{"gene":"MNT","run_date":"2026-06-10T02:59:50","timeline":{"discoveries":[{"year":1997,"finding":"MNT (Rox/Mnt) heterodimerizes with Max via bHLHZip domains, and the Mnt:Max heterodimer binds CACGTG E-box sequences and acts as a transcriptional repressor. Transcriptional repression maps to a 13-amino-acid N-terminal Sin3 interaction domain (SID); deletion of SID converts Mnt from a repressor to an activator and from a suppressor of Myc+Ras cotransformation to a cooperating oncogene.","method":"Interaction mating (two-hybrid), co-immunoprecipitation, reporter gene transcription assays, mutagenesis of SID domain, primary cell transformation assay","journal":"Genes & development","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — multiple orthogonal methods (co-IP, DNA binding, transcription assay, mutagenesis, transformation assay) in a single rigorous study, replicated across subsequent papers","pmids":["9000049"],"is_preprint":false},{"year":1997,"finding":"Rox (human MNT ortholog) heterodimerizes with Max and weakly homodimerizes; the Rox-Max heterodimer preferentially binds the non-canonical CACGCG site over the canonical CACGTG E-box. Rox represses transcription in human HEK293 cells and yeast, and repression in yeast is mediated through interaction of its N-terminus with the Sin3 co-repressor.","method":"Interaction mating (two-hybrid), co-immunoprecipitation, electrophoretic mobility shift assay (EMSA), reporter gene transcription assays","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — reciprocal co-IP, EMSA with specificity comparisons, and transcription assays across two cell systems in one study; replicated conceptually by PMID:9000049","pmids":["9184233"],"is_preprint":false},{"year":2003,"finding":"Deletion of Mnt in mouse embryo fibroblasts (MEFs) causes premature S-phase entry and faster proliferation linked to upregulation of Cdk4 and cyclin E; Cdk4 is a direct target of Mnt-Myc antagonism. Mnt-null MEFs are prone to apoptosis, bypass senescence, and can be transformed by oncogenic Ras alone, phenocopying Myc overexpression. Conditional deletion of Mnt in breast epithelium leads to adenocarcinomas.","method":"Conditional knockout (Cre/lox) mice, MEF proliferation and cell cycle assays, flow cytometry, ChIP, transformation assay with oncogenic Ras","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 2 / Strong — clean KO with defined cellular phenotypes, multiple orthogonal readouts, replicated across studies (PMID:14749372)","pmids":["12970171"],"is_preprint":false},{"year":2004,"finding":"In quiescent cells, Mnt-Max complexes occupy E-boxes (e.g., at the Odc gene); upon cell proliferation, Myc-Max complexes displace Mnt-Max. Stable RNAi knockdown of Mnt triggers Myc target gene expression, accelerated proliferation, apoptosis, and transformation of primary fibroblasts with Ras even in cells lacking c-myc, establishing Mnt as a transcriptional repressor of Myc target genes that functions partly independently of Myc.","method":"Chromatin immunoprecipitation (ChIP), stable retroviral RNAi, luciferase reporter assay, proliferation and transformation assays, c-myc null MEFs","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — ChIP occupancy data, RNAi loss-of-function with multiple readouts, genetic test in Myc-null cells; independently replicated concept","pmids":["14749372"],"is_preprint":false},{"year":2005,"finding":"Mnt is phosphorylated upon serum-stimulated cell cycle re-entry; this phosphorylation disrupts the Mnt-mSin3 interaction and reduces Mnt-associated HDAC activity. Mnt binds and recruits mSin3 to the Myc target gene cyclin D2 in quiescent fibroblasts, repressing it; RNAi-mediated reduction of Mnt upregulates cyclin D2 in growth-arrested cells.","method":"Co-immunoprecipitation, HDAC activity assay, ChIP, RNAi knockdown, western blot for phosphorylation, serum stimulation cell cycle model","journal":"Oncogene","confidence":"High","confidence_rationale":"Tier 2 / Strong — ChIP, co-IP showing disrupted complex, RNAi with gene expression readout; multiple orthogonal methods in one study","pmids":["16103876"],"is_preprint":false},{"year":2005,"finding":"c-Myc induction during G0-to-S transition causes a transient switch in the ratio of Mnt-Max to Myc-Max on shared target gene promoters. Mnt overexpression suppresses cell cycle entry and proliferation. Simultaneous Cre-lox deletion of both Mnt and c-Myc in MEFs rescues the cell cycle block caused by c-Myc ablation alone, demonstrating direct Mnt-Myc antagonism in cell cycle entry.","method":"ChIP, co-immunoprecipitation, retroviral overexpression, conditional double knockout (Cre/lox), proliferation and cell cycle assays","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — ChIP showing complex switching, genetic epistasis by double KO rescue, multiple methods in one study","pmids":["15866886"],"is_preprint":false},{"year":2009,"finding":"MNT mRNA contains multiple miR-210 binding sites in its 3′ UTR; miR-210 overexpression reduces MNT levels and the resulting MNT knockdown phenocopies miR-210 overexpression (bypass of hypoxia-induced cell cycle arrest). Loss of MYC abolishes the miR-210-mediated override, placing MNT downstream of miR-210 and upstream of MYC-dependent transcription in the hypoxia response.","method":"3′ UTR reporter assays, siRNA knockdown, microarray gene expression profiling, cell cycle analysis, MYC knockout cell line epistasis","journal":"Cell cycle (Georgetown, Tex.)","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — 3′ UTR validation, knockdown phenocopy, and MYC epistasis in one study but no in vitro binding reconstitution","pmids":["19652553"],"is_preprint":false},{"year":2009,"finding":"During cholestasis, a switch from Mnt-Max to Myc-Max binding at E-box elements in the p53 and cyclin D1 promoters is responsible for upregulation of p53 and cyclin D1 and hepatocyte apoptosis; lentiviral c-myc siRNA in bile duct-ligated mice prevented this switch and protected against apoptosis.","method":"Electrophoretic mobility shift assay (EMSA) for E-box binding, nuclear fractionation, promoter activity assays, lentiviral siRNA in vivo, bile duct ligation mouse model","journal":"Hepatology (Baltimore, Md.)","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — EMSA binding switch correlated with gene expression, confirmed by in vivo RNAi, single lab","pmids":["19086036"],"is_preprint":false},{"year":2006,"finding":"Conditional deletion of Mnt in T cells causes increased apoptosis of thymic T cells, disrupted T-cell development, Th1 cytokine skewing, and ultimately T-cell lymphoma, demonstrating that Mnt is required for T-cell homeostasis and functions as a tumor suppressor in the T-cell lineage.","method":"Conditional Cre/lox knockout in T cells, flow cytometry, cytokine profiling, histopathology, in vivo tumor development","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — conditional KO with multiple well-defined cellular and in vivo phenotypes, replicated concept across T-cell studies","pmids":["16507988"],"is_preprint":false},{"year":2012,"finding":"Deletion of Mnt in T cells prevented Myc-driven T-cell proliferative expansion and thymoma formation; tumor suppression was linked to increased apoptosis mediated by reactive oxygen species (ROS). Mnt-null MEFs were refractory to oncogenic transformation by Myc, redefining Mnt's dominant physiological role as suppression of apoptosis in Myc-driven oncogenesis.","method":"T-cell-specific conditional Mnt knockout in Myc-transgenic mice, ROS measurement, apoptosis assays, in vitro transformation assays with MEFs","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic epistasis in vivo with Myc transgenic mice, ROS mechanistic follow-up, multiple orthogonal readouts","pmids":["23150551"],"is_preprint":false},{"year":2006,"finding":"Conditional loss of Mnt in mammary epithelium disrupts involution by reducing apoptosis and leads to hyperplastic ducts; promoter array analysis shows Mnt and c-Myc bind similar promoters, and mRNA expression profiles of Mnt-null mammary tumors resemble those of MMTV-c-Myc transgenic tumors, functionally linking Mnt loss to deregulated Myc target gene activation.","method":"Conditional Cre/lox knockout, promoter array (ChIP-chip), oligonucleotide expression arrays, histopathology","journal":"Cancer research","confidence":"High","confidence_rationale":"Tier 2 / Strong — conditional KO with ChIP-chip and expression array confirmation of overlapping target genes; multiple orthogonal methods","pmids":["16740691"],"is_preprint":false},{"year":2016,"finding":"E6AP (E6-associated protein), an E3 ubiquitin ligase, physically associates with MNT and promotes its ubiquitin-mediated proteasomal degradation; catalytically inactive E6AP (C843A mutant) stabilizes MNT rather than degrading it. ATRA treatment inhibits E6AP and stabilizes MNT, and E6AP knockdown restores MNT expression and promotes myeloid differentiation.","method":"Co-immunoprecipitation, proteasome inhibitor assays, catalytic mutant of E6AP, siRNA knockdown, western blot, myeloid differentiation assays (HL60 cells)","journal":"Oncotarget","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — co-IP with active-site mutant, RNAi epistasis and differentiation phenotype; single lab, two orthogonal methods","pmids":["26506232"],"is_preprint":false},{"year":2020,"finding":"MNT autoregulates its own expression: MNT-MAX dimers bind and repress the MNT promoter via an E-box. In MAX-deficient cells, MNT relocalizes from nucleus to cytoplasm, forms homodimers and MNT-MLX heterodimers, and regulates cell cycle and DNA repair genes independently of MAX; MNT homodimers regulate transcription of some cell proliferation genes. MNT is required for cell proliferation even in the absence of MAX.","method":"ChIP, E-box deletion reporter assay, co-immunoprecipitation, RNA-seq in MAX-deficient cells, subcellular fractionation/localization, siRNA knockdown of MNT in MAX-null cells","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Moderate — ChIP, co-IP, RNA-seq, and localization studies with functional cell proliferation readout; multiple orthogonal methods in one study","pmids":["31919096"],"is_preprint":false},{"year":2011,"finding":"Max-Mnt-Sin3a-HDAC complexes repress transcription of pro-apoptotic and cell cycle arrest genes in proliferating cells; inhibition of PI3-kinase leads to loss of Max/Mnt binding at target gene promoters, enabling transcriptional induction by MITF and USF1 and FoxO, linking PI3K/Akt/GSK3 signaling to regulation of Mnt-dependent repressor complexes.","method":"Chromatin immunoprecipitation, RNA interference, promoter activity assays, PI3-kinase inhibitor treatment, identification of GSK3 phosphorylation sites on USF1","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP and RNAi with apoptosis phenotype, single lab; signaling pathway placement supported by inhibitor and siRNA experiments","pmids":["21873430"],"is_preprint":false},{"year":2008,"finding":"In parous mammary glands responding to carcinogen exposure, Mnt is upregulated and a novel HDAC1/c-Myc/Mnt/Max complex forms on promoters of Myc target genes (ornithine decarboxylase, cyclin D2, TGFβ1), repressing their transcription and blocking proliferative response; this complex disassembles in serum-stimulated cells.","method":"Co-immunoprecipitation, ChIP, western blot, in vivo carcinogen treatment model","journal":"Cancer science","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — co-IP and ChIP demonstrating complex at target promoters, single lab, in vivo model","pmids":["18271930"],"is_preprint":false},{"year":2004,"finding":"Loss of the Max-interacting protein Mnt in mice results in perinatal lethality, intrauterine growth restriction, and craniofacial defects including cleft palate; Mnt-deficient embryos show reduced c-Myc and N-Myc levels, placing Mnt upstream of Myc regulation in embryonic development.","method":"Germline and conditional knockout mice (Cre/lox), histopathology, western blot for Myc proteins","journal":"Human molecular genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — clean KO with specific developmental phenotype and Myc protein level measurement, single lab","pmids":["15028671"],"is_preprint":false},{"year":2020,"finding":"In Eμ-Myc mice, homozygous Mnt deletion greatly reduced lymphoma incidence by enhancing MYC-driven apoptosis, primarily by failing to suppress pro-apoptotic BIM levels. Inducible deletion of Mnt within established transplanted Eμ-Myc lymphoma cells significantly extended recipient survival, establishing that MNT suppresses MYC-driven apoptosis through reduction of BIM.","method":"Conditional and inducible Cre/lox Mnt deletion in Eμ-Myc transgenic mice, transplantation survival assay, BIM protein measurement, apoptosis assays","journal":"Blood","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo genetic epistasis with Myc transgenic model, mechanistic link to BIM, inducible deletion in established tumors; multiple readouts","pmids":["31978211"],"is_preprint":false},{"year":2011,"finding":"OX40 engagement in antigen-stimulated T cells leads to increased protein stability of Mnt (and Mxd4), translocation to the nucleus, and increased cell survival; siRNA knockdown of Mnt led to increased cell death, demonstrating that Mnt stability contributes to OX40-mediated T-cell survival.","method":"Flow cytometry, nuclear fractionation, siRNA knockdown, protein stability assay, ex vivo antigen stimulation of murine T cells","journal":"European journal of immunology","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — protein localization and stability with siRNA functional validation; single lab, direct but not deeply mechanistic","pmids":["21400495"],"is_preprint":false},{"year":2004,"finding":"In neuroblastoma cells during retinoic-acid-induced differentiation, MYCN is rapidly downregulated and MYCN/Max DNA-binding activity decreases, while Mnt expression and Mnt/Max DNA-binding activity do not change significantly; overexpression of Mnt in MYCN-amplified cells does not block differentiation capacity, indicating that MYCN downregulation rather than changes in Mnt is essential for neuroblastoma differentiation.","method":"EMSA, western blot, flow cytometry, retroviral overexpression in neuroblastoma cells","journal":"Journal of cellular biochemistry","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — EMSA binding data combined with overexpression and differentiation assay; single lab","pmids":["15258910"],"is_preprint":false},{"year":1999,"finding":"Mnt protein interacts with Max to form a heterodimer that binds DNA specifically at E-box/CACGTG sequences in medulloblastoma cell lines; the functional bHLHZip domain is intact. No somatic mutations were found in the bHLHZip or SID regions in 44 medulloblastoma samples, making MNT an unlikely frequent target for 17p13.3 deletion-driven tumorigenesis in medulloblastoma.","method":"EMSA, RT-PCR, western blot, SSCP mutation analysis","journal":"International journal of cancer","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — EMSA confirms Max interaction and DNA binding; mutation screen is a negative result for coding mutations","pmids":["10446446"],"is_preprint":false}],"current_model":"MNT (also known as ROX/MXD6) is a bHLHZip transcriptional repressor that heterodimerizes with MAX (and can also form homodimers or MLX heterodimers in MAX-deficient contexts) to bind E-box sequences (preferentially CACGCG over CACGTG), recruiting mSIN3-HDAC co-repressor complexes via its N-terminal SID domain to repress MYC target genes; it is constitutively expressed in proliferating cells where it directly antagonizes MYC-MAX transcriptional activation, is regulated post-translationally by phosphorylation (which disrupts SIN3 interaction at cell cycle entry), by E6AP-mediated ubiquitin-proteasome degradation, and by OX40-driven stabilization, and functions in vivo as a tumor suppressor that restrains MYC-driven proliferation and oncogenesis while paradoxically suppressing MYC-induced apoptosis—primarily by reducing pro-apoptotic BIM levels."},"narrative":{"mechanistic_narrative":"MNT (ROX/MXD6) is a bHLHZip transcriptional repressor that heterodimerizes with MAX to bind E-box sequences and antagonize MYC-MAX–driven transcription, functioning as a brake on MYC-dependent proliferation and oncogenesis [PMID:9000049, PMID:15866886]. Repression depends on a 13-amino-acid N-terminal Sin3 interaction domain (SID) that recruits mSIN3-HDAC co-repressor complexes; deleting the SID converts MNT from a repressor and tumor suppressor into a transcriptional activator and cooperating oncogene [PMID:9000049, PMID:9184233]. MNT-MAX preferentially occupies the non-canonical CACGCG E-box and is constitutively present in quiescent and proliferating cells, where MYC induction at cell cycle entry transiently switches promoter occupancy from MNT-MAX to MYC-MAX at shared targets such as Cdk4, cyclin D2, and Odc [PMID:9184233, PMID:14749372, PMID:15866886]. Loss of MNT phenocopies MYC overexpression—premature S-phase entry, upregulation of Cdk4 and cyclin E, escape from senescence, and Ras-driven transformation independent of c-Myc—and genetic deletion produces adenocarcinoma and T-cell lymphoma in vivo, establishing MNT as a tumor suppressor [PMID:12970171, PMID:14749372, PMID:16507988]. Paradoxically, MNT also restrains MYC-induced apoptosis: in Eμ-Myc lymphoma its deletion enhances apoptosis by failing to suppress pro-apoptotic BIM, so MNT loss reduces lymphoma incidence and extends survival of established tumors [PMID:23150551, PMID:31978211]. MNT activity is set post-translationally—cell-cycle-entry phosphorylation disrupts the MNT-mSIN3 interaction and lowers associated HDAC activity, E6AP-mediated ubiquitination drives its proteasomal degradation, and OX40 signaling stabilizes it in T cells [PMID:16103876, PMID:26506232, PMID:21400495]. MNT also autoregulates its promoter via an E-box, and in MAX-deficient cells relocalizes to the cytoplasm and forms MNT homodimers and MNT-MLX heterodimers that regulate cell cycle and DNA repair genes, remaining required for proliferation even without MAX [PMID:31919096].","teleology":[{"year":1997,"claim":"Established MNT's core biochemical identity: how a MAX partner could oppose rather than mimic MYC, and which protein element confers repression.","evidence":"Two-hybrid, co-IP, EMSA, reporter assays and SID mutagenesis defining MNT-MAX dimers as E-box repressors that recruit Sin3","pmids":["9000049","9184233"],"confidence":"High","gaps":["Endogenous promoter occupancy not yet shown","In vivo physiological role undefined"]},{"year":2003,"claim":"Tested whether MNT physiologically restrains proliferation, resolving its role as a tumor suppressor that phenocopies MYC when lost.","evidence":"Conditional knockout MEFs and breast epithelium with cell cycle, ChIP, and Ras transformation readouts","pmids":["12970171"],"confidence":"High","gaps":["Apoptosis-suppressing role not yet appreciated","Direct target gene set incompletely mapped"]},{"year":2004,"claim":"Defined the dynamic MNT-MAX/MYC-MAX promoter switch and showed MNT can repress MYC targets independently of MYC itself.","evidence":"ChIP occupancy at Odc, stable RNAi, and transformation assays in c-myc-null MEFs","pmids":["14749372"],"confidence":"High","gaps":["Mechanism of complex displacement not resolved","MYC-independent target scope unclear"]},{"year":2004,"claim":"Addressed MNT's developmental requirement, revealing perinatal lethality and craniofacial defects and an upstream influence on Myc protein levels.","evidence":"Germline/conditional knockout mice with histopathology and Myc western blots","pmids":["15028671"],"confidence":"Medium","gaps":["Mechanism by which MNT loss reduces Myc protein not defined","Single lab"]},{"year":2005,"claim":"Connected signaling to MNT function by showing cell-cycle-entry phosphorylation dismantles the MNT-mSIN3 repressor complex, and confirmed direct MNT-MYC antagonism genetically.","evidence":"Co-IP, HDAC assays, ChIP at cyclin D2, and Mnt/c-Myc double-knockout rescue of cell cycle block","pmids":["16103876","15866886"],"confidence":"High","gaps":["Kinase responsible for MNT phosphorylation not identified","Phosphosite mapping incomplete"]},{"year":2006,"claim":"Extended MNT tumor suppression to specific lineages and linked its loss to overlapping MYC target gene programs.","evidence":"T-cell and mammary conditional knockouts with cytokine profiling, ChIP-chip promoter arrays, and expression profiling","pmids":["16507988","16740691"],"confidence":"High","gaps":["Whether lymphoma arises from proliferation or apoptosis defect not yet separated","Direct targets driving phenotype not isolated"]},{"year":2009,"claim":"Placed MNT within stress and hypoxia signaling axes by identifying upstream regulators and context-specific promoter switches.","evidence":"miR-210 3'UTR reporter and MYC epistasis in hypoxia; EMSA promoter switch at p53/cyclin D1 with in vivo c-myc siRNA in cholestasis","pmids":["19652553","19086036"],"confidence":"Medium","gaps":["No in vitro reconstitution of miR-210–MNT binding","Promoter-switch causality inferred from correlation in vivo"]},{"year":2011,"claim":"Defined post-translational control of MNT abundance/localization by survival signaling, and linked PI3K signaling to MNT repressor occupancy.","evidence":"OX40-driven stabilization and nuclear translocation with siRNA survival readout; ChIP and PI3K inhibition controlling Max/Mnt promoter binding","pmids":["21400495","21873430"],"confidence":"Medium","gaps":["Direct kinase/ligase intermediates between signaling and MNT not all defined","Single-lab signaling placements"]},{"year":2012,"claim":"Reframed MNT's dominant physiological role as suppression of MYC-induced apoptosis, mediated by ROS, rather than purely proliferation control.","evidence":"T-cell conditional Mnt knockout in Myc-transgenic mice with ROS and apoptosis assays and MEF transformation refractoriness","pmids":["23150551"],"confidence":"High","gaps":["Molecular link between MNT and ROS unresolved","Apoptotic effectors not yet identified"]},{"year":2016,"claim":"Identified an E3 ligase controlling MNT turnover, providing a druggable node for restoring MNT in differentiation.","evidence":"Co-IP, proteasome inhibition, E6AP catalytic mutant, and ATRA/E6AP knockdown in HL60 myeloid differentiation","pmids":["26506232"],"confidence":"Medium","gaps":["Ubiquitination sites on MNT not mapped","Single-lab finding"]},{"year":2020,"claim":"Pinned down the apoptosis mechanism to BIM and revealed MAX-independent MNT functions, broadening the regulatory model.","evidence":"Inducible Mnt deletion in Eμ-Myc lymphoma with BIM measurement and survival; ChIP/RNA-seq/localization in MAX-deficient cells","pmids":["31978211","31919096"],"confidence":"High","gaps":["How MNT represses BIM mechanistically not fully defined","Functional importance of MNT homodimers/MNT-MLX in normal cells unclear"]},{"year":null,"claim":"How MNT integrates its repressor and apoptosis-suppressing functions—and the molecular link between MNT, ROS, and BIM regulation—remains unresolved.","evidence":"","pmids":[],"confidence":"High","gaps":["No structural model of MNT-MAX–SIN3 assembly on chromatin","Direct mechanism connecting MNT to BIM/ROS undefined","Kinase and full ligase network controlling MNT not mapped"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[0,1,3,5,12]},{"term_id":"GO:0003677","term_label":"DNA binding","supporting_discovery_ids":[0,1,19]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[0,1,4]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[12,17]},{"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":[0,1,3,5]},{"term_id":"R-HSA-1640170","term_label":"Cell Cycle","supporting_discovery_ids":[2,5]},{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[9,16]},{"term_id":"R-HSA-4839726","term_label":"Chromatin organization","supporting_discovery_ids":[4,14]}],"complexes":["MNT-MAX heterodimer","mSIN3-HDAC co-repressor complex"],"partners":["MAX","SIN3A","HDAC1","MLX","UBE3A","MYC"],"other_free_text":[]}},"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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Independent effects of mutations at different positions in the operator.","date":"1993","source":"Journal of molecular biology","url":"https://pubmed.ncbi.nlm.nih.gov/8445649","citation_count":14,"is_preprint":false},{"pmid":"11226234","id":"PMC_11226234","title":"Contributions of distinct quaternary contacts to cooperative operator binding by Mnt repressor.","date":"2001","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/11226234","citation_count":13,"is_preprint":false},{"pmid":"18271930","id":"PMC_18271930","title":"Induction of a novel histone deacetylase 1/c-Myc/Mnt/Max complex formation is implicated in parity-induced refractoriness to mammary carcinogenesis.","date":"2008","source":"Cancer science","url":"https://pubmed.ncbi.nlm.nih.gov/18271930","citation_count":13,"is_preprint":false},{"pmid":"17577784","id":"PMC_17577784","title":"Expression and mutation analysis of genes that encode the Myc antagonists Mad1, Mxi1 and Rox in acute leukaemia.","date":"2007","source":"Leukemia & lymphoma","url":"https://pubmed.ncbi.nlm.nih.gov/17577784","citation_count":12,"is_preprint":false},{"pmid":"28800127","id":"PMC_28800127","title":"Mnt modulates Myc-driven lymphomagenesis.","date":"2017","source":"Cell death and differentiation","url":"https://pubmed.ncbi.nlm.nih.gov/28800127","citation_count":11,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":42964,"output_tokens":5376,"usd":0.104766,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":13815,"output_tokens":3737,"usd":0.08125,"stage2_stop_reason":"end_turn"},"total_usd":0.186016,"stage1_batch_id":"msgbatch_01BbTCMyrRPyhtEq6b1MdwCN","stage2_batch_id":"msgbatch_011dEed5bbxYvTAaQWKJevxu","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1997,\n      \"finding\": \"MNT (Rox/Mnt) heterodimerizes with Max via bHLHZip domains, and the Mnt:Max heterodimer binds CACGTG E-box sequences and acts as a transcriptional repressor. Transcriptional repression maps to a 13-amino-acid N-terminal Sin3 interaction domain (SID); deletion of SID converts Mnt from a repressor to an activator and from a suppressor of Myc+Ras cotransformation to a cooperating oncogene.\",\n      \"method\": \"Interaction mating (two-hybrid), co-immunoprecipitation, reporter gene transcription assays, mutagenesis of SID domain, primary cell transformation assay\",\n      \"journal\": \"Genes & development\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — multiple orthogonal methods (co-IP, DNA binding, transcription assay, mutagenesis, transformation assay) in a single rigorous study, replicated across subsequent papers\",\n      \"pmids\": [\"9000049\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1997,\n      \"finding\": \"Rox (human MNT ortholog) heterodimerizes with Max and weakly homodimerizes; the Rox-Max heterodimer preferentially binds the non-canonical CACGCG site over the canonical CACGTG E-box. Rox represses transcription in human HEK293 cells and yeast, and repression in yeast is mediated through interaction of its N-terminus with the Sin3 co-repressor.\",\n      \"method\": \"Interaction mating (two-hybrid), co-immunoprecipitation, electrophoretic mobility shift assay (EMSA), reporter gene transcription assays\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — reciprocal co-IP, EMSA with specificity comparisons, and transcription assays across two cell systems in one study; replicated conceptually by PMID:9000049\",\n      \"pmids\": [\"9184233\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"Deletion of Mnt in mouse embryo fibroblasts (MEFs) causes premature S-phase entry and faster proliferation linked to upregulation of Cdk4 and cyclin E; Cdk4 is a direct target of Mnt-Myc antagonism. Mnt-null MEFs are prone to apoptosis, bypass senescence, and can be transformed by oncogenic Ras alone, phenocopying Myc overexpression. Conditional deletion of Mnt in breast epithelium leads to adenocarcinomas.\",\n      \"method\": \"Conditional knockout (Cre/lox) mice, MEF proliferation and cell cycle assays, flow cytometry, ChIP, transformation assay with oncogenic Ras\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — clean KO with defined cellular phenotypes, multiple orthogonal readouts, replicated across studies (PMID:14749372)\",\n      \"pmids\": [\"12970171\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"In quiescent cells, Mnt-Max complexes occupy E-boxes (e.g., at the Odc gene); upon cell proliferation, Myc-Max complexes displace Mnt-Max. Stable RNAi knockdown of Mnt triggers Myc target gene expression, accelerated proliferation, apoptosis, and transformation of primary fibroblasts with Ras even in cells lacking c-myc, establishing Mnt as a transcriptional repressor of Myc target genes that functions partly independently of Myc.\",\n      \"method\": \"Chromatin immunoprecipitation (ChIP), stable retroviral RNAi, luciferase reporter assay, proliferation and transformation assays, c-myc null MEFs\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — ChIP occupancy data, RNAi loss-of-function with multiple readouts, genetic test in Myc-null cells; independently replicated concept\",\n      \"pmids\": [\"14749372\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"Mnt is phosphorylated upon serum-stimulated cell cycle re-entry; this phosphorylation disrupts the Mnt-mSin3 interaction and reduces Mnt-associated HDAC activity. Mnt binds and recruits mSin3 to the Myc target gene cyclin D2 in quiescent fibroblasts, repressing it; RNAi-mediated reduction of Mnt upregulates cyclin D2 in growth-arrested cells.\",\n      \"method\": \"Co-immunoprecipitation, HDAC activity assay, ChIP, RNAi knockdown, western blot for phosphorylation, serum stimulation cell cycle model\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — ChIP, co-IP showing disrupted complex, RNAi with gene expression readout; multiple orthogonal methods in one study\",\n      \"pmids\": [\"16103876\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"c-Myc induction during G0-to-S transition causes a transient switch in the ratio of Mnt-Max to Myc-Max on shared target gene promoters. Mnt overexpression suppresses cell cycle entry and proliferation. Simultaneous Cre-lox deletion of both Mnt and c-Myc in MEFs rescues the cell cycle block caused by c-Myc ablation alone, demonstrating direct Mnt-Myc antagonism in cell cycle entry.\",\n      \"method\": \"ChIP, co-immunoprecipitation, retroviral overexpression, conditional double knockout (Cre/lox), proliferation and cell cycle assays\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — ChIP showing complex switching, genetic epistasis by double KO rescue, multiple methods in one study\",\n      \"pmids\": [\"15866886\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"MNT mRNA contains multiple miR-210 binding sites in its 3′ UTR; miR-210 overexpression reduces MNT levels and the resulting MNT knockdown phenocopies miR-210 overexpression (bypass of hypoxia-induced cell cycle arrest). Loss of MYC abolishes the miR-210-mediated override, placing MNT downstream of miR-210 and upstream of MYC-dependent transcription in the hypoxia response.\",\n      \"method\": \"3′ UTR reporter assays, siRNA knockdown, microarray gene expression profiling, cell cycle analysis, MYC knockout cell line epistasis\",\n      \"journal\": \"Cell cycle (Georgetown, Tex.)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — 3′ UTR validation, knockdown phenocopy, and MYC epistasis in one study but no in vitro binding reconstitution\",\n      \"pmids\": [\"19652553\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"During cholestasis, a switch from Mnt-Max to Myc-Max binding at E-box elements in the p53 and cyclin D1 promoters is responsible for upregulation of p53 and cyclin D1 and hepatocyte apoptosis; lentiviral c-myc siRNA in bile duct-ligated mice prevented this switch and protected against apoptosis.\",\n      \"method\": \"Electrophoretic mobility shift assay (EMSA) for E-box binding, nuclear fractionation, promoter activity assays, lentiviral siRNA in vivo, bile duct ligation mouse model\",\n      \"journal\": \"Hepatology (Baltimore, Md.)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — EMSA binding switch correlated with gene expression, confirmed by in vivo RNAi, single lab\",\n      \"pmids\": [\"19086036\"],\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, disrupted T-cell development, Th1 cytokine skewing, and ultimately T-cell lymphoma, demonstrating that Mnt is required for T-cell homeostasis and functions as a tumor suppressor in the T-cell lineage.\",\n      \"method\": \"Conditional Cre/lox knockout in T cells, flow cytometry, cytokine profiling, histopathology, in vivo tumor development\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — conditional KO with multiple well-defined cellular and in vivo phenotypes, replicated concept across T-cell studies\",\n      \"pmids\": [\"16507988\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Deletion of Mnt in T cells prevented Myc-driven T-cell proliferative expansion and thymoma formation; tumor suppression was linked to increased apoptosis mediated by reactive oxygen species (ROS). Mnt-null MEFs were refractory to oncogenic transformation by Myc, redefining Mnt's dominant physiological role as suppression of apoptosis in Myc-driven oncogenesis.\",\n      \"method\": \"T-cell-specific conditional Mnt knockout in Myc-transgenic mice, ROS measurement, apoptosis assays, in vitro transformation assays with MEFs\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic epistasis in vivo with Myc transgenic mice, ROS mechanistic follow-up, multiple orthogonal readouts\",\n      \"pmids\": [\"23150551\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"Conditional loss of Mnt in mammary epithelium disrupts involution by reducing apoptosis and leads to hyperplastic ducts; promoter array analysis shows Mnt and c-Myc bind similar promoters, and mRNA expression profiles of Mnt-null mammary tumors resemble those of MMTV-c-Myc transgenic tumors, functionally linking Mnt loss to deregulated Myc target gene activation.\",\n      \"method\": \"Conditional Cre/lox knockout, promoter array (ChIP-chip), oligonucleotide expression arrays, histopathology\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — conditional KO with ChIP-chip and expression array confirmation of overlapping target genes; multiple orthogonal methods\",\n      \"pmids\": [\"16740691\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"E6AP (E6-associated protein), an E3 ubiquitin ligase, physically associates with MNT and promotes its ubiquitin-mediated proteasomal degradation; catalytically inactive E6AP (C843A mutant) stabilizes MNT rather than degrading it. ATRA treatment inhibits E6AP and stabilizes MNT, and E6AP knockdown restores MNT expression and promotes myeloid differentiation.\",\n      \"method\": \"Co-immunoprecipitation, proteasome inhibitor assays, catalytic mutant of E6AP, siRNA knockdown, western blot, myeloid differentiation assays (HL60 cells)\",\n      \"journal\": \"Oncotarget\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — co-IP with active-site mutant, RNAi epistasis and differentiation phenotype; single lab, two orthogonal methods\",\n      \"pmids\": [\"26506232\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"MNT autoregulates its own expression: MNT-MAX dimers bind and repress the MNT promoter via an E-box. In MAX-deficient cells, MNT relocalizes from nucleus to cytoplasm, forms homodimers and MNT-MLX heterodimers, and regulates cell cycle and DNA repair genes independently of MAX; MNT homodimers regulate transcription of some cell proliferation genes. MNT is required for cell proliferation even in the absence of MAX.\",\n      \"method\": \"ChIP, E-box deletion reporter assay, co-immunoprecipitation, RNA-seq in MAX-deficient cells, subcellular fractionation/localization, siRNA knockdown of MNT in MAX-null cells\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP, co-IP, RNA-seq, and localization studies with functional cell proliferation readout; multiple orthogonal methods in one study\",\n      \"pmids\": [\"31919096\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Max-Mnt-Sin3a-HDAC complexes repress transcription of pro-apoptotic and cell cycle arrest genes in proliferating cells; inhibition of PI3-kinase leads to loss of Max/Mnt binding at target gene promoters, enabling transcriptional induction by MITF and USF1 and FoxO, linking PI3K/Akt/GSK3 signaling to regulation of Mnt-dependent repressor complexes.\",\n      \"method\": \"Chromatin immunoprecipitation, RNA interference, promoter activity assays, PI3-kinase inhibitor treatment, identification of GSK3 phosphorylation sites on USF1\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP and RNAi with apoptosis phenotype, single lab; signaling pathway placement supported by inhibitor and siRNA experiments\",\n      \"pmids\": [\"21873430\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"In parous mammary glands responding to carcinogen exposure, Mnt is upregulated and a novel HDAC1/c-Myc/Mnt/Max complex forms on promoters of Myc target genes (ornithine decarboxylase, cyclin D2, TGFβ1), repressing their transcription and blocking proliferative response; this complex disassembles in serum-stimulated cells.\",\n      \"method\": \"Co-immunoprecipitation, ChIP, western blot, in vivo carcinogen treatment model\",\n      \"journal\": \"Cancer science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — co-IP and ChIP demonstrating complex at target promoters, single lab, in vivo model\",\n      \"pmids\": [\"18271930\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"Loss of the Max-interacting protein Mnt in mice results in perinatal lethality, intrauterine growth restriction, and craniofacial defects including cleft palate; Mnt-deficient embryos show reduced c-Myc and N-Myc levels, placing Mnt upstream of Myc regulation in embryonic development.\",\n      \"method\": \"Germline and conditional knockout mice (Cre/lox), histopathology, western blot for Myc proteins\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — clean KO with specific developmental phenotype and Myc protein level measurement, single lab\",\n      \"pmids\": [\"15028671\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"In Eμ-Myc mice, homozygous Mnt deletion greatly reduced lymphoma incidence by enhancing MYC-driven apoptosis, primarily by failing to suppress pro-apoptotic BIM levels. Inducible deletion of Mnt within established transplanted Eμ-Myc lymphoma cells significantly extended recipient survival, establishing that MNT suppresses MYC-driven apoptosis through reduction of BIM.\",\n      \"method\": \"Conditional and inducible Cre/lox Mnt deletion in Eμ-Myc transgenic mice, transplantation survival assay, BIM protein measurement, apoptosis assays\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo genetic epistasis with Myc transgenic model, mechanistic link to BIM, inducible deletion in established tumors; multiple readouts\",\n      \"pmids\": [\"31978211\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"OX40 engagement in antigen-stimulated T cells leads to increased protein stability of Mnt (and Mxd4), translocation to the nucleus, and increased cell survival; siRNA knockdown of Mnt led to increased cell death, demonstrating that Mnt stability contributes to OX40-mediated T-cell survival.\",\n      \"method\": \"Flow cytometry, nuclear fractionation, siRNA knockdown, protein stability assay, ex vivo antigen stimulation of murine T cells\",\n      \"journal\": \"European journal of immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — protein localization and stability with siRNA functional validation; single lab, direct but not deeply mechanistic\",\n      \"pmids\": [\"21400495\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"In neuroblastoma cells during retinoic-acid-induced differentiation, MYCN is rapidly downregulated and MYCN/Max DNA-binding activity decreases, while Mnt expression and Mnt/Max DNA-binding activity do not change significantly; overexpression of Mnt in MYCN-amplified cells does not block differentiation capacity, indicating that MYCN downregulation rather than changes in Mnt is essential for neuroblastoma differentiation.\",\n      \"method\": \"EMSA, western blot, flow cytometry, retroviral overexpression in neuroblastoma cells\",\n      \"journal\": \"Journal of cellular biochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — EMSA binding data combined with overexpression and differentiation assay; single lab\",\n      \"pmids\": [\"15258910\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"Mnt protein interacts with Max to form a heterodimer that binds DNA specifically at E-box/CACGTG sequences in medulloblastoma cell lines; the functional bHLHZip domain is intact. No somatic mutations were found in the bHLHZip or SID regions in 44 medulloblastoma samples, making MNT an unlikely frequent target for 17p13.3 deletion-driven tumorigenesis in medulloblastoma.\",\n      \"method\": \"EMSA, RT-PCR, western blot, SSCP mutation analysis\",\n      \"journal\": \"International journal of cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — EMSA confirms Max interaction and DNA binding; mutation screen is a negative result for coding mutations\",\n      \"pmids\": [\"10446446\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"MNT (also known as ROX/MXD6) is a bHLHZip transcriptional repressor that heterodimerizes with MAX (and can also form homodimers or MLX heterodimers in MAX-deficient contexts) to bind E-box sequences (preferentially CACGCG over CACGTG), recruiting mSIN3-HDAC co-repressor complexes via its N-terminal SID domain to repress MYC target genes; it is constitutively expressed in proliferating cells where it directly antagonizes MYC-MAX transcriptional activation, is regulated post-translationally by phosphorylation (which disrupts SIN3 interaction at cell cycle entry), by E6AP-mediated ubiquitin-proteasome degradation, and by OX40-driven stabilization, and functions in vivo as a tumor suppressor that restrains MYC-driven proliferation and oncogenesis while paradoxically suppressing MYC-induced apoptosis—primarily by reducing pro-apoptotic BIM levels.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"MNT (ROX/MXD6) is a bHLHZip transcriptional repressor that heterodimerizes with MAX to bind E-box sequences and antagonize MYC-MAX–driven transcription, functioning as a brake on MYC-dependent proliferation and oncogenesis [#0, #5]. Repression depends on a 13-amino-acid N-terminal Sin3 interaction domain (SID) that recruits mSIN3-HDAC co-repressor complexes; deleting the SID converts MNT from a repressor and tumor suppressor into a transcriptional activator and cooperating oncogene [#0, #1]. MNT-MAX preferentially occupies the non-canonical CACGCG E-box and is constitutively present in quiescent and proliferating cells, where MYC induction at cell cycle entry transiently switches promoter occupancy from MNT-MAX to MYC-MAX at shared targets such as Cdk4, cyclin D2, and Odc [#1, #3, #5]. Loss of MNT phenocopies MYC overexpression—premature S-phase entry, upregulation of Cdk4 and cyclin E, escape from senescence, and Ras-driven transformation independent of c-Myc—and genetic deletion produces adenocarcinoma and T-cell lymphoma in vivo, establishing MNT as a tumor suppressor [#2, #3, #8]. Paradoxically, MNT also restrains MYC-induced apoptosis: in Eμ-Myc lymphoma its deletion enhances apoptosis by failing to suppress pro-apoptotic BIM, so MNT loss reduces lymphoma incidence and extends survival of established tumors [#9, #16]. MNT activity is set post-translationally—cell-cycle-entry phosphorylation disrupts the MNT-mSIN3 interaction and lowers associated HDAC activity, E6AP-mediated ubiquitination drives its proteasomal degradation, and OX40 signaling stabilizes it in T cells [#4, #11, #17]. MNT also autoregulates its promoter via an E-box, and in MAX-deficient cells relocalizes to the cytoplasm and forms MNT homodimers and MNT-MLX heterodimers that regulate cell cycle and DNA repair genes, remaining required for proliferation even without MAX [#12].\",\n  \"teleology\": [\n    {\n      \"year\": 1997,\n      \"claim\": \"Established MNT's core biochemical identity: how a MAX partner could oppose rather than mimic MYC, and which protein element confers repression.\",\n      \"evidence\": \"Two-hybrid, co-IP, EMSA, reporter assays and SID mutagenesis defining MNT-MAX dimers as E-box repressors that recruit Sin3\",\n      \"pmids\": [\"9000049\", \"9184233\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Endogenous promoter occupancy not yet shown\", \"In vivo physiological role undefined\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Tested whether MNT physiologically restrains proliferation, resolving its role as a tumor suppressor that phenocopies MYC when lost.\",\n      \"evidence\": \"Conditional knockout MEFs and breast epithelium with cell cycle, ChIP, and Ras transformation readouts\",\n      \"pmids\": [\"12970171\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Apoptosis-suppressing role not yet appreciated\", \"Direct target gene set incompletely mapped\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Defined the dynamic MNT-MAX/MYC-MAX promoter switch and showed MNT can repress MYC targets independently of MYC itself.\",\n      \"evidence\": \"ChIP occupancy at Odc, stable RNAi, and transformation assays in c-myc-null MEFs\",\n      \"pmids\": [\"14749372\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism of complex displacement not resolved\", \"MYC-independent target scope unclear\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Addressed MNT's developmental requirement, revealing perinatal lethality and craniofacial defects and an upstream influence on Myc protein levels.\",\n      \"evidence\": \"Germline/conditional knockout mice with histopathology and Myc western blots\",\n      \"pmids\": [\"15028671\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism by which MNT loss reduces Myc protein not defined\", \"Single lab\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Connected signaling to MNT function by showing cell-cycle-entry phosphorylation dismantles the MNT-mSIN3 repressor complex, and confirmed direct MNT-MYC antagonism genetically.\",\n      \"evidence\": \"Co-IP, HDAC assays, ChIP at cyclin D2, and Mnt/c-Myc double-knockout rescue of cell cycle block\",\n      \"pmids\": [\"16103876\", \"15866886\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Kinase responsible for MNT phosphorylation not identified\", \"Phosphosite mapping incomplete\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Extended MNT tumor suppression to specific lineages and linked its loss to overlapping MYC target gene programs.\",\n      \"evidence\": \"T-cell and mammary conditional knockouts with cytokine profiling, ChIP-chip promoter arrays, and expression profiling\",\n      \"pmids\": [\"16507988\", \"16740691\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether lymphoma arises from proliferation or apoptosis defect not yet separated\", \"Direct targets driving phenotype not isolated\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Placed MNT within stress and hypoxia signaling axes by identifying upstream regulators and context-specific promoter switches.\",\n      \"evidence\": \"miR-210 3'UTR reporter and MYC epistasis in hypoxia; EMSA promoter switch at p53/cyclin D1 with in vivo c-myc siRNA in cholestasis\",\n      \"pmids\": [\"19652553\", \"19086036\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No in vitro reconstitution of miR-210–MNT binding\", \"Promoter-switch causality inferred from correlation in vivo\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Defined post-translational control of MNT abundance/localization by survival signaling, and linked PI3K signaling to MNT repressor occupancy.\",\n      \"evidence\": \"OX40-driven stabilization and nuclear translocation with siRNA survival readout; ChIP and PI3K inhibition controlling Max/Mnt promoter binding\",\n      \"pmids\": [\"21400495\", \"21873430\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct kinase/ligase intermediates between signaling and MNT not all defined\", \"Single-lab signaling placements\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Reframed MNT's dominant physiological role as suppression of MYC-induced apoptosis, mediated by ROS, rather than purely proliferation control.\",\n      \"evidence\": \"T-cell conditional Mnt knockout in Myc-transgenic mice with ROS and apoptosis assays and MEF transformation refractoriness\",\n      \"pmids\": [\"23150551\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular link between MNT and ROS unresolved\", \"Apoptotic effectors not yet identified\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Identified an E3 ligase controlling MNT turnover, providing a druggable node for restoring MNT in differentiation.\",\n      \"evidence\": \"Co-IP, proteasome inhibition, E6AP catalytic mutant, and ATRA/E6AP knockdown in HL60 myeloid differentiation\",\n      \"pmids\": [\"26506232\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Ubiquitination sites on MNT not mapped\", \"Single-lab finding\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Pinned down the apoptosis mechanism to BIM and revealed MAX-independent MNT functions, broadening the regulatory model.\",\n      \"evidence\": \"Inducible Mnt deletion in Eμ-Myc lymphoma with BIM measurement and survival; ChIP/RNA-seq/localization in MAX-deficient cells\",\n      \"pmids\": [\"31978211\", \"31919096\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How MNT represses BIM mechanistically not fully defined\", \"Functional importance of MNT homodimers/MNT-MLX in normal cells unclear\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How MNT integrates its repressor and apoptosis-suppressing functions—and the molecular link between MNT, ROS, and BIM regulation—remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No structural model of MNT-MAX–SIN3 assembly on chromatin\", \"Direct mechanism connecting MNT to BIM/ROS undefined\", \"Kinase and full ligase network controlling MNT not mapped\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [0, 1, 3, 5, 12]},\n      {\"term_id\": \"GO:0003677\", \"supporting_discovery_ids\": [0, 1, 19]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [0, 1, 4]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [12, 17]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [12]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [0, 1, 3, 5]},\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [2, 5]},\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [9, 16]},\n      {\"term_id\": \"R-HSA-4839726\", \"supporting_discovery_ids\": [4, 14]}\n    ],\n    \"complexes\": [\"MNT-MAX heterodimer\", \"mSIN3-HDAC co-repressor complex\"],\n    \"partners\": [\"MAX\", \"SIN3A\", \"HDAC1\", \"MLX\", \"UBE3A\", \"MYC\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}