{"gene":"MYCT1","run_date":"2026-04-29T11:37:56","timeline":{"discoveries":[{"year":2003,"finding":"MYCT1 (MTLC) was cloned from laryngeal cancer cells and shown to localize to nuclei of human hepatocellular carcinoma cells (Bel7402). The protein contains a nuclear localization signal motif and no other conserved domains; the 5' flanking sequence contains two c-Myc binding sites.","method":"RT-PCR, subcellular localization experiment, Northern blotting, bioinformatics","journal":"Chinese journal of medical genetics","confidence":"Medium","confidence_rationale":"Tier 3 — original cloning and localization paper, single lab, foundational but limited functional validation","pmids":["12673574"],"is_preprint":false},{"year":2003,"finding":"Overexpression of MYCT1 (MTLC) in gastric carcinoma BGC823 cells promoted apoptosis as detected by TUNEL assay, without affecting growth rate.","method":"Transfection of pcDNA3.1-MTLC, TUNEL assay, cell counting","journal":"World journal of gastroenterology","confidence":"Medium","confidence_rationale":"Tier 3 — single lab, single method (TUNEL), clear phenotypic readout","pmids":["14562369"],"is_preprint":false},{"year":2011,"finding":"c-Myc directly regulates MYCT1 promoter activity by binding to E-box elements within the -886 to -655 bp region of the MYCT1-TV transcript promoter.","method":"Luciferase reporter assay, EMSA, ChIP, site-directed mutagenesis, RNAi","journal":"PloS one","confidence":"High","confidence_rationale":"Tier 1-2 — multiple orthogonal methods (luciferase, EMSA, ChIP, mutagenesis) in a single study","pmids":["21998677"],"is_preprint":false},{"year":2012,"finding":"Promoter hypermethylation of the CGCG site (-695 to -692) in MYCT1 prevents c-Myc from binding its promoter, leading to transcriptional downregulation; demethylation by 5-aza-C restored c-Myc occupancy and increased MYCT1 expression.","method":"Bisulfite-specific PCR, luciferase reporter assay, EMSA, ChIP, site-directed mutagenesis","journal":"BMC cancer","confidence":"High","confidence_rationale":"Tier 1-2 — multiple orthogonal methods (EMSA, ChIP, mutagenesis, luciferase) demonstrating methylation blocks c-Myc binding","pmids":["22672838"],"is_preprint":false},{"year":2017,"finding":"YY1 directly binds the MYCT1 promoter and inhibits its activity, thereby suppressing MYCT1 expression. YY1-mediated promotion of laryngeal cancer cell proliferation and migration is dependent on MYCT1 repression.","method":"ChIP, dual luciferase assay, RNAi, cell viability, colony formation, scratch and Transwell assays, flow cytometry","journal":"Cancer medicine","confidence":"High","confidence_rationale":"Tier 1-2 — ChIP and luciferase confirm direct binding; epistasis (MYCT1 knockdown rescues YY1-silencing effects) across multiple orthogonal assays","pmids":["28485541"],"is_preprint":false},{"year":2018,"finding":"CREB directly binds the MYCT1 promoter and inhibits MYCT1 expression, which in turn relieves repression of NAT10; CREB thus promotes laryngeal cancer cell migration via the MYCT1/NAT10 axis.","method":"Luciferase reporter assay, ChIP, RT-PCR, Western blot, Transwell migration assay, gene transfection","journal":"OncoTargets and therapy","confidence":"High","confidence_rationale":"Tier 2 — ChIP and luciferase confirm direct promoter binding; epistasis established by rescue experiments","pmids":["29563811"],"is_preprint":false},{"year":2018,"finding":"MYCT1 overexpression in AML cells (HL-60, KG-1a) inhibits proliferation, arrests cell cycle at G0/G1 (downregulating cyclins D and E), and induces apoptosis via activation of caspase-3 and -9, upregulation of Bax, and downregulation of Bcl-2; MYCT1 promoter is hypermethylated in AML.","method":"Lentiviral overexpression, cell proliferation assay, flow cytometry, Western blot, xenograft tumor model","journal":"Frontiers in pharmacology","confidence":"Medium","confidence_rationale":"Tier 2 — clean overexpression with multiple phenotypic readouts and in vivo validation, single lab","pmids":["30283340"],"is_preprint":false},{"year":2019,"finding":"MYCT1 interacts with MAX as a co-transcription factor component of the MAX transcriptional complex to drive expression of miR-181a; miR-181a then targets NPM1 to suppress its expression, promoting apoptosis via extracellular and intracellular apoptotic pathways in laryngeal cancer cells.","method":"Luciferase reporter assay, ChIP, RT-PCR, Western blot, cell viability, colony formation, flow cytometry, miRNA inhibitor/overexpression rescue experiments","journal":"The FEBS journal","confidence":"Medium","confidence_rationale":"Tier 2 — pathway placed by epistasis with miR-181a and NPM1 rescue; MYCT1-MAX interaction inferred functionally but not by direct Co-IP","pmids":["31152622"],"is_preprint":false},{"year":2019,"finding":"miR-632 directly targets the 3'UTR of MYCT1 and negatively regulates MYCT1 expression, thereby promoting HCC cell proliferation, colony formation, and invasion.","method":"Dual luciferase reporter assay, qRT-PCR, Western blot, CCK-8, colony formation, Transwell invasion, siRNA knockdown rescue","journal":"Human gene therapy. Clinical development","confidence":"Medium","confidence_rationale":"Tier 2 — luciferase confirms direct 3'UTR targeting; functional rescue experiments support the mechanistic link","pmids":["30982352"],"is_preprint":false},{"year":2020,"finding":"MYCT1 inhibits EMT and migration of laryngeal cancer cells through the SP1/miR-629-3p/ESRP2 pathway: MYCT1 suppresses SP1, which reduces miR-629-3p transcription, thereby de-repressing ESRP2 expression.","method":"Gene transfection, RT-PCR, Western blot, luciferase reporter assay (miR-629-3p/ESRP2 3'UTR), ChIP, Transwell migration assay, EMT marker analysis","journal":"Cellular signalling","confidence":"Medium","confidence_rationale":"Tier 2 — pathway established by multiple methods including ChIP and luciferase; epistasis supported by rescue experiments","pmids":["32659265"],"is_preprint":false},{"year":2020,"finding":"YY1 inhibits MYCT1 expression by directly binding to its promoter region; in the context of liver cancer, miR-34a-5p targets YY1, thereby relieving MYCT1 repression and inhibiting HCC cell invasion and metastasis.","method":"ChIP, dual luciferase assay, Western blot, Transwell invasion assay, wound-healing assay, siRNA/miRNA manipulation","journal":"Acta histochemica","confidence":"High","confidence_rationale":"Tier 2 — replicates YY1→MYCT1 promoter binding (ChIP + luciferase) in a second cancer context with epistasis rescue experiments","pmids":["32778238"],"is_preprint":false},{"year":2021,"finding":"MYCT1 interacts with tight junction protein ZO-1 (Zona Occludens 1) and regulates Rho GTPase-mediated actin cytoskeleton dynamics, thereby promoting endothelial motility in the angiogenic environment. Myct1 deficiency reduced angiogenesis, enhanced high endothelial venule formation, and promoted antitumor immunity in mouse tumor models.","method":"Co-immunoprecipitation, endothelial-specific Myct1 knockout mouse models, in vitro endothelial motility assays, trans-endothelial migration assay, macrophage polarization assay","journal":"Science translational medicine","confidence":"High","confidence_rationale":"Tier 2 — Co-IP identifies ZO-1 interaction; genetic KO in multiple in vivo tumor models with defined cellular phenotypes; multiple orthogonal mechanistic readouts","pmids":["33658356"],"is_preprint":false},{"year":2021,"finding":"MYCT1 inhibits adhesion and migration of laryngeal cancer cells by repressing COL6 (Collagen VI, including COL6A1, COL6A2, COL6A3) expression.","method":"RNA-seq, qRT-PCR, Western blot, cell adhesion assay, wound healing assay, migration assay, bioinformatics (WGCNA)","journal":"Frontiers in oncology","confidence":"Medium","confidence_rationale":"Tier 3 — functional assays support COL6 as MYCT1 target, but mechanistic link relies on RNA-seq and expression validation rather than direct regulatory assay","pmids":["33680912"],"is_preprint":false},{"year":2021,"finding":"In vascular smooth muscle cells, MYCT1 maintains expression of ribosomal protein genes; nitrosative stress downregulates MYCT1, which in turn reduces ribosomal protein expression and compromises translational capacity for collagen production.","method":"MYCT1 knockdown and overexpression in primary SMCs, real-time PCR, Western blot, caspase 3/7 activity assay, ELISA for collagen","journal":"European review for medical and pharmacological sciences","confidence":"Medium","confidence_rationale":"Tier 3 — functional epistasis between MYCT1 and ribosomal proteins shown by gain/loss-of-function, single lab","pmids":["34604957"],"is_preprint":false},{"year":2022,"finding":"MYCT1 promotes translation efficiency of PGM1, UGP2, and GSK3A in hepatic cells in a RACK1-dependent manner, thereby enhancing the glycogen shunt; global Myct1 inactivation in mice leads to progressive hepatic glycogen accumulation.","method":"Myct1 global knockout mice, metabolic intermediate analysis, translational efficiency assay, RACK1 interaction studies in hepatic cells","journal":"iScience","confidence":"Medium","confidence_rationale":"Tier 2 — in vivo KO model with metabolic phenotype plus mechanistic RACK1-dependent translational regulation, single lab","pmids":["35281731"],"is_preprint":false},{"year":2023,"finding":"VDR (Vitamin D receptor) transcriptionally upregulates MYCT1 by binding to the MYCT1 promoter. MYCT1 in turn suppresses SP1 transcription and TGF-β1/SMAD3 pathway activation, attenuating renal fibrosis in diabetic kidney disease.","method":"Dual-luciferase reporter assay, ChIP, AAV-Myct1 in diabetic db/db mice, Western blot, siRNA knockdown in tubular epithelial cells","journal":"iScience","confidence":"High","confidence_rationale":"Tier 2 — ChIP and luciferase confirm VDR-MYCT1 promoter binding; pathway placed by in vivo rescue (AAV-Myct1) plus in vitro mechanistic assays","pmids":["37664593"],"is_preprint":false},{"year":2024,"finding":"MYCT1 localizes to the endosomal membrane in human HSCs and interacts with vesicle trafficking regulators and signaling machinery. MYCT1 loss leads to excessive endocytosis and hyperactive signaling responses; restoring MYCT1 balances endocytosis and dysregulated signaling, thereby preserving HSC stemness.","method":"Lentivirus-mediated KD/OE in cord blood HSPCs, single-cell RNA-seq, direct localization imaging (endosomal membrane), co-immunoprecipitation with trafficking regulators, endocytosis assays, xenograft engraftment","journal":"Nature","confidence":"High","confidence_rationale":"Tier 1-2 — multiple orthogonal methods (scRNA-seq, Co-IP, functional rescue, in vivo engraftment, endocytosis quantification) in a high-impact journal","pmids":["38839950"],"is_preprint":false},{"year":2024,"finding":"MYCT1 physically interacts with MAX protein in diffuse large B-cell lymphoma cells; this interaction represses MAX-driven RUNX1 transcription (MAX directly promotes RUNX1 transcription by binding its promoter), thereby inhibiting proliferation and cell cycle progression.","method":"Co-IP, immunofluorescence, ChIP, dual-luciferase reporter assay, flow cytometry, CCK-8 assay, R banding karyotype analysis","journal":"Cellular & molecular biology letters","confidence":"High","confidence_rationale":"Tier 2 — Co-IP confirms MYCT1-MAX interaction; ChIP and luciferase establish MAX binding to RUNX1 promoter; multiple orthogonal methods in single study","pmids":["38172714"],"is_preprint":false},{"year":2025,"finding":"MARCH1 (an E3 ubiquitin ligase transcriptionally activated by POU2F2) physically interacts with MYCT1 and promotes its ubiquitination and proteasomal degradation in AML cells, thereby facilitating AML cell proliferation and suppressing apoptosis.","method":"Co-immunoprecipitation, ubiquitination assay, gain/loss-of-function experiments, in vivo AML mouse model, luciferase reporter for POU2F2-MARCH1 axis","journal":"Oncogene","confidence":"High","confidence_rationale":"Tier 2 — Co-IP identifies MARCH1-MYCT1 interaction; ubiquitination assay establishes mechanism; epistasis confirmed by MYCT1 KD rescue of MARCH1 KD phenotype; in vivo validation","pmids":["40533483"],"is_preprint":false},{"year":2025,"finding":"TBX21 promotes MYCT1 expression, and MYCT1 in turn interacts with ZO-1 to regulate the cytoskeleton, suppressing colorectal cancer cell metastasis via the MYCT1/ZO-1 pathway.","method":"RNA sequencing, ectopic TBX21 expression, in vitro migration assay, in vivo metastasis model, MYCT1 knockdown rescue experiments","journal":"International journal of biological sciences","confidence":"Medium","confidence_rationale":"Tier 3 — MYCT1-ZO-1 interaction inferred from pathway analysis and rescue but not directly demonstrated by Co-IP in this paper; functional epistasis supports pathway placement","pmids":["39744435"],"is_preprint":false},{"year":2026,"finding":"MYCT1 interacts with transmembrane endolysosomal proteins IFITM2/3 to restrict nutrient consumption by the vascular endothelial barrier. Loss of MYCT1 causes IFITM2/3 accumulation in early endosomes, promoting excessive endolysosomal degradation and mTORC1 hyperactivation, limiting white adipose tissue energy storage capacity.","method":"Endothelial-specific MYCT1 deletion, Co-immunoprecipitation (MYCT1-IFITM2/3), endosomal trafficking assays, mTORC1 activity measurement, TSC1 deletion phenocopy experiment, WAT expansion assay","journal":"The Journal of experimental medicine","confidence":"High","confidence_rationale":"Tier 1-2 — Co-IP identifies MYCT1-IFITM2/3 complex; endothelial-specific KO with defined metabolic phenotype; mTORC1 hyperactivation mechanistically linked; TSC1-KO phenocopy provides epistasis","pmids":["41880193"],"is_preprint":false}],"current_model":"MYCT1 is a c-Myc target gene (regulated by c-Myc, YY1, CREB, and VDR at the promoter level, and silenced by promoter hypermethylation or miR-632) that localizes to endosomal membranes where it moderates endocytosis and environmental sensing; it interacts with ZO-1 to regulate actin cytoskeleton dynamics and endothelial motility, with IFITM2/3 to control endolysosomal nutrient trafficking and mTORC1 signaling, with MAX to repress transcription of target genes such as RUNX1, and with RACK1 to selectively promote translation of metabolic enzymes (PGM1, UGP2, GSK3A), while its protein stability is controlled by MARCH1-mediated ubiquitination and degradation, collectively establishing MYCT1 as a multifunctional regulator of endocytosis, vesicle trafficking, cytoskeletal organization, transcription, and translation that suppresses tumor progression and preserves stem cell identity."},"narrative":{"teleology":[{"year":2003,"claim":"Identification of MYCT1 as a novel c-Myc-associated gene established its existence and initial localization, providing the molecular entry point for all subsequent functional studies.","evidence":"Cloning from laryngeal cancer cells, RT-PCR, subcellular localization, bioinformatics identification of c-Myc binding sites and NLS","pmids":["12673574"],"confidence":"Medium","gaps":["No functional domain identified beyond NLS","Localization studied in only one cell line","No interaction partners identified"]},{"year":2003,"claim":"Demonstrating that MYCT1 overexpression promoted apoptosis in gastric cancer cells established the first functional phenotype and framed MYCT1 as a potential tumor suppressor.","evidence":"Overexpression in BGC823 cells, TUNEL assay","pmids":["14562369"],"confidence":"Medium","gaps":["Single cell line and single method (TUNEL)","Mechanism of apoptosis induction unknown","No loss-of-function data"]},{"year":2011,"claim":"Establishing that c-Myc directly binds E-box elements in the MYCT1 promoter resolved how MYCT1 is transcriptionally activated and confirmed it as a bona fide c-Myc target gene.","evidence":"Luciferase reporter, EMSA, ChIP, site-directed mutagenesis, RNAi in multiple cell lines","pmids":["21998677"],"confidence":"High","gaps":["Whether c-Myc activates or represses MYCT1 in different contexts not resolved","Other transcription factors at the promoter not yet identified"]},{"year":2012,"claim":"Showing that promoter CpG methylation blocks c-Myc binding and silences MYCT1 explained the frequent downregulation of MYCT1 in cancers and linked epigenetic regulation to its tumor-suppressive loss.","evidence":"Bisulfite-specific PCR, EMSA, ChIP, mutagenesis, 5-aza-C demethylation rescue","pmids":["22672838"],"confidence":"High","gaps":["Whether methylation is a driver or passenger event in tumorigenesis","Methylation status across diverse tumor types not systematically assessed"]},{"year":2017,"claim":"Identifying YY1 as a direct transcriptional repressor of MYCT1 expanded the regulatory logic at the MYCT1 promoter and demonstrated that MYCT1 mediates YY1's oncogenic effects in laryngeal cancer.","evidence":"ChIP, dual luciferase, epistasis rescue (MYCT1 KD reverses YY1-silencing phenotypes), proliferation and migration assays","pmids":["28485541"],"confidence":"High","gaps":["Whether YY1 and c-Myc compete at the same promoter region not tested","Downstream effectors of MYCT1 in this context unknown"]},{"year":2018,"claim":"Demonstrating that CREB represses MYCT1 to de-repress NAT10 and that MYCT1 overexpression induces G0/G1 arrest and intrinsic apoptosis in AML cells broadened the tumor-suppressive repertoire of MYCT1 to hematological malignancies and identified cell cycle and apoptosis machinery as downstream effectors.","evidence":"ChIP and luciferase for CREB-MYCT1 promoter; lentiviral overexpression in AML lines with cell cycle, apoptosis, and xenograft readouts","pmids":["29563811","30283340"],"confidence":"High","gaps":["How MYCT1 mechanistically regulates cyclin D/E and Bcl-2 family members not resolved","NAT10 downstream pathway poorly defined"]},{"year":2019,"claim":"Identifying MYCT1's interaction with MAX as a co-transcriptional mechanism and its post-transcriptional regulation by miR-632 revealed both nuclear effector function (driving miR-181a/NPM1 apoptosis axis) and an additional silencing route via 3′UTR targeting.","evidence":"Luciferase, ChIP, miRNA inhibitor/overexpression rescue for MYCT1-MAX-miR-181a-NPM1 axis; dual luciferase 3′UTR assay for miR-632 targeting","pmids":["31152622","30982352"],"confidence":"Medium","gaps":["MYCT1-MAX interaction inferred functionally but not validated by direct Co-IP in 2019 study","Whether MYCT1-MAX complex is stoichiometric or transient unknown"]},{"year":2020,"claim":"Mapping the MYCT1→SP1→miR-629-3p→ESRP2 pathway and confirming YY1-mediated MYCT1 repression in a second cancer type (HCC) established MYCT1's anti-EMT function and validated the generalizability of its transcriptional regulation.","evidence":"ChIP, luciferase, Transwell migration, EMT marker analysis in laryngeal cancer; YY1/miR-34a-5p epistasis in HCC","pmids":["32659265","32778238"],"confidence":"Medium","gaps":["How MYCT1 suppresses SP1 expression mechanistically unknown","Whether ESRP2 is a direct or indirect target not fully resolved"]},{"year":2021,"claim":"Discovery that MYCT1 physically interacts with ZO-1 and regulates Rho GTPase-actin dynamics in endothelium, with endothelial-specific knockout enhancing antitumor immunity, pivoted understanding of MYCT1 from a purely cancer-cell-intrinsic suppressor to a regulator of endothelial biology and the tumor microenvironment.","evidence":"Co-IP for MYCT1-ZO-1, endothelial-specific Myct1 knockout mice, in vivo tumor models, motility and trans-endothelial migration assays","pmids":["33658356"],"confidence":"High","gaps":["Which Rho GTPase is the direct target not specified","How ZO-1 interaction is regulated unclear","Role in non-tumor vasculature not defined"]},{"year":2022,"claim":"Demonstrating that MYCT1 promotes translation of glycogen-shunt enzymes via RACK1 interaction, with global knockout causing hepatic glycogen accumulation, established MYCT1 as a translational regulator with metabolic consequences in vivo.","evidence":"Myct1 global KO mice, metabolic intermediate analysis, translational efficiency assays, RACK1 interaction studies in hepatic cells","pmids":["35281731"],"confidence":"Medium","gaps":["Whether RACK1 interaction is direct or within a larger ribosomal complex not resolved","Full spectrum of RACK1-dependent MYCT1 translational targets unknown","Single lab finding"]},{"year":2023,"claim":"Identifying VDR as a direct transcriptional activator of MYCT1 and showing that MYCT1 attenuates renal fibrosis via SP1/TGF-β1/SMAD3 suppression extended MYCT1's physiological relevance to diabetic kidney disease.","evidence":"ChIP and luciferase for VDR-MYCT1 promoter, AAV-Myct1 in diabetic db/db mice, Western blot and siRNA in tubular epithelial cells","pmids":["37664593"],"confidence":"High","gaps":["Whether VDR-MYCT1 axis operates in non-renal tissues unknown","Direct molecular link between MYCT1 and SP1 suppression still unresolved"]},{"year":2024,"claim":"Localizing MYCT1 to endosomal membranes in human HSCs and showing it restrains endocytosis to preserve stemness fundamentally reframed MYCT1 as a membrane-associated endosomal gatekeeper rather than a purely nuclear factor.","evidence":"Lentiviral KD/OE in cord blood HSPCs, scRNA-seq, endosomal membrane imaging, Co-IP with trafficking regulators, endocytosis assays, xenograft engraftment","pmids":["38839950"],"confidence":"High","gaps":["Specific endosomal trafficking regulators interacting with MYCT1 not all named","Whether endosomal localization is universal across cell types or HSC-specific unclear"]},{"year":2024,"claim":"Confirming MYCT1-MAX physical interaction by Co-IP and showing it represses RUNX1 transcription in DLBCL validated the nuclear transcriptional repressor arm of MYCT1 function with direct protein-protein evidence.","evidence":"Co-IP, immunofluorescence, ChIP, dual-luciferase, flow cytometry, CCK-8 in DLBCL cells","pmids":["38172714"],"confidence":"High","gaps":["Whether MYCT1 alters MAX-MYC versus MAX-MXD1 complex equilibrium unknown","Genome-wide MYCT1-MAX target repertoire not defined"]},{"year":2025,"claim":"Identifying MARCH1 as the E3 ligase that ubiquitinates and degrades MYCT1 protein resolved a major gap in understanding how MYCT1 protein levels are controlled post-translationally, explaining another route of MYCT1 inactivation in AML.","evidence":"Co-IP, ubiquitination assay, gain/loss-of-function, in vivo AML mouse model, POU2F2-MARCH1 luciferase axis","pmids":["40533483"],"confidence":"High","gaps":["Ubiquitination site(s) on MYCT1 not mapped","Whether other E3 ligases target MYCT1 unknown"]},{"year":2025,"claim":"Demonstrating that MYCT1 interacts with IFITM2/3 at endolysosomes to restrain nutrient trafficking and mTORC1 signaling in endothelium, with loss causing defective white adipose energy storage, provided a molecular mechanism for MYCT1's endosomal gatekeeper function and linked it to systemic metabolic regulation.","evidence":"Endothelial-specific MYCT1 deletion, Co-IP for MYCT1-IFITM2/3, endosomal trafficking assays, mTORC1 activity measurement, TSC1-KO phenocopy, WAT expansion assay","pmids":["41880193"],"confidence":"High","gaps":["Structural basis of MYCT1-IFITM2/3 interaction unknown","Whether MYCT1-IFITM interaction is regulated by post-translational modifications not tested","Relevance to non-endothelial MYCT1 functions not established"]},{"year":null,"claim":"How MYCT1 coordinates its dual endosomal and nuclear functions — whether these represent distinct protein pools, cell-type-specific roles, or a shuttling mechanism — remains unresolved, and no structural model of MYCT1 or its complexes exists.","evidence":"","pmids":[],"confidence":"Low","gaps":["No crystal structure or cryo-EM model of MYCT1","Dual localization (endosome vs. nucleus) mechanism unexplained","Full interactome not defined by unbiased proteomics","Relative importance of transcriptional, translational, and trafficking functions in different tissues not delineated"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[7,14,16,17,20]},{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[7,9,17]},{"term_id":"GO:0045182","term_label":"translation regulator activity","supporting_discovery_ids":[13,14]},{"term_id":"GO:0008092","term_label":"cytoskeletal protein binding","supporting_discovery_ids":[11,19]}],"localization":[{"term_id":"GO:0005768","term_label":"endosome","supporting_discovery_ids":[16,20]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[0,7,17]},{"term_id":"GO:0005764","term_label":"lysosome","supporting_discovery_ids":[20]}],"pathway":[{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[1,6,7,18]},{"term_id":"R-HSA-1640170","term_label":"Cell Cycle","supporting_discovery_ids":[6,17]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[16,20]},{"term_id":"R-HSA-5653656","term_label":"Vesicle-mediated transport","supporting_discovery_ids":[16,20]},{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[7,9,17]},{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[14,20]},{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[14,18]}],"complexes":["MAX transcriptional complex"],"partners":["MAX","ZO-1","RACK1","IFITM2","IFITM3","MARCH1"],"other_free_text":[]},"mechanistic_narrative":"MYCT1 is a multifunctional membrane-associated and nuclear protein that integrates endosomal trafficking, cytoskeletal regulation, transcriptional repression, and translational control to restrain cell proliferation, preserve stem cell identity, and suppress tumor progression. At endosomal membranes, MYCT1 moderates endocytosis and interacts with IFITM2/3 to limit endolysosomal nutrient degradation and mTORC1 signaling, and with ZO-1 to regulate Rho GTPase-dependent actin dynamics and endothelial motility [PMID:38839950, PMID:41880193, PMID:33658356]. In the nucleus, MYCT1 partners with MAX to repress transcription of targets including RUNX1, and interacts with RACK1 to selectively promote translation of glycogen-shunt enzymes PGM1, UGP2, and GSK3A [PMID:38172714, PMID:35281731]. MYCT1 expression is directly activated by c-Myc and VDR, repressed by YY1 and CREB at the promoter level or silenced by promoter hypermethylation, and its protein is turned over by MARCH1-mediated ubiquitination and proteasomal degradation [PMID:21998677, PMID:22672838, PMID:28485541, PMID:37664593, PMID:40533483]."},"prefetch_data":{"uniprot":{"accession":"Q8N699","full_name":"Myc target protein 1","aliases":["Myc target in myeloid cells protein 1"],"length_aa":235,"mass_kda":26.6,"function":"May regulate certain MYC target genes, MYC seems to be a direct upstream transcriptional activator. Does not seem to significantly affect growth cell capacity. Overexpression seems to mediate many of the known phenotypic features associated with MYC, including promotion of apoptosis, alteration of morphology, enhancement of anchorage-independent growth, tumorigenic conversion, promotion of genomic instability, and inhibition of hematopoietic differentiation (By similarity)","subcellular_location":"Nucleus","url":"https://www.uniprot.org/uniprotkb/Q8N699/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/MYCT1","classification":"Not Classified","n_dependent_lines":4,"n_total_lines":1208,"dependency_fraction":0.0033112582781456954},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/MYCT1","total_profiled":1310},"omim":[{"mim_id":"616805","title":"MYC TARGET IN MYELOID CELLS 1; MYCT1","url":"https://www.omim.org/entry/616805"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Nucleoplasm","reliability":"Supported"},{"location":"Nuclear bodies","reliability":"Additional"},{"location":"Vesicles","reliability":"Additional"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"lymphoid tissue","ntpm":46.7}],"url":"https://www.proteinatlas.org/search/MYCT1"},"hgnc":{"alias_symbol":["MTLC","FLJ21269"],"prev_symbol":[]},"alphafold":{"accession":"Q8N699","domains":[{"cath_id":"1.20.58","chopping":"3-51_70-97","consensus_level":"medium","plddt":80.0214,"start":3,"end":97}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q8N699","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q8N699-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q8N699-F1-predicted_aligned_error_v6.png","plddt_mean":60.56},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=MYCT1","jax_strain_url":"https://www.jax.org/strain/search?query=MYCT1"},"sequence":{"accession":"Q8N699","fasta_url":"https://rest.uniprot.org/uniprotkb/Q8N699.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q8N699/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q8N699"}},"corpus_meta":[{"pmid":"33658356","id":"PMC_33658356","title":"Dual role of endothelial Myct1 in tumor angiogenesis and tumor immunity.","date":"2021","source":"Science translational medicine","url":"https://pubmed.ncbi.nlm.nih.gov/33658356","citation_count":59,"is_preprint":false},{"pmid":"28485541","id":"PMC_28485541","title":"YY1 directly suppresses MYCT1 leading to laryngeal tumorigenesis and progress.","date":"2017","source":"Cancer medicine","url":"https://pubmed.ncbi.nlm.nih.gov/28485541","citation_count":28,"is_preprint":false},{"pmid":"29563811","id":"PMC_29563811","title":"CREB promotes laryngeal cancer cell migration via MYCT1/NAT10 axis.","date":"2018","source":"OncoTargets and therapy","url":"https://pubmed.ncbi.nlm.nih.gov/29563811","citation_count":27,"is_preprint":false},{"pmid":"32778238","id":"PMC_32778238","title":"miR-34a-5p suppresses the invasion and metastasis of liver cancer by targeting the transcription factor YY1 to mediate MYCT1 upregulation.","date":"2020","source":"Acta histochemica","url":"https://pubmed.ncbi.nlm.nih.gov/32778238","citation_count":26,"is_preprint":false},{"pmid":"32659265","id":"PMC_32659265","title":"MYCT1 inhibits the EMT and migration of laryngeal cancer cells via the SP1/miR-629-3p/ESRP2 pathway.","date":"2020","source":"Cellular signalling","url":"https://pubmed.ncbi.nlm.nih.gov/32659265","citation_count":24,"is_preprint":false},{"pmid":"21998677","id":"PMC_21998677","title":"MYCT1-TV, a novel MYCT1 transcript, is regulated by c-Myc and may participate in laryngeal carcinogenesis.","date":"2011","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/21998677","citation_count":22,"is_preprint":false},{"pmid":"31152622","id":"PMC_31152622","title":"MYCT1 represses apoptosis of laryngeal cancerous cells through the MAX/miR-181a/NPM1 pathway.","date":"2019","source":"The FEBS journal","url":"https://pubmed.ncbi.nlm.nih.gov/31152622","citation_count":22,"is_preprint":false},{"pmid":"22672838","id":"PMC_22672838","title":"Promoter hypermethylation-induced transcriptional down-regulation of the gene MYCT1 in laryngeal squamous cell carcinoma.","date":"2012","source":"BMC cancer","url":"https://pubmed.ncbi.nlm.nih.gov/22672838","citation_count":20,"is_preprint":false},{"pmid":"30982352","id":"PMC_30982352","title":"miR-632 Functions as Oncogene in Hepatocellular Carcinoma via Targeting MYCT1.","date":"2019","source":"Human gene therapy. Clinical development","url":"https://pubmed.ncbi.nlm.nih.gov/30982352","citation_count":16,"is_preprint":false},{"pmid":"33680912","id":"PMC_33680912","title":"MYCT1 Inhibits the Adhesion and Migration of Laryngeal Cancer Cells Potentially Through Repressing Collagen VI.","date":"2021","source":"Frontiers in oncology","url":"https://pubmed.ncbi.nlm.nih.gov/33680912","citation_count":14,"is_preprint":false},{"pmid":"30283340","id":"PMC_30283340","title":"Overexpression of MYCT1 Inhibits Proliferation and Induces Apoptosis in Human Acute Myeloid Leukemia HL-60 and KG-1a Cells in vitro and in vivo.","date":"2018","source":"Frontiers in pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/30283340","citation_count":14,"is_preprint":false},{"pmid":"14562369","id":"PMC_14562369","title":"Expression of MTLC gene in gastric carcinoma.","date":"2003","source":"World journal of gastroenterology","url":"https://pubmed.ncbi.nlm.nih.gov/14562369","citation_count":13,"is_preprint":false},{"pmid":"12673574","id":"PMC_12673574","title":"[Cloning and characterization of MTLC, a novel gene in 6q25].","date":"2003","source":"Zhonghua yi xue yi chuan xue za zhi = Zhonghua yixue yichuanxue zazhi = Chinese journal of medical genetics","url":"https://pubmed.ncbi.nlm.nih.gov/12673574","citation_count":13,"is_preprint":false},{"pmid":"37664593","id":"PMC_37664593","title":"MYCT1 attenuates renal fibrosis and tubular injury in diabetic kidney disease.","date":"2023","source":"iScience","url":"https://pubmed.ncbi.nlm.nih.gov/37664593","citation_count":12,"is_preprint":false},{"pmid":"38839950","id":"PMC_38839950","title":"MYCT1 controls environmental sensing in human haematopoietic stem cells.","date":"2024","source":"Nature","url":"https://pubmed.ncbi.nlm.nih.gov/38839950","citation_count":11,"is_preprint":false},{"pmid":"35281731","id":"PMC_35281731","title":"MYCT1 alters the glycogen shunt by regulating selective translation of RACK1-mediated enzymes.","date":"2022","source":"iScience","url":"https://pubmed.ncbi.nlm.nih.gov/35281731","citation_count":9,"is_preprint":false},{"pmid":"37499454","id":"PMC_37499454","title":"MYCT1 in cancer development: Gene structure, regulation, and biological implications for diagnosis and treatment.","date":"2023","source":"Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie","url":"https://pubmed.ncbi.nlm.nih.gov/37499454","citation_count":6,"is_preprint":false},{"pmid":"39744435","id":"PMC_39744435","title":"TBX21 inhibits colorectal cancer metastasis through ARHGAP29/GSK3β inhibitory signaling- and MYCT1/ZO-1 signaling-dependent manner.","date":"2025","source":"International journal of biological sciences","url":"https://pubmed.ncbi.nlm.nih.gov/39744435","citation_count":5,"is_preprint":false},{"pmid":"34604957","id":"PMC_34604957","title":"Nitrosative stress induces downregulation of ribosomal protein genes via MYCT1 in vascular smooth muscle cells.","date":"2021","source":"European review for medical and pharmacological sciences","url":"https://pubmed.ncbi.nlm.nih.gov/34604957","citation_count":3,"is_preprint":false},{"pmid":"40533483","id":"PMC_40533483","title":"MARCH1, transcriptionally regulated by POU2F2, facilitates acute myeloid leukemia progression via inducing MYCT1 degradation.","date":"2025","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/40533483","citation_count":2,"is_preprint":false},{"pmid":"38172714","id":"PMC_38172714","title":"MYCT1 inhibits hematopoiesis in diffuse large B-cell lymphoma by suppressing RUNX1 transcription.","date":"2024","source":"Cellular & molecular biology letters","url":"https://pubmed.ncbi.nlm.nih.gov/38172714","citation_count":1,"is_preprint":false},{"pmid":"36263566","id":"PMC_36263566","title":"Author Correction: Nitrosative stress induces downregulation of ribosomal protein genes via MYCT1 in vascular smooth muscle cells.","date":"2022","source":"European review for medical and pharmacological sciences","url":"https://pubmed.ncbi.nlm.nih.gov/36263566","citation_count":0,"is_preprint":false},{"pmid":"41880193","id":"PMC_41880193","title":"MYCT1-IFITM2/3 interaction links endothelial endolysosomal trafficking to white adipose tissue expansion.","date":"2026","source":"The Journal of experimental medicine","url":"https://pubmed.ncbi.nlm.nih.gov/41880193","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":12596,"output_tokens":5001,"usd":0.056402},"stage2":{"model":"claude-opus-4-6","input_tokens":8512,"output_tokens":4075,"usd":0.216652},"total_usd":0.273054,"stage1_batch_id":"msgbatch_012ZiiCUBfB62NCTQd4Bk1Jo","stage2_batch_id":"msgbatch_01Xuqq9aUHoQouS7UVGZNStZ","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2003,\n      \"finding\": \"MYCT1 (MTLC) was cloned from laryngeal cancer cells and shown to localize to nuclei of human hepatocellular carcinoma cells (Bel7402). The protein contains a nuclear localization signal motif and no other conserved domains; the 5' flanking sequence contains two c-Myc binding sites.\",\n      \"method\": \"RT-PCR, subcellular localization experiment, Northern blotting, bioinformatics\",\n      \"journal\": \"Chinese journal of medical genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — original cloning and localization paper, single lab, foundational but limited functional validation\",\n      \"pmids\": [\"12673574\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"Overexpression of MYCT1 (MTLC) in gastric carcinoma BGC823 cells promoted apoptosis as detected by TUNEL assay, without affecting growth rate.\",\n      \"method\": \"Transfection of pcDNA3.1-MTLC, TUNEL assay, cell counting\",\n      \"journal\": \"World journal of gastroenterology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — single lab, single method (TUNEL), clear phenotypic readout\",\n      \"pmids\": [\"14562369\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"c-Myc directly regulates MYCT1 promoter activity by binding to E-box elements within the -886 to -655 bp region of the MYCT1-TV transcript promoter.\",\n      \"method\": \"Luciferase reporter assay, EMSA, ChIP, site-directed mutagenesis, RNAi\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — multiple orthogonal methods (luciferase, EMSA, ChIP, mutagenesis) in a single study\",\n      \"pmids\": [\"21998677\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Promoter hypermethylation of the CGCG site (-695 to -692) in MYCT1 prevents c-Myc from binding its promoter, leading to transcriptional downregulation; demethylation by 5-aza-C restored c-Myc occupancy and increased MYCT1 expression.\",\n      \"method\": \"Bisulfite-specific PCR, luciferase reporter assay, EMSA, ChIP, site-directed mutagenesis\",\n      \"journal\": \"BMC cancer\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — multiple orthogonal methods (EMSA, ChIP, mutagenesis, luciferase) demonstrating methylation blocks c-Myc binding\",\n      \"pmids\": [\"22672838\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"YY1 directly binds the MYCT1 promoter and inhibits its activity, thereby suppressing MYCT1 expression. YY1-mediated promotion of laryngeal cancer cell proliferation and migration is dependent on MYCT1 repression.\",\n      \"method\": \"ChIP, dual luciferase assay, RNAi, cell viability, colony formation, scratch and Transwell assays, flow cytometry\",\n      \"journal\": \"Cancer medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — ChIP and luciferase confirm direct binding; epistasis (MYCT1 knockdown rescues YY1-silencing effects) across multiple orthogonal assays\",\n      \"pmids\": [\"28485541\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"CREB directly binds the MYCT1 promoter and inhibits MYCT1 expression, which in turn relieves repression of NAT10; CREB thus promotes laryngeal cancer cell migration via the MYCT1/NAT10 axis.\",\n      \"method\": \"Luciferase reporter assay, ChIP, RT-PCR, Western blot, Transwell migration assay, gene transfection\",\n      \"journal\": \"OncoTargets and therapy\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — ChIP and luciferase confirm direct promoter binding; epistasis established by rescue experiments\",\n      \"pmids\": [\"29563811\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"MYCT1 overexpression in AML cells (HL-60, KG-1a) inhibits proliferation, arrests cell cycle at G0/G1 (downregulating cyclins D and E), and induces apoptosis via activation of caspase-3 and -9, upregulation of Bax, and downregulation of Bcl-2; MYCT1 promoter is hypermethylated in AML.\",\n      \"method\": \"Lentiviral overexpression, cell proliferation assay, flow cytometry, Western blot, xenograft tumor model\",\n      \"journal\": \"Frontiers in pharmacology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — clean overexpression with multiple phenotypic readouts and in vivo validation, single lab\",\n      \"pmids\": [\"30283340\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"MYCT1 interacts with MAX as a co-transcription factor component of the MAX transcriptional complex to drive expression of miR-181a; miR-181a then targets NPM1 to suppress its expression, promoting apoptosis via extracellular and intracellular apoptotic pathways in laryngeal cancer cells.\",\n      \"method\": \"Luciferase reporter assay, ChIP, RT-PCR, Western blot, cell viability, colony formation, flow cytometry, miRNA inhibitor/overexpression rescue experiments\",\n      \"journal\": \"The FEBS journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — pathway placed by epistasis with miR-181a and NPM1 rescue; MYCT1-MAX interaction inferred functionally but not by direct Co-IP\",\n      \"pmids\": [\"31152622\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"miR-632 directly targets the 3'UTR of MYCT1 and negatively regulates MYCT1 expression, thereby promoting HCC cell proliferation, colony formation, and invasion.\",\n      \"method\": \"Dual luciferase reporter assay, qRT-PCR, Western blot, CCK-8, colony formation, Transwell invasion, siRNA knockdown rescue\",\n      \"journal\": \"Human gene therapy. Clinical development\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — luciferase confirms direct 3'UTR targeting; functional rescue experiments support the mechanistic link\",\n      \"pmids\": [\"30982352\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"MYCT1 inhibits EMT and migration of laryngeal cancer cells through the SP1/miR-629-3p/ESRP2 pathway: MYCT1 suppresses SP1, which reduces miR-629-3p transcription, thereby de-repressing ESRP2 expression.\",\n      \"method\": \"Gene transfection, RT-PCR, Western blot, luciferase reporter assay (miR-629-3p/ESRP2 3'UTR), ChIP, Transwell migration assay, EMT marker analysis\",\n      \"journal\": \"Cellular signalling\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — pathway established by multiple methods including ChIP and luciferase; epistasis supported by rescue experiments\",\n      \"pmids\": [\"32659265\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"YY1 inhibits MYCT1 expression by directly binding to its promoter region; in the context of liver cancer, miR-34a-5p targets YY1, thereby relieving MYCT1 repression and inhibiting HCC cell invasion and metastasis.\",\n      \"method\": \"ChIP, dual luciferase assay, Western blot, Transwell invasion assay, wound-healing assay, siRNA/miRNA manipulation\",\n      \"journal\": \"Acta histochemica\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — replicates YY1→MYCT1 promoter binding (ChIP + luciferase) in a second cancer context with epistasis rescue experiments\",\n      \"pmids\": [\"32778238\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"MYCT1 interacts with tight junction protein ZO-1 (Zona Occludens 1) and regulates Rho GTPase-mediated actin cytoskeleton dynamics, thereby promoting endothelial motility in the angiogenic environment. Myct1 deficiency reduced angiogenesis, enhanced high endothelial venule formation, and promoted antitumor immunity in mouse tumor models.\",\n      \"method\": \"Co-immunoprecipitation, endothelial-specific Myct1 knockout mouse models, in vitro endothelial motility assays, trans-endothelial migration assay, macrophage polarization assay\",\n      \"journal\": \"Science translational medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — Co-IP identifies ZO-1 interaction; genetic KO in multiple in vivo tumor models with defined cellular phenotypes; multiple orthogonal mechanistic readouts\",\n      \"pmids\": [\"33658356\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"MYCT1 inhibits adhesion and migration of laryngeal cancer cells by repressing COL6 (Collagen VI, including COL6A1, COL6A2, COL6A3) expression.\",\n      \"method\": \"RNA-seq, qRT-PCR, Western blot, cell adhesion assay, wound healing assay, migration assay, bioinformatics (WGCNA)\",\n      \"journal\": \"Frontiers in oncology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — functional assays support COL6 as MYCT1 target, but mechanistic link relies on RNA-seq and expression validation rather than direct regulatory assay\",\n      \"pmids\": [\"33680912\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"In vascular smooth muscle cells, MYCT1 maintains expression of ribosomal protein genes; nitrosative stress downregulates MYCT1, which in turn reduces ribosomal protein expression and compromises translational capacity for collagen production.\",\n      \"method\": \"MYCT1 knockdown and overexpression in primary SMCs, real-time PCR, Western blot, caspase 3/7 activity assay, ELISA for collagen\",\n      \"journal\": \"European review for medical and pharmacological sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — functional epistasis between MYCT1 and ribosomal proteins shown by gain/loss-of-function, single lab\",\n      \"pmids\": [\"34604957\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"MYCT1 promotes translation efficiency of PGM1, UGP2, and GSK3A in hepatic cells in a RACK1-dependent manner, thereby enhancing the glycogen shunt; global Myct1 inactivation in mice leads to progressive hepatic glycogen accumulation.\",\n      \"method\": \"Myct1 global knockout mice, metabolic intermediate analysis, translational efficiency assay, RACK1 interaction studies in hepatic cells\",\n      \"journal\": \"iScience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — in vivo KO model with metabolic phenotype plus mechanistic RACK1-dependent translational regulation, single lab\",\n      \"pmids\": [\"35281731\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"VDR (Vitamin D receptor) transcriptionally upregulates MYCT1 by binding to the MYCT1 promoter. MYCT1 in turn suppresses SP1 transcription and TGF-β1/SMAD3 pathway activation, attenuating renal fibrosis in diabetic kidney disease.\",\n      \"method\": \"Dual-luciferase reporter assay, ChIP, AAV-Myct1 in diabetic db/db mice, Western blot, siRNA knockdown in tubular epithelial cells\",\n      \"journal\": \"iScience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — ChIP and luciferase confirm VDR-MYCT1 promoter binding; pathway placed by in vivo rescue (AAV-Myct1) plus in vitro mechanistic assays\",\n      \"pmids\": [\"37664593\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"MYCT1 localizes to the endosomal membrane in human HSCs and interacts with vesicle trafficking regulators and signaling machinery. MYCT1 loss leads to excessive endocytosis and hyperactive signaling responses; restoring MYCT1 balances endocytosis and dysregulated signaling, thereby preserving HSC stemness.\",\n      \"method\": \"Lentivirus-mediated KD/OE in cord blood HSPCs, single-cell RNA-seq, direct localization imaging (endosomal membrane), co-immunoprecipitation with trafficking regulators, endocytosis assays, xenograft engraftment\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — multiple orthogonal methods (scRNA-seq, Co-IP, functional rescue, in vivo engraftment, endocytosis quantification) in a high-impact journal\",\n      \"pmids\": [\"38839950\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"MYCT1 physically interacts with MAX protein in diffuse large B-cell lymphoma cells; this interaction represses MAX-driven RUNX1 transcription (MAX directly promotes RUNX1 transcription by binding its promoter), thereby inhibiting proliferation and cell cycle progression.\",\n      \"method\": \"Co-IP, immunofluorescence, ChIP, dual-luciferase reporter assay, flow cytometry, CCK-8 assay, R banding karyotype analysis\",\n      \"journal\": \"Cellular & molecular biology letters\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — Co-IP confirms MYCT1-MAX interaction; ChIP and luciferase establish MAX binding to RUNX1 promoter; multiple orthogonal methods in single study\",\n      \"pmids\": [\"38172714\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"MARCH1 (an E3 ubiquitin ligase transcriptionally activated by POU2F2) physically interacts with MYCT1 and promotes its ubiquitination and proteasomal degradation in AML cells, thereby facilitating AML cell proliferation and suppressing apoptosis.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay, gain/loss-of-function experiments, in vivo AML mouse model, luciferase reporter for POU2F2-MARCH1 axis\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — Co-IP identifies MARCH1-MYCT1 interaction; ubiquitination assay establishes mechanism; epistasis confirmed by MYCT1 KD rescue of MARCH1 KD phenotype; in vivo validation\",\n      \"pmids\": [\"40533483\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"TBX21 promotes MYCT1 expression, and MYCT1 in turn interacts with ZO-1 to regulate the cytoskeleton, suppressing colorectal cancer cell metastasis via the MYCT1/ZO-1 pathway.\",\n      \"method\": \"RNA sequencing, ectopic TBX21 expression, in vitro migration assay, in vivo metastasis model, MYCT1 knockdown rescue experiments\",\n      \"journal\": \"International journal of biological sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — MYCT1-ZO-1 interaction inferred from pathway analysis and rescue but not directly demonstrated by Co-IP in this paper; functional epistasis supports pathway placement\",\n      \"pmids\": [\"39744435\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"MYCT1 interacts with transmembrane endolysosomal proteins IFITM2/3 to restrict nutrient consumption by the vascular endothelial barrier. Loss of MYCT1 causes IFITM2/3 accumulation in early endosomes, promoting excessive endolysosomal degradation and mTORC1 hyperactivation, limiting white adipose tissue energy storage capacity.\",\n      \"method\": \"Endothelial-specific MYCT1 deletion, Co-immunoprecipitation (MYCT1-IFITM2/3), endosomal trafficking assays, mTORC1 activity measurement, TSC1 deletion phenocopy experiment, WAT expansion assay\",\n      \"journal\": \"The Journal of experimental medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — Co-IP identifies MYCT1-IFITM2/3 complex; endothelial-specific KO with defined metabolic phenotype; mTORC1 hyperactivation mechanistically linked; TSC1-KO phenocopy provides epistasis\",\n      \"pmids\": [\"41880193\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"MYCT1 is a c-Myc target gene (regulated by c-Myc, YY1, CREB, and VDR at the promoter level, and silenced by promoter hypermethylation or miR-632) that localizes to endosomal membranes where it moderates endocytosis and environmental sensing; it interacts with ZO-1 to regulate actin cytoskeleton dynamics and endothelial motility, with IFITM2/3 to control endolysosomal nutrient trafficking and mTORC1 signaling, with MAX to repress transcription of target genes such as RUNX1, and with RACK1 to selectively promote translation of metabolic enzymes (PGM1, UGP2, GSK3A), while its protein stability is controlled by MARCH1-mediated ubiquitination and degradation, collectively establishing MYCT1 as a multifunctional regulator of endocytosis, vesicle trafficking, cytoskeletal organization, transcription, and translation that suppresses tumor progression and preserves stem cell identity.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"MYCT1 is a multifunctional membrane-associated and nuclear protein that integrates endosomal trafficking, cytoskeletal regulation, transcriptional repression, and translational control to restrain cell proliferation, preserve stem cell identity, and suppress tumor progression. At endosomal membranes, MYCT1 moderates endocytosis and interacts with IFITM2/3 to limit endolysosomal nutrient degradation and mTORC1 signaling, and with ZO-1 to regulate Rho GTPase-dependent actin dynamics and endothelial motility [PMID:38839950, PMID:41880193, PMID:33658356]. In the nucleus, MYCT1 partners with MAX to repress transcription of targets including RUNX1, and interacts with RACK1 to selectively promote translation of glycogen-shunt enzymes PGM1, UGP2, and GSK3A [PMID:38172714, PMID:35281731]. MYCT1 expression is directly activated by c-Myc and VDR, repressed by YY1 and CREB at the promoter level or silenced by promoter hypermethylation, and its protein is turned over by MARCH1-mediated ubiquitination and proteasomal degradation [PMID:21998677, PMID:22672838, PMID:28485541, PMID:37664593, PMID:40533483].\",\n  \"teleology\": [\n    {\n      \"year\": 2003,\n      \"claim\": \"Identification of MYCT1 as a novel c-Myc-associated gene established its existence and initial localization, providing the molecular entry point for all subsequent functional studies.\",\n      \"evidence\": \"Cloning from laryngeal cancer cells, RT-PCR, subcellular localization, bioinformatics identification of c-Myc binding sites and NLS\",\n      \"pmids\": [\"12673574\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No functional domain identified beyond NLS\", \"Localization studied in only one cell line\", \"No interaction partners identified\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Demonstrating that MYCT1 overexpression promoted apoptosis in gastric cancer cells established the first functional phenotype and framed MYCT1 as a potential tumor suppressor.\",\n      \"evidence\": \"Overexpression in BGC823 cells, TUNEL assay\",\n      \"pmids\": [\"14562369\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single cell line and single method (TUNEL)\", \"Mechanism of apoptosis induction unknown\", \"No loss-of-function data\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Establishing that c-Myc directly binds E-box elements in the MYCT1 promoter resolved how MYCT1 is transcriptionally activated and confirmed it as a bona fide c-Myc target gene.\",\n      \"evidence\": \"Luciferase reporter, EMSA, ChIP, site-directed mutagenesis, RNAi in multiple cell lines\",\n      \"pmids\": [\"21998677\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether c-Myc activates or represses MYCT1 in different contexts not resolved\", \"Other transcription factors at the promoter not yet identified\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Showing that promoter CpG methylation blocks c-Myc binding and silences MYCT1 explained the frequent downregulation of MYCT1 in cancers and linked epigenetic regulation to its tumor-suppressive loss.\",\n      \"evidence\": \"Bisulfite-specific PCR, EMSA, ChIP, mutagenesis, 5-aza-C demethylation rescue\",\n      \"pmids\": [\"22672838\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether methylation is a driver or passenger event in tumorigenesis\", \"Methylation status across diverse tumor types not systematically assessed\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Identifying YY1 as a direct transcriptional repressor of MYCT1 expanded the regulatory logic at the MYCT1 promoter and demonstrated that MYCT1 mediates YY1's oncogenic effects in laryngeal cancer.\",\n      \"evidence\": \"ChIP, dual luciferase, epistasis rescue (MYCT1 KD reverses YY1-silencing phenotypes), proliferation and migration assays\",\n      \"pmids\": [\"28485541\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether YY1 and c-Myc compete at the same promoter region not tested\", \"Downstream effectors of MYCT1 in this context unknown\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Demonstrating that CREB represses MYCT1 to de-repress NAT10 and that MYCT1 overexpression induces G0/G1 arrest and intrinsic apoptosis in AML cells broadened the tumor-suppressive repertoire of MYCT1 to hematological malignancies and identified cell cycle and apoptosis machinery as downstream effectors.\",\n      \"evidence\": \"ChIP and luciferase for CREB-MYCT1 promoter; lentiviral overexpression in AML lines with cell cycle, apoptosis, and xenograft readouts\",\n      \"pmids\": [\"29563811\", \"30283340\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How MYCT1 mechanistically regulates cyclin D/E and Bcl-2 family members not resolved\", \"NAT10 downstream pathway poorly defined\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Identifying MYCT1's interaction with MAX as a co-transcriptional mechanism and its post-transcriptional regulation by miR-632 revealed both nuclear effector function (driving miR-181a/NPM1 apoptosis axis) and an additional silencing route via 3′UTR targeting.\",\n      \"evidence\": \"Luciferase, ChIP, miRNA inhibitor/overexpression rescue for MYCT1-MAX-miR-181a-NPM1 axis; dual luciferase 3′UTR assay for miR-632 targeting\",\n      \"pmids\": [\"31152622\", \"30982352\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"MYCT1-MAX interaction inferred functionally but not validated by direct Co-IP in 2019 study\", \"Whether MYCT1-MAX complex is stoichiometric or transient unknown\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Mapping the MYCT1→SP1→miR-629-3p→ESRP2 pathway and confirming YY1-mediated MYCT1 repression in a second cancer type (HCC) established MYCT1's anti-EMT function and validated the generalizability of its transcriptional regulation.\",\n      \"evidence\": \"ChIP, luciferase, Transwell migration, EMT marker analysis in laryngeal cancer; YY1/miR-34a-5p epistasis in HCC\",\n      \"pmids\": [\"32659265\", \"32778238\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"How MYCT1 suppresses SP1 expression mechanistically unknown\", \"Whether ESRP2 is a direct or indirect target not fully resolved\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Discovery that MYCT1 physically interacts with ZO-1 and regulates Rho GTPase-actin dynamics in endothelium, with endothelial-specific knockout enhancing antitumor immunity, pivoted understanding of MYCT1 from a purely cancer-cell-intrinsic suppressor to a regulator of endothelial biology and the tumor microenvironment.\",\n      \"evidence\": \"Co-IP for MYCT1-ZO-1, endothelial-specific Myct1 knockout mice, in vivo tumor models, motility and trans-endothelial migration assays\",\n      \"pmids\": [\"33658356\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Which Rho GTPase is the direct target not specified\", \"How ZO-1 interaction is regulated unclear\", \"Role in non-tumor vasculature not defined\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Demonstrating that MYCT1 promotes translation of glycogen-shunt enzymes via RACK1 interaction, with global knockout causing hepatic glycogen accumulation, established MYCT1 as a translational regulator with metabolic consequences in vivo.\",\n      \"evidence\": \"Myct1 global KO mice, metabolic intermediate analysis, translational efficiency assays, RACK1 interaction studies in hepatic cells\",\n      \"pmids\": [\"35281731\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether RACK1 interaction is direct or within a larger ribosomal complex not resolved\", \"Full spectrum of RACK1-dependent MYCT1 translational targets unknown\", \"Single lab finding\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Identifying VDR as a direct transcriptional activator of MYCT1 and showing that MYCT1 attenuates renal fibrosis via SP1/TGF-β1/SMAD3 suppression extended MYCT1's physiological relevance to diabetic kidney disease.\",\n      \"evidence\": \"ChIP and luciferase for VDR-MYCT1 promoter, AAV-Myct1 in diabetic db/db mice, Western blot and siRNA in tubular epithelial cells\",\n      \"pmids\": [\"37664593\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether VDR-MYCT1 axis operates in non-renal tissues unknown\", \"Direct molecular link between MYCT1 and SP1 suppression still unresolved\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Localizing MYCT1 to endosomal membranes in human HSCs and showing it restrains endocytosis to preserve stemness fundamentally reframed MYCT1 as a membrane-associated endosomal gatekeeper rather than a purely nuclear factor.\",\n      \"evidence\": \"Lentiviral KD/OE in cord blood HSPCs, scRNA-seq, endosomal membrane imaging, Co-IP with trafficking regulators, endocytosis assays, xenograft engraftment\",\n      \"pmids\": [\"38839950\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Specific endosomal trafficking regulators interacting with MYCT1 not all named\", \"Whether endosomal localization is universal across cell types or HSC-specific unclear\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Confirming MYCT1-MAX physical interaction by Co-IP and showing it represses RUNX1 transcription in DLBCL validated the nuclear transcriptional repressor arm of MYCT1 function with direct protein-protein evidence.\",\n      \"evidence\": \"Co-IP, immunofluorescence, ChIP, dual-luciferase, flow cytometry, CCK-8 in DLBCL cells\",\n      \"pmids\": [\"38172714\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether MYCT1 alters MAX-MYC versus MAX-MXD1 complex equilibrium unknown\", \"Genome-wide MYCT1-MAX target repertoire not defined\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Identifying MARCH1 as the E3 ligase that ubiquitinates and degrades MYCT1 protein resolved a major gap in understanding how MYCT1 protein levels are controlled post-translationally, explaining another route of MYCT1 inactivation in AML.\",\n      \"evidence\": \"Co-IP, ubiquitination assay, gain/loss-of-function, in vivo AML mouse model, POU2F2-MARCH1 luciferase axis\",\n      \"pmids\": [\"40533483\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Ubiquitination site(s) on MYCT1 not mapped\", \"Whether other E3 ligases target MYCT1 unknown\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Demonstrating that MYCT1 interacts with IFITM2/3 at endolysosomes to restrain nutrient trafficking and mTORC1 signaling in endothelium, with loss causing defective white adipose energy storage, provided a molecular mechanism for MYCT1's endosomal gatekeeper function and linked it to systemic metabolic regulation.\",\n      \"evidence\": \"Endothelial-specific MYCT1 deletion, Co-IP for MYCT1-IFITM2/3, endosomal trafficking assays, mTORC1 activity measurement, TSC1-KO phenocopy, WAT expansion assay\",\n      \"pmids\": [\"41880193\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of MYCT1-IFITM2/3 interaction unknown\", \"Whether MYCT1-IFITM interaction is regulated by post-translational modifications not tested\", \"Relevance to non-endothelial MYCT1 functions not established\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How MYCT1 coordinates its dual endosomal and nuclear functions — whether these represent distinct protein pools, cell-type-specific roles, or a shuttling mechanism — remains unresolved, and no structural model of MYCT1 or its complexes exists.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No crystal structure or cryo-EM model of MYCT1\", \"Dual localization (endosome vs. nucleus) mechanism unexplained\", \"Full interactome not defined by unbiased proteomics\", \"Relative importance of transcriptional, translational, and trafficking functions in different tissues not delineated\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [7, 14, 16, 17, 20]},\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [7, 9, 17]},\n      {\"term_id\": \"GO:0045182\", \"supporting_discovery_ids\": [13, 14]},\n      {\"term_id\": \"GO:0008092\", \"supporting_discovery_ids\": [11, 19]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005768\", \"supporting_discovery_ids\": [16, 20]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [0, 7, 17]},\n      {\"term_id\": \"GO:0005764\", \"supporting_discovery_ids\": [20]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [1, 6, 7, 18]},\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [6, 17]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [16, 20]},\n      {\"term_id\": \"R-HSA-5653656\", \"supporting_discovery_ids\": [16, 20]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [7, 9, 17]},\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [14, 20]},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [14, 18]}\n    ],\n    \"complexes\": [\n      \"MAX transcriptional complex\"\n    ],\n    \"partners\": [\n      \"MAX\",\n      \"ZO-1\",\n      \"RACK1\",\n      \"IFITM2\",\n      \"IFITM3\",\n      \"MARCH1\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}