-lox conditional KO, mammary gland histology, promoter array (ChIP-chip), oligonucleotide expression arrays\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — conditional KO with ChIP-chip genome-wide promoter occupancy comparison and expression arrays\",\n      \"pmids\": [\"16740691\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"The human ROX/MNT gene encodes a bHLHZip protein that heterodimerizes with Max, represses transcription in an E-box reporter system, and its expression is down-regulated in proliferating cells; the gene maps to chromosome 17p13.3, a region frequently deleted in human malignancies.\",\n      \"method\": \"Co-immunoprecipitation, reporter gene assays, Northern blot cell-cycle expression analysis\",\n      \"journal\": \"Genomics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — Co-IP and reporter assays confirm binding and repressor activity, corroborating founding study\",\n      \"pmids\": [\"9598315\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"MNT is a bHLHZip transcriptional repressor that heterodimerizes with MAX (and can also homodimerize or partner with MLX in the absence of MAX) to bind E-box sequences (CACGTG/CACGCG) and recruit the mSin3-HDAC co-repressor complex via an N-terminal Sin3-interaction domain, thereby antagonizing MYC-MAX transcriptional activation of shared target genes; its repressive activity is regulated by phosphorylation-induced dissociation from mSin3-HDAC upon mitogen stimulation and by E6AP-mediated ubiquitin-proteasomal degradation, while miR-210 suppresses MNT expression post-transcriptionally to allow a MYC-like hypoxic response; genetic deletion studies establish MNT as a tumor suppressor whose loss phenocopies MYC overexpression in proliferation, apoptosis susceptibility, and oncogenesis, yet paradoxically MNT also supports MYC-driven lymphomagenesis by suppressing MYC-induced apoptosis through downregulation of BIM.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"MNT is a bHLHZip transcriptional repressor that functions as the principal physiological antagonist of MYC-family oncoproteins by competing for heterodimerization with MAX and occupancy of E-box elements on shared target gene promoters. MNT:MAX heterodimers recruit the mSin3-HDAC co-repressor complex through a 13-amino-acid N-terminal Sin3-interaction domain (SID), maintaining transcriptional repression of proliferative genes such as cyclin D2, CDK4, and ODC in quiescent cells; mitogenic signaling triggers MNT phosphorylation that disrupts mSin3 binding, while E6AP-mediated ubiquitin-proteasomal degradation and miR-210-dependent post-transcriptional suppression further relieve MNT repression to permit MYC-driven gene activation [PMID:9000049, PMID:16103876, PMID:26506232, PMID:19652553]. Genetic deletion of Mnt in mice phenocopies MYC overexpression—accelerating proliferation, enhancing apoptosis, bypassing senescence, and causing mammary adenocarcinomas and T-cell lymphomas—establishing MNT as a bona fide tumor suppressor; paradoxically, in MYC-driven lymphomagenesis MNT is required to suppress BIM-dependent apoptosis, so its loss prevents MYC-driven lymphoma [PMID:12970171, PMID:16507988, PMID:31978211]. In MAX-deficient contexts, MNT forms homodimers or MNT:MLX heterodimers and redistributes to the cytoplasm, where it supports proliferation through MAX-independent gene regulation [PMID:31919096].\",\n  \"teleology\": [\n    {\n      \"year\": 1997,\n      \"claim\": \"The founding question—how MYC-MAX transcriptional activation is counterbalanced—was answered by the identification of MNT as a MAX-interacting bHLHZip repressor that recruits mSin3 corepressors via a discrete SID to E-box elements, and whose SID deletion converts it from repressor to activator/oncoprotein.\",\n      \"evidence\": \"Interaction mating, co-immunoprecipitation, E-box reporter assays, deletion mutagenesis, and primary cell transformation assays in multiple labs\",\n      \"pmids\": [\"9000049\", \"9184233\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"No genome-wide target gene identification\",\n        \"Mechanism by which SID-deleted MNT activates transcription undefined\",\n        \"In vivo relevance as tumor suppressor not yet tested genetically\"\n      ]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Whether MNT loss alone is sufficient to phenocopy MYC gain was resolved: Mnt-knockout MEFs showed premature S-phase entry, CDK4/cyclin E upregulation, apoptosis, senescence bypass, and Ras-mediated transformation, while conditional mammary knockout produced adenocarcinomas, establishing MNT as a tumor suppressor in vivo.\",\n      \"evidence\": \"Mnt gene knockout mice, MEF cell cycle and apoptosis analysis, conditional Cre-lox mammary deletion\",\n      \"pmids\": [\"12970171\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Identity of direct versus indirect MNT target genes genome-wide unknown\",\n        \"Whether tumor suppression requires MAX dimerization not tested\"\n      ]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"The dynamic occupancy model was demonstrated: ChIP showed that quiescent cells harbor MAX:MNT on E-box promoters (e.g., ODC) and mitogens trigger a switch to MYC:MAX; stable MNT RNAi alone was sufficient to transform fibroblasts with Ras even without c-Myc.\",\n      \"evidence\": \"ChIP for occupancy switch, stable retroviral RNAi, transformation assay in MEFs, Mnt-null mouse perinatal phenotyping\",\n      \"pmids\": [\"14749372\", \"15028671\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Kinetics and signaling pathway driving the occupancy switch not defined\",\n        \"Whether MNT loss fully recapitulates all MYC targets unresolved\"\n      ]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"The mechanism by which mitogenic signals inactivate MNT repression was identified: phosphorylation of MNT upon serum stimulation disrupts the MNT-mSin3 interaction and reduces associated HDAC activity, derepressing targets such as cyclin D2; double knockout of Mnt and c-Myc rescued proliferative defects of c-Myc loss, confirming epistatic antagonism.\",\n      \"evidence\": \"Co-IP, ChIP, phosphorylation analysis, HDAC activity assays, Cre-lox double-KO MEFs\",\n      \"pmids\": [\"16103876\", \"15866886\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Identity of the kinase(s) phosphorylating MNT unknown\",\n        \"Phosphorylation site mapping incomplete\",\n        \"Structural basis of phosphorylation-induced SID-mSin3 dissociation undefined\"\n      ]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Tissue-specific consequences of MNT loss were mapped: conditional deletion in T cells caused increased apoptosis, disrupted development, Th1 skewing, and eventual T-cell lymphoma; in mammary gland, Mnt loss disrupted involution and produced tumors with expression profiles resembling MMTV-c-Myc tumors.\",\n      \"evidence\": \"Cre-lox conditional KO in T cells and mammary epithelium, FACS, ChIP-chip promoter arrays, expression arrays\",\n      \"pmids\": [\"16507988\", \"16740691\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Cell-type-specific MNT target genes not fully catalogued\",\n        \"Mechanism of disrupted involution not molecularly resolved\"\n      ]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Post-transcriptional regulation of MNT was established: miR-210 targets MNT mRNA via 3′UTR sites, and MNT knockdown phenocopies miR-210 overexpression in bypassing hypoxia-induced cell cycle arrest in a MYC-dependent manner; separately, a physiological MNT-to-MYC promoter occupancy switch on p53 and cyclin D1 was demonstrated during cholestasis-induced hepatocyte apoptosis.\",\n      \"evidence\": \"3′UTR reporter assays, siRNA knockdown, microarray, cell cycle analysis; ChIP/EMSA, in vivo lentiviral MYC siRNA\",\n      \"pmids\": [\"19652553\", \"19086036\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Whether miR-210 regulation of MNT is operative in non-hypoxic physiological contexts unknown\",\n        \"Additional miRNAs targeting MNT not systematically explored\"\n      ]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"The paradox of MNT's dual role was clarified: while MNT loss alone increases apoptosis (tumor suppressor), in the context of MYC-driven T-cell expansion MNT is required to restrain MYC-induced ROS-mediated apoptosis, so MNT loss prevents MYC-driven thymoma.\",\n      \"evidence\": \"Conditional Mnt KO crossed with Myc transgenic mice, ROS measurement, apoptosis assays, tumor incidence\",\n      \"pmids\": [\"23150551\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Direct transcriptional targets mediating ROS regulation by MNT not identified\",\n        \"Whether this anti-apoptotic role extends to non-T-cell tumors unclear at this point\"\n      ]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Proteasomal control of MNT protein levels was established: E6AP (UBE3A) physically associates with MNT and promotes its ubiquitination and degradation; a catalytically inactive E6AP mutant stabilizes MNT, and E6AP overexpression opposes MNT-dependent myeloid differentiation.\",\n      \"evidence\": \"Co-immunoprecipitation with wild-type and C843A mutant E6AP, proteasome inhibitor experiments, differentiation assays\",\n      \"pmids\": [\"26506232\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Ubiquitination sites on MNT not mapped\",\n        \"Whether E6AP regulation of MNT operates in all tissues unknown\",\n        \"Reciprocal validation in E6AP-knockout cells not shown\"\n      ]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Two breakthroughs resolved MAX-independent functions and the in vivo apoptotic paradox: in MAX-deficient cells MNT forms homodimers and MNT-MLX heterodimers that redistribute to the cytoplasm and regulate cell cycle/DNA repair genes independently of MAX; in Eμ-Myc B-cell lymphomagenesis MNT suppresses BIM-dependent apoptosis, so its deletion prevents lymphoma by unleashing MYC-driven apoptosis.\",\n      \"evidence\": \"ChIP, RNA-seq, Co-IP and localization in MAX-null cells; Cre-lox and inducible KO in Eμ-Myc mouse model, BIM protein analysis, transplantation\",\n      \"pmids\": [\"31919096\", \"31978211\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Genomic targets of MNT homodimers and MNT-MLX dimers not fully defined\",\n        \"Whether cytoplasmic MNT has non-transcriptional functions unknown\",\n        \"Structural basis for MNT homodimerization not resolved\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Key unresolved questions include the identity of the kinase(s) phosphorylating MNT, the structural basis of SID–mSin3 regulation by phosphorylation, the full genome-wide target repertoire specific to MNT homodimers versus MNT-MLX versus MNT-MAX, and whether MNT's context-dependent pro-survival versus tumor-suppressive functions can be therapeutically exploited.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"No kinase responsible for MNT phosphorylation identified\",\n        \"No structural model of MNT or MNT-MAX complex available\",\n        \"Therapeutic relevance of modulating MNT in MYC-driven cancers untested\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [0, 1, 2, 4, 6, 12]},\n      {\"term_id\": \"GO:0003677\", \"supporting_discovery_ids\": [0, 1, 4, 5, 8]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [0, 4, 5, 12]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [12]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [0, 1, 4, 5, 6, 8, 12]},\n      {\"term_id\": \"R-HSA-4839726\", \"supporting_discovery_ids\": [0, 6, 9]},\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [3, 4, 5, 6, 7]},\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [3, 10, 13, 15]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [3, 15, 17]}\n    ],\n    \"complexes\": [\n      \"MNT-MAX heterodimer\",\n      \"MNT-MAX-mSin3-HDAC co-repressor complex\",\n      \"MNT-MLX heterodimer\"\n    ],\n    \"partners\": [\n      \"MAX\",\n      \"MLX\",\n      \"SIN3A\",\n      \"SIN3B\",\n      \"HDAC1\",\n      \"UBE3A\",\n      \"MYC\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}