{"gene":"HMBOX1","run_date":"2026-06-10T01:55:22","timeline":{"discoveries":[{"year":2013,"finding":"HMBOX1 (HOT1) directly and specifically binds double-stranded telomere repeat sequences in vitro and associates with actively processed telomeres in vivo. It physically associates with the active telomerase complex and promotes chromatin association of telomerase, functioning as a positive regulator of telomere length.","method":"SILAC-based DNA-protein interaction screen, in vitro DNA binding assays, immunoprecipitation, cell fractionation, depletion and overexpression experiments","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal co-IP, cell fractionation, in vitro binding assays, and functional KD/OE experiments all converging on same conclusion in a single rigorous study","pmids":["23685356"],"is_preprint":false},{"year":2013,"finding":"HMBOX1 (TAH1) binds double-stranded telomeric DNA and associates with PML nuclear bodies (APBs) in ALT cells. TAH1 knockdown significantly reduced the number of APBs, increased DNA damage response signals at telomeres, and notably reduced telomere C-circles, indicating a role in ALT activity.","method":"Direct telomeric DNA binding assay, immunofluorescence co-localization with PML bodies, siRNA knockdown with quantification of APBs, C-circle assay, DNA damage response measurement","journal":"Journal of cell science","confidence":"High","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (DNA binding, co-localization, functional KD with multiple readouts) in a single study","pmids":["23813958"],"is_preprint":false},{"year":2006,"finding":"HMBOX1 protein accumulates predominantly in the cytoplasm relative to the nucleus (EGFP fusion live imaging), and acts as a transcriptional repressor as demonstrated by GAL4-fusion luciferase reporter assay in HEK-293T cells.","method":"HMBOX1::EGFP fusion protein imaging, GAL4-fusion co-transfection luciferase reporter assay","journal":"Cytogenetic and genome research","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — two orthogonal methods (localization and reporter assay) in a single lab study","pmids":["16825764"],"is_preprint":false},{"year":2011,"finding":"HMBOX1 overexpression inhibits NK cell natural cytotoxicity against tumor cells, degranulation (CD107a), and production of cytolytic proteins (perforin and granzymes) by negatively regulating expression of NKG2D and activation of the NKG2D/DAP10 signaling pathway; HMBOX1 knockdown reverses this effect.","method":"Overexpression and siRNA knockdown in NK cells, cytotoxicity assays, flow cytometry for CD107a, Western blot for perforin/granzymes, NKG2D/DAP10 pathway analysis","journal":"Cellular & molecular immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — gain- and loss-of-function with multiple functional readouts and pathway analysis, single lab","pmids":["21706044"],"is_preprint":false},{"year":2011,"finding":"HMBOX1 suppresses IFN-γ transcription in NK cells; overexpression inhibited IFN-γ expression and production in response to tumor cells and PMA/ionomycin, and luciferase reporter assay showed HMBOX1 directly suppresses the IFN-γ promoter activity.","method":"Overexpression in NK cells, luciferase reporter assay with IFN-γ promoter, ELISA for IFN-γ production, qPCR","journal":"International immunopharmacology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reporter assay combined with functional gain-of-function experiments, single lab","pmids":["21839858"],"is_preprint":false},{"year":2015,"finding":"HMBOX1 interacts with metallothionein 2A (MT2A) as identified by yeast two-hybrid and confirmed by co-immunoprecipitation. This interaction regulates intracellular free zinc levels; HMBOX1 overexpression elevated free zinc, and MT2A knockdown blocked this effect. HMBOX1-mediated regulation of zinc via MT2A inhibits apoptosis and promotes autophagy in vascular endothelial cells, as the zinc chelator TPEN reversed these effects.","method":"Yeast two-hybrid, co-immunoprecipitation, zinc chelation (TPEN), siRNA knockdown, apoptosis and autophagy assays","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — two orthogonal methods for interaction (yeast two-hybrid + co-IP) plus mechanistic rescue experiment with zinc chelator, single lab","pmids":["26456220"],"is_preprint":false},{"year":2018,"finding":"In hepatocytes, HMBOX1 negatively regulates NF-κB signal transduction; hepatocyte-specific HMBOX1 knockout increased CCL2 expression through NF-κB activation, enhancing macrophage infiltration and activation. Overexpression of HMBOX1 rescued liver injury in knockout mice.","method":"Hepatocyte-specific Hmbox1 conditional knockout mice, LPS/D-GalN acute liver failure model, NF-κB signaling assays, CCL2 measurement, macrophage infiltration and activation assays, HMBOX1 overexpression rescue experiment","journal":"Molecular immunology","confidence":"High","confidence_rationale":"Tier 2 / Moderate — tissue-specific KO mouse with defined phenotypic readouts, pathway placement (NF-κB), and rescue by overexpression in a single rigorous study","pmids":["30032072"],"is_preprint":false},{"year":2009,"finding":"HMBOX1 splicing variant HMBOX1b, which lacks the homeodomain, retains only faint transcriptional repressor activity in reporter assays, demonstrating that the homeodomain is required for full transcriptional repressor function.","method":"RT-PCR characterization of splice variant, immunofluorescence for subcellular localization, transcriptional reporter assay","journal":"Molecular biology reports","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — reporter assay and localization in a single study, implicates homeodomain in repressor function","pmids":["19757162"],"is_preprint":false},{"year":2010,"finding":"Hmbox1 upregulation is required for ABO-induced differentiation of bone marrow stromal cells (BMSCs) into vascular endothelial cells; Hmbox1 siRNA knockdown blocked ABO-induced BMSC differentiation and increased IP-10 while decreasing Ets-1, placing Hmbox1 upstream of IP-10 and Ets-1 in this pathway.","method":"siRNA knockdown, microarray analysis, RT-PCR, Western blot, capillary-like tube formation assay, endothelial marker expression analysis","journal":"ACS chemical biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss-of-function with defined cellular phenotype and downstream pathway placement, single lab","pmids":["20822188"],"is_preprint":false},{"year":2012,"finding":"Hmbox1 acts upstream of FGF-2 to regulate mouse embryonic stem cell differentiation into vascular endothelial cells; R-ABO-induced ESC differentiation into VECs requires Hmbox1, which acts upstream of FGF-2 in this pathway.","method":"Compound treatment, Hmbox1 knockdown/overexpression, endothelial differentiation assays, FGF-2 measurement","journal":"Stem cells and development","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss-of-function with defined differentiation phenotype and pathway placement, single lab","pmids":["22671696"],"is_preprint":false},{"year":2020,"finding":"WTAP-mediated m6A modification at the 3'UTR of HMBOX1 mRNA regulates HMBOX1 mRNA stability; WTAP promotes m6A modification on HMBOX1 mRNA leading to decreased HMBOX1 expression, and HMBOX1 acts downstream of WTAP in the PI3K/AKT pathway in osteosarcoma.","method":"m6A dot blot, MeRIP-seq, MeRIP-qRT-PCR, luciferase reporter assay, RNA-seq, in vitro and in vivo functional assays","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods for m6A detection and functional consequence, single lab","pmids":["32814762"],"is_preprint":false},{"year":2016,"finding":"ANXA7 (annexin A7) is an endogenous regulator of HMBOX1 expression at the translational level; inhibition of ANXA7 GTPase activity by ABO elevates HMBOX1 protein through a mechanism involving TGFB2-OT1 and LARP1. ABO failed to increase HMBOX1 protein in ANXA7-deficient HUVECs.","method":"ANXA7 knockdown, GTPase activity inhibition, Western blot, protein translation level analysis, TGFB2-OT1/LARP1 pathway analysis in HUVECs and apoE-/- mice","journal":"The international journal of biochemistry & cell biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic (KD) and pharmacological inhibition of upstream regulator with defined molecular consequence at translation level, single lab","pmids":["27506770"],"is_preprint":false},{"year":2018,"finding":"HMBOX1 inhibits LPS-induced NF-κB and MAPK signaling in endothelial cells; HMBOX1 knockdown abolished the anti-inflammatory and anti-oxidative effects of TDD and blocked inhibition of NF-κB and MAPK activation, establishing HMBOX1 as a mediator of NF-κB/MAPK suppression.","method":"RNA interference knockdown, NF-κB and MAPK pathway activation assays, inflammatory cytokine measurement (IL-6, IL-1β, MCP-1, TNF-α), ROS production assay in EA.hy926 cells","journal":"Journal of cellular and molecular medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss-of-function with pathway placement and multiple downstream readouts, single lab","pmids":["30358079"],"is_preprint":false},{"year":2024,"finding":"Hmbox1 acts as a transcriptional repressor of glucokinase (Gck); inhibition of Hmbox1 transcriptionally upregulates Gck via Akt/mTOR/P70S6K pathway activation, leading to reduced cardiomyocyte apoptosis and improved mitochondrial respiration and glycolysis. ETS1 functions as an upstream negative transcriptional regulator of Hmbox1.","method":"RNA sequencing, promoter prediction and binding assays (ChIP), AAV9-mediated knockdown, cardiac myocyte-specific KO mice, I/R injury model, Akt/mTOR/P70S6K pathway analysis, ETS1 overexpression in vivo","journal":"Circulation","confidence":"High","confidence_rationale":"Tier 2 / Strong — cardiac-specific KO mouse + AAV knockdown + binding assays + multiple orthogonal methods establishing mechanism in vivo and in vitro, single rigorous study with multiple lines of evidence","pmids":["38708602"],"is_preprint":false},{"year":2025,"finding":"HMBOX1 promotes transcription of the E3 ubiquitin ligase HACE1, which in turn mediates K63-ubiquitination and subsequent proteasome-mediated degradation of ATG5, thereby inhibiting autophagy and reducing 5-FU resistance in colorectal cancer cells.","method":"Mass-spectrometry-based proteomics, RNA sequencing, ChIP assay (HACE1 transcription), co-immunoprecipitation (ATG5 ubiquitination), cycloheximide chase, in vitro and in vivo functional assays","journal":"Autophagy","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — ChIP for direct transcriptional target, co-IP for ubiquitination substrate, proteomics, multiple orthogonal methods in a single rigorous study","pmids":["40126194"],"is_preprint":false},{"year":2022,"finding":"miR-885-5p directly binds the 3'UTR of HMBOX1 mRNA and negatively regulates HMBOX1 expression; overexpression of HMBOX1 reversed miR-885-5p-induced elevation of inflammatory cytokines and upregulation of NLRP3/caspase-1/GSDMD-N through an NF-κB-dependent mechanism, suppressing cardiomyocyte pyroptosis.","method":"Luciferase 3'UTR reporter assay for miR-885-5p/HMBOX1 interaction, lentiviral KD/OE, NLRP3/caspase-1/GSDMD-N Western blot, NF-κB pathway analysis, flow cytometry for pyroptosis, ELISA for IL-1β/IL-18","journal":"Frontiers in cardiovascular medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — luciferase reporter for direct miRNA-target interaction, gain- and loss-of-function with pathway placement and rescue, single lab","pmids":["35345489"],"is_preprint":false},{"year":2023,"finding":"HMBOX1 inhibits macrophage proliferation by suppressing glutamine metabolism; elevated HMBOX1 in RAW264.7 cells decreased glutamine concentrations and downregulated the glutamine transporter SLC1A5, and SLC1A5 overexpression reversed HMBOX1-mediated inhibition of macrophage proliferation.","method":"UPLC-MS/MS metabolomics, CCK8 assay, clone formation, SLC1A5 overexpression rescue experiment","journal":"BMC genomics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — metabolomics combined with rescue experiment identifying SLC1A5 as downstream effector, single lab","pmids":["37208615"],"is_preprint":false},{"year":2022,"finding":"METTL3-mediated m6A modification stabilizes Hmbox1 mRNA; METTL3 knockdown in GC-2 cells reduced m6A modification and Hmbox1 stability, leading to further shortening of telomere length, establishing Hmbox1 as an m6A-regulated telomere maintenance factor.","method":"MeRIP-qPCR, RIP assay, Mettl3 siRNA knockdown, telomere length measurement in DEHP/MEHP exposure model","journal":"Life sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — MeRIP and RIP for m6A detection, loss-of-function with defined molecular consequence, single lab","pmids":["36174712"],"is_preprint":false},{"year":2019,"finding":"HMBOX1 knockout in mouse aortic endothelial cells promotes LPS-induced apoptosis and inhibits autophagy in vivo, confirming HMBOX1's role in endothelial cell survival under stress. However, HMBOX1 deletion had no influence on secretion of TNF-α and IL-6, and overexpression/knockdown failed to regulate multiple pro-apoptotic genes in vitro.","method":"TALEN-generated HMBOX1 KO mouse, LPS stimulation of aortic endothelial cells, apoptosis and autophagy assays in vivo, cytokine ELISA, in vitro gene expression analysis","journal":"Apoptosis","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo KO model with defined phenotypic readout under stress conditions, single lab","pmids":["31583496"],"is_preprint":false},{"year":2025,"finding":"HMBOX1 inhibits hepatocellular carcinoma progression through a PTPN1/AKT1 axis; overexpression of HMBOX1 activates PTPN1 signaling which mediates regulation of AKT1 phosphorylation, inhibiting cell proliferation and migration. In vivo tumor-bearing experiments validated the HMBOX1/PTPN1/AKT1 pathway.","method":"Proteomics combined with bioinformatics, Western blot, overexpression and silencing in HCC cell lines, in vivo xenograft experiments","journal":"Oncology reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — proteomics for pathway identification, in vivo validation, gain- and loss-of-function, single lab","pmids":["41574716"],"is_preprint":false},{"year":2009,"finding":"HMBOX1 protein is localized in both cytoplasm and nucleus in human normal tissues as detected by anti-HMBOX1 monoclonal antibodies; expression is detected in 10 human normal tissues including cerebrum, pancreas, kidney, and liver.","method":"Immunohistochemistry with anti-HMBOX1 monoclonal antibody in normal and carcinoma tissues","journal":"Cellular & molecular immunology","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single immunohistochemistry method establishing localization without direct functional consequence","pmids":["19728927"],"is_preprint":false},{"year":2022,"finding":"HMBOX1 attenuates LPS-induced injury in periodontal ligament stem cells by inhibiting CXCL10 expression via suppression of NF-κB signaling; NF-κB agonist PMA reversed HMBOX1 overexpression effects and si-CXCL10 re-rescued them, placing HMBOX1 upstream of NF-κB/CXCL10.","method":"HMBOX1 overexpression, NF-κB agonist treatment, siRNA silencing of CXCL10, qPCR and Western blot for pathway components, CCK8, ELISA, TUNEL","journal":"Experimental and therapeutic medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — epistasis-like rescue experiment placing HMBOX1 upstream of NF-κB/CXCL10, single lab","pmids":["35222701"],"is_preprint":false}],"current_model":"HMBOX1 is a homeobox-containing transcriptional repressor that directly binds double-stranded telomere repeats to promote telomerase recruitment and telomere elongation (including in ALT cells via APB association), suppresses NF-κB and MAPK signaling to inhibit inflammation, represses NK cell cytotoxicity by downregulating the NKG2D/DAP10 pathway and IFN-γ transcription, promotes vascular endothelial cell survival by interacting with MT2A to regulate intracellular zinc and thereby controlling autophagy/apoptosis, drives cardiac glucose metabolism by transcriptionally repressing glucokinase (Gck) under control of upstream regulator ETS1, and promotes chemosensitivity in colorectal cancer by transcriptionally activating HACE1 to drive K63-ubiquitination and degradation of ATG5; its own expression is post-transcriptionally regulated by m6A modification (written by METTL3/WTAP) and by multiple miRNAs targeting its 3'UTR."},"narrative":{"mechanistic_narrative":"HMBOX1 is a homeodomain-containing transcriptional repressor with dual roles in telomere maintenance and the negative regulation of inflammatory and stress-response signaling [PMID:23685356, PMID:16825764, PMID:30032072]. At telomeres, HMBOX1 (also termed HOT1/TAH1) directly and specifically binds double-stranded telomere repeats, associates with the active telomerase complex to promote its chromatin loading, and thereby acts as a positive regulator of telomere length [PMID:23685356]; in ALT cells it localizes to PML/APB nuclear bodies and supports ALT-associated C-circle production and telomere integrity [PMID:23813958]. Its repressor function depends on the homeodomain, loss of which abolishes most reporter repression [PMID:19757162]. As a transcriptional regulator, HMBOX1 represses defined target genes including the IFN-γ promoter in NK cells [PMID:21839858], glucokinase (Gck) in cardiomyocytes downstream of the upstream repressor ETS1 [PMID:38708602], and the glutamine transporter SLC1A5 to restrain macrophage proliferation [PMID:37208615], while it activates transcription of the E3 ligase HACE1, which drives K63-ubiquitination and degradation of ATG5 to inhibit autophagy and sensitize colorectal cancer cells to 5-FU [PMID:40126194]. Across multiple cell types HMBOX1 functions as a brake on NF-κB and MAPK signaling, limiting inflammatory cytokine and chemokine output and protecting cells from injury and apoptosis [PMID:30032072, PMID:30358079, PMID:35222701]. It also restrains NK-cell cytotoxicity by downregulating the NKG2D/DAP10 pathway [PMID:21706044] and supports endothelial cell survival, in part through an interaction with metallothionein MT2A that raises intracellular free zinc to modulate autophagy and apoptosis [PMID:26456220, PMID:31583496]. HMBOX1 expression is itself controlled post-transcriptionally by m6A modification, with WTAP destabilizing and METTL3 stabilizing its mRNA, and by 3'UTR-targeting miRNAs such as miR-885-5p [PMID:32814762, PMID:36174712, PMID:35345489].","teleology":[{"year":2006,"claim":"Established the foundational biochemical identity of HMBOX1 as a transcriptional repressor and defined its subcellular distribution, framing all subsequent functional work.","evidence":"EGFP-fusion live imaging and GAL4-fusion luciferase reporter assays in HEK-293T cells","pmids":["16825764"],"confidence":"Medium","gaps":["No endogenous target genes identified","DNA-binding specificity not defined","Repression mechanism/co-repressor partners unknown"]},{"year":2009,"claim":"Mapped the determinant of repressor activity to the homeodomain, linking the protein's structural module to its molecular function.","evidence":"Characterization of the homeodomain-lacking HMBOX1b splice variant by RT-PCR and reporter assay","pmids":["19757162","19728927"],"confidence":"Medium","gaps":["Did not identify direct DNA targets of the homeodomain","Functional role of the splice variant in vivo unknown"]},{"year":2011,"claim":"Placed HMBOX1 in immune regulation by showing it suppresses NK-cell cytotoxicity and IFN-γ, defining an immunosuppressive transcriptional output.","evidence":"Gain-/loss-of-function in NK cells with cytotoxicity assays and IFN-γ promoter luciferase reporter","pmids":["21706044","21839858"],"confidence":"Medium","gaps":["Direct binding of HMBOX1 to the NKG2D locus not shown","Mechanism linking HMBOX1 to NKG2D/DAP10 downregulation unresolved"]},{"year":2013,"claim":"Identified HMBOX1 as a sequence-specific double-stranded telomere-binding protein that recruits telomerase, resolving its core nuclear function in telomere length control and ALT.","evidence":"SILAC DNA-protein screen, in vitro binding, telomerase co-IP, fractionation; plus APB co-localization and C-circle assays in ALT cells","pmids":["23685356","23813958"],"confidence":"High","gaps":["Structural basis of telomere repeat recognition not solved","How telomere binding relates to its repressor activity at other loci is unclear"]},{"year":2015,"claim":"Connected HMBOX1 to cytoprotective metal homeostasis by identifying MT2A as a physical partner controlling intracellular zinc and downstream autophagy/apoptosis.","evidence":"Yeast two-hybrid, co-IP, zinc chelation (TPEN) and apoptosis/autophagy assays in vascular endothelial cells","pmids":["26456220"],"confidence":"Medium","gaps":["Whether the MT2A interaction is transcriptional or post-translational unclear","Direct zinc-sensing role not established"]},{"year":2018,"claim":"Genetically established HMBOX1 as an in vivo brake on NF-κB/MAPK inflammatory signaling, moving beyond cell-line correlations.","evidence":"Hepatocyte-specific conditional KO mice in acute liver failure model with NF-κB readouts and overexpression rescue; endothelial knockdown of NF-κB/MAPK","pmids":["30032072","30358079","31583496","35222701"],"confidence":"High","gaps":["Direct transcriptional targets within the NF-κB axis not defined","Mechanism by which a nuclear repressor restrains cytoplasmic signaling unresolved"]},{"year":2022,"claim":"Revealed that HMBOX1 abundance is set post-transcriptionally by opposing m6A regulators and miRNAs, explaining context-dependent expression.","evidence":"MeRIP/RIP with WTAP and METTL3 manipulation; luciferase 3'UTR reporter for miR-885-5p","pmids":["32814762","36174712","35345489"],"confidence":"Medium","gaps":["Which m6A reader executes the stability change not identified","Whether m6A regulation operates in vivo across tissues unknown"]},{"year":2024,"claim":"Identified glucokinase as a direct repressed target and ETS1 as an upstream repressor, defining a cardiac metabolic axis controlled by HMBOX1 in vivo.","evidence":"Cardiac-specific KO mice, AAV9 knockdown, ChIP/promoter binding, Akt/mTOR/P70S6K pathway analysis in I/R injury","pmids":["38708602"],"confidence":"High","gaps":["Whether ETS1-HMBOX1 regulation extends beyond cardiac tissue unknown","Co-repressor machinery at the Gck promoter not characterized"]},{"year":2025,"claim":"Extended HMBOX1's repertoire to transcriptional activation, showing it induces HACE1 to drive K63-ubiquitination and degradation of ATG5 and control autophagy-linked chemosensitivity.","evidence":"ChIP for HACE1 transcription, co-IP for ATG5 ubiquitination, cycloheximide chase, in vitro/in vivo CRC assays; plus PTPN1/AKT1 axis in HCC","pmids":["40126194","41574716"],"confidence":"High","gaps":["How HMBOX1 switches between repression and activation is unexplained","Direct binding at the HACE1 promoter versus indirect activation needs further delineation"]},{"year":null,"claim":"It remains unresolved how a single homeodomain protein integrates direct telomere binding, sequence-specific gene repression and activation, and suppression of cytoplasmic NF-κB/MAPK signaling into one coherent molecular mechanism.","evidence":"No single study reconciles the telomeric, transcriptional, and signaling roles","pmids":[],"confidence":"Low","gaps":["No structure of HMBOX1 bound to DNA or partners","Co-regulator complexes undefined","Determinants of cell-type-specific target selection unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[2,4,7,13,14,16]},{"term_id":"GO:0003677","term_label":"DNA binding","supporting_discovery_ids":[0,1,13]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[0,1,2,20]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[2,20]},{"term_id":"GO:0000228","term_label":"nuclear chromosome","supporting_discovery_ids":[0,1]}],"pathway":[{"term_id":"R-HSA-1640170","term_label":"Cell Cycle","supporting_discovery_ids":[0,1]},{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[2,4,13,14]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[3,4,6,12]},{"term_id":"R-HSA-9612973","term_label":"Autophagy","supporting_discovery_ids":[5,14,18]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[6,12,13,19,21]}],"complexes":[],"partners":["MT2A"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q6NT76","full_name":"Homeobox-containing protein 1","aliases":["Homeobox telomere-binding protein 1","Telomere-associated homeobox-containing protein 1"],"length_aa":420,"mass_kda":47.3,"function":"Binds directly to 5'-TTAGGG-3' repeats in telomeric DNA (PubMed:23685356, PubMed:23813958). Associates with the telomerase complex at sites of active telomere processing and positively regulates telomere elongation (PubMed:23685356). Important for TERT binding to chromatin, indicating a role in recruitment of the telomerase complex to telomeres (By similarity). Also plays a role in the alternative lengthening of telomeres (ALT) pathway in telomerase-negative cells where it promotes formation and/or maintenance of ALT-associated promyelocytic leukemia bodies (APBs) (PubMed:23813958). Enhances formation of telomere C-circles in ALT cells, suggesting a possible role in telomere recombination (PubMed:23813958). Might also be involved in the DNA damage response at telomeres (PubMed:23813958)","subcellular_location":"Nucleus; Cytoplasm","url":"https://www.uniprot.org/uniprotkb/Q6NT76/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/HMBOX1","classification":"Not Classified","n_dependent_lines":0,"n_total_lines":1208,"dependency_fraction":0.0},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"CALM3","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/HMBOX1","total_profiled":1310},"omim":[{"mim_id":"618610","title":"HOMEOBOX-CONTAINING PROTEIN 1; HMBOX1","url":"https://www.omim.org/entry/618610"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Nucleoplasm","reliability":"Supported"},{"location":"Nuclear bodies","reliability":"Additional"},{"location":"Cytosol","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/HMBOX1"},"hgnc":{"alias_symbol":["HNF1LA","PBHNF","FLJ21616","HOT1"],"prev_symbol":[]},"alphafold":{"accession":"Q6NT76","domains":[{"cath_id":"1.10.260.40","chopping":"153-229","consensus_level":"medium","plddt":91.8023,"start":153,"end":229},{"cath_id":"1.10.10.60","chopping":"275-349","consensus_level":"high","plddt":94.8988,"start":275,"end":349},{"cath_id":"1.20.5","chopping":"23-57","consensus_level":"medium","plddt":89.95,"start":23,"end":57}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q6NT76","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q6NT76-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q6NT76-F1-predicted_aligned_error_v6.png","plddt_mean":68.31},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=HMBOX1","jax_strain_url":"https://www.jax.org/strain/search?query=HMBOX1"},"sequence":{"accession":"Q6NT76","fasta_url":"https://rest.uniprot.org/uniprotkb/Q6NT76.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q6NT76/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q6NT76"}},"corpus_meta":[{"pmid":"12743037","id":"PMC_12743037","title":"Osmostress-induced transcription by Hot1 depends on a Hog1-mediated recruitment of the RNA Pol II.","date":"2003","source":"The EMBO journal","url":"https://pubmed.ncbi.nlm.nih.gov/12743037","citation_count":154,"is_preprint":false},{"pmid":"32814762","id":"PMC_32814762","title":"WTAP promotes osteosarcoma tumorigenesis by repressing HMBOX1 expression in an m6A-dependent manner.","date":"2020","source":"Cell death & disease","url":"https://pubmed.ncbi.nlm.nih.gov/32814762","citation_count":113,"is_preprint":false},{"pmid":"2076817","id":"PMC_2076817","title":"Gene conversion tracts stimulated by HOT1-promoted transcription are long and continuous.","date":"1990","source":"Genetics","url":"https://pubmed.ncbi.nlm.nih.gov/2076817","citation_count":66,"is_preprint":false},{"pmid":"23685356","id":"PMC_23685356","title":"HOT1 is a mammalian direct telomere repeat-binding protein contributing to telomerase recruitment.","date":"2013","source":"The EMBO 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immunology","url":"https://pubmed.ncbi.nlm.nih.gov/37206587","citation_count":11,"is_preprint":false},{"pmid":"28369931","id":"PMC_28369931","title":"A farnesoic acid-responsive transcription factor, Hot1, regulates yeast-hypha morphogenesis in Candida albicans.","date":"2017","source":"FEBS letters","url":"https://pubmed.ncbi.nlm.nih.gov/28369931","citation_count":11,"is_preprint":false},{"pmid":"15066122","id":"PMC_15066122","title":"Transcription-mediated hyper-recombination in HOT1.","date":"2004","source":"Genes to cells : devoted to molecular & cellular mechanisms","url":"https://pubmed.ncbi.nlm.nih.gov/15066122","citation_count":10,"is_preprint":false},{"pmid":"32804965","id":"PMC_32804965","title":"Hog1-induced transcription of RTC3 and HSP12 is robust and occurs in cells lacking Msn2, Msn4, Hot1 and Sko1.","date":"2020","source":"PloS 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It physically associates with the active telomerase complex and promotes chromatin association of telomerase, functioning as a positive regulator of telomere length.\",\n      \"method\": \"SILAC-based DNA-protein interaction screen, in vitro DNA binding assays, immunoprecipitation, cell fractionation, depletion and overexpression experiments\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal co-IP, cell fractionation, in vitro binding assays, and functional KD/OE experiments all converging on same conclusion in a single rigorous study\",\n      \"pmids\": [\"23685356\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"HMBOX1 (TAH1) binds double-stranded telomeric DNA and associates with PML nuclear bodies (APBs) in ALT cells. TAH1 knockdown significantly reduced the number of APBs, increased DNA damage response signals at telomeres, and notably reduced telomere C-circles, indicating a role in ALT activity.\",\n      \"method\": \"Direct telomeric DNA binding assay, immunofluorescence co-localization with PML bodies, siRNA knockdown with quantification of APBs, C-circle assay, DNA damage response measurement\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (DNA binding, co-localization, functional KD with multiple readouts) in a single study\",\n      \"pmids\": [\"23813958\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"HMBOX1 protein accumulates predominantly in the cytoplasm relative to the nucleus (EGFP fusion live imaging), and acts as a transcriptional repressor as demonstrated by GAL4-fusion luciferase reporter assay in HEK-293T cells.\",\n      \"method\": \"HMBOX1::EGFP fusion protein imaging, GAL4-fusion co-transfection luciferase reporter assay\",\n      \"journal\": \"Cytogenetic and genome research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — two orthogonal methods (localization and reporter assay) in a single lab study\",\n      \"pmids\": [\"16825764\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"HMBOX1 overexpression inhibits NK cell natural cytotoxicity against tumor cells, degranulation (CD107a), and production of cytolytic proteins (perforin and granzymes) by negatively regulating expression of NKG2D and activation of the NKG2D/DAP10 signaling pathway; HMBOX1 knockdown reverses this effect.\",\n      \"method\": \"Overexpression and siRNA knockdown in NK cells, cytotoxicity assays, flow cytometry for CD107a, Western blot for perforin/granzymes, NKG2D/DAP10 pathway analysis\",\n      \"journal\": \"Cellular & molecular immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — gain- and loss-of-function with multiple functional readouts and pathway analysis, single lab\",\n      \"pmids\": [\"21706044\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"HMBOX1 suppresses IFN-γ transcription in NK cells; overexpression inhibited IFN-γ expression and production in response to tumor cells and PMA/ionomycin, and luciferase reporter assay showed HMBOX1 directly suppresses the IFN-γ promoter activity.\",\n      \"method\": \"Overexpression in NK cells, luciferase reporter assay with IFN-γ promoter, ELISA for IFN-γ production, qPCR\",\n      \"journal\": \"International immunopharmacology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reporter assay combined with functional gain-of-function experiments, single lab\",\n      \"pmids\": [\"21839858\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"HMBOX1 interacts with metallothionein 2A (MT2A) as identified by yeast two-hybrid and confirmed by co-immunoprecipitation. This interaction regulates intracellular free zinc levels; HMBOX1 overexpression elevated free zinc, and MT2A knockdown blocked this effect. HMBOX1-mediated regulation of zinc via MT2A inhibits apoptosis and promotes autophagy in vascular endothelial cells, as the zinc chelator TPEN reversed these effects.\",\n      \"method\": \"Yeast two-hybrid, co-immunoprecipitation, zinc chelation (TPEN), siRNA knockdown, apoptosis and autophagy assays\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — two orthogonal methods for interaction (yeast two-hybrid + co-IP) plus mechanistic rescue experiment with zinc chelator, single lab\",\n      \"pmids\": [\"26456220\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"In hepatocytes, HMBOX1 negatively regulates NF-κB signal transduction; hepatocyte-specific HMBOX1 knockout increased CCL2 expression through NF-κB activation, enhancing macrophage infiltration and activation. Overexpression of HMBOX1 rescued liver injury in knockout mice.\",\n      \"method\": \"Hepatocyte-specific Hmbox1 conditional knockout mice, LPS/D-GalN acute liver failure model, NF-κB signaling assays, CCL2 measurement, macrophage infiltration and activation assays, HMBOX1 overexpression rescue experiment\",\n      \"journal\": \"Molecular immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — tissue-specific KO mouse with defined phenotypic readouts, pathway placement (NF-κB), and rescue by overexpression in a single rigorous study\",\n      \"pmids\": [\"30032072\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"HMBOX1 splicing variant HMBOX1b, which lacks the homeodomain, retains only faint transcriptional repressor activity in reporter assays, demonstrating that the homeodomain is required for full transcriptional repressor function.\",\n      \"method\": \"RT-PCR characterization of splice variant, immunofluorescence for subcellular localization, transcriptional reporter assay\",\n      \"journal\": \"Molecular biology reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — reporter assay and localization in a single study, implicates homeodomain in repressor function\",\n      \"pmids\": [\"19757162\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Hmbox1 upregulation is required for ABO-induced differentiation of bone marrow stromal cells (BMSCs) into vascular endothelial cells; Hmbox1 siRNA knockdown blocked ABO-induced BMSC differentiation and increased IP-10 while decreasing Ets-1, placing Hmbox1 upstream of IP-10 and Ets-1 in this pathway.\",\n      \"method\": \"siRNA knockdown, microarray analysis, RT-PCR, Western blot, capillary-like tube formation assay, endothelial marker expression analysis\",\n      \"journal\": \"ACS chemical biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss-of-function with defined cellular phenotype and downstream pathway placement, single lab\",\n      \"pmids\": [\"20822188\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Hmbox1 acts upstream of FGF-2 to regulate mouse embryonic stem cell differentiation into vascular endothelial cells; R-ABO-induced ESC differentiation into VECs requires Hmbox1, which acts upstream of FGF-2 in this pathway.\",\n      \"method\": \"Compound treatment, Hmbox1 knockdown/overexpression, endothelial differentiation assays, FGF-2 measurement\",\n      \"journal\": \"Stem cells and development\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss-of-function with defined differentiation phenotype and pathway placement, single lab\",\n      \"pmids\": [\"22671696\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"WTAP-mediated m6A modification at the 3'UTR of HMBOX1 mRNA regulates HMBOX1 mRNA stability; WTAP promotes m6A modification on HMBOX1 mRNA leading to decreased HMBOX1 expression, and HMBOX1 acts downstream of WTAP in the PI3K/AKT pathway in osteosarcoma.\",\n      \"method\": \"m6A dot blot, MeRIP-seq, MeRIP-qRT-PCR, luciferase reporter assay, RNA-seq, in vitro and in vivo functional assays\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods for m6A detection and functional consequence, single lab\",\n      \"pmids\": [\"32814762\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"ANXA7 (annexin A7) is an endogenous regulator of HMBOX1 expression at the translational level; inhibition of ANXA7 GTPase activity by ABO elevates HMBOX1 protein through a mechanism involving TGFB2-OT1 and LARP1. ABO failed to increase HMBOX1 protein in ANXA7-deficient HUVECs.\",\n      \"method\": \"ANXA7 knockdown, GTPase activity inhibition, Western blot, protein translation level analysis, TGFB2-OT1/LARP1 pathway analysis in HUVECs and apoE-/- mice\",\n      \"journal\": \"The international journal of biochemistry & cell biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic (KD) and pharmacological inhibition of upstream regulator with defined molecular consequence at translation level, single lab\",\n      \"pmids\": [\"27506770\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"HMBOX1 inhibits LPS-induced NF-κB and MAPK signaling in endothelial cells; HMBOX1 knockdown abolished the anti-inflammatory and anti-oxidative effects of TDD and blocked inhibition of NF-κB and MAPK activation, establishing HMBOX1 as a mediator of NF-κB/MAPK suppression.\",\n      \"method\": \"RNA interference knockdown, NF-κB and MAPK pathway activation assays, inflammatory cytokine measurement (IL-6, IL-1β, MCP-1, TNF-α), ROS production assay in EA.hy926 cells\",\n      \"journal\": \"Journal of cellular and molecular medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss-of-function with pathway placement and multiple downstream readouts, single lab\",\n      \"pmids\": [\"30358079\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Hmbox1 acts as a transcriptional repressor of glucokinase (Gck); inhibition of Hmbox1 transcriptionally upregulates Gck via Akt/mTOR/P70S6K pathway activation, leading to reduced cardiomyocyte apoptosis and improved mitochondrial respiration and glycolysis. ETS1 functions as an upstream negative transcriptional regulator of Hmbox1.\",\n      \"method\": \"RNA sequencing, promoter prediction and binding assays (ChIP), AAV9-mediated knockdown, cardiac myocyte-specific KO mice, I/R injury model, Akt/mTOR/P70S6K pathway analysis, ETS1 overexpression in vivo\",\n      \"journal\": \"Circulation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — cardiac-specific KO mouse + AAV knockdown + binding assays + multiple orthogonal methods establishing mechanism in vivo and in vitro, single rigorous study with multiple lines of evidence\",\n      \"pmids\": [\"38708602\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"HMBOX1 promotes transcription of the E3 ubiquitin ligase HACE1, which in turn mediates K63-ubiquitination and subsequent proteasome-mediated degradation of ATG5, thereby inhibiting autophagy and reducing 5-FU resistance in colorectal cancer cells.\",\n      \"method\": \"Mass-spectrometry-based proteomics, RNA sequencing, ChIP assay (HACE1 transcription), co-immunoprecipitation (ATG5 ubiquitination), cycloheximide chase, in vitro and in vivo functional assays\",\n      \"journal\": \"Autophagy\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — ChIP for direct transcriptional target, co-IP for ubiquitination substrate, proteomics, multiple orthogonal methods in a single rigorous study\",\n      \"pmids\": [\"40126194\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"miR-885-5p directly binds the 3'UTR of HMBOX1 mRNA and negatively regulates HMBOX1 expression; overexpression of HMBOX1 reversed miR-885-5p-induced elevation of inflammatory cytokines and upregulation of NLRP3/caspase-1/GSDMD-N through an NF-κB-dependent mechanism, suppressing cardiomyocyte pyroptosis.\",\n      \"method\": \"Luciferase 3'UTR reporter assay for miR-885-5p/HMBOX1 interaction, lentiviral KD/OE, NLRP3/caspase-1/GSDMD-N Western blot, NF-κB pathway analysis, flow cytometry for pyroptosis, ELISA for IL-1β/IL-18\",\n      \"journal\": \"Frontiers in cardiovascular medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — luciferase reporter for direct miRNA-target interaction, gain- and loss-of-function with pathway placement and rescue, single lab\",\n      \"pmids\": [\"35345489\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"HMBOX1 inhibits macrophage proliferation by suppressing glutamine metabolism; elevated HMBOX1 in RAW264.7 cells decreased glutamine concentrations and downregulated the glutamine transporter SLC1A5, and SLC1A5 overexpression reversed HMBOX1-mediated inhibition of macrophage proliferation.\",\n      \"method\": \"UPLC-MS/MS metabolomics, CCK8 assay, clone formation, SLC1A5 overexpression rescue experiment\",\n      \"journal\": \"BMC genomics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — metabolomics combined with rescue experiment identifying SLC1A5 as downstream effector, single lab\",\n      \"pmids\": [\"37208615\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"METTL3-mediated m6A modification stabilizes Hmbox1 mRNA; METTL3 knockdown in GC-2 cells reduced m6A modification and Hmbox1 stability, leading to further shortening of telomere length, establishing Hmbox1 as an m6A-regulated telomere maintenance factor.\",\n      \"method\": \"MeRIP-qPCR, RIP assay, Mettl3 siRNA knockdown, telomere length measurement in DEHP/MEHP exposure model\",\n      \"journal\": \"Life sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — MeRIP and RIP for m6A detection, loss-of-function with defined molecular consequence, single lab\",\n      \"pmids\": [\"36174712\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"HMBOX1 knockout in mouse aortic endothelial cells promotes LPS-induced apoptosis and inhibits autophagy in vivo, confirming HMBOX1's role in endothelial cell survival under stress. However, HMBOX1 deletion had no influence on secretion of TNF-α and IL-6, and overexpression/knockdown failed to regulate multiple pro-apoptotic genes in vitro.\",\n      \"method\": \"TALEN-generated HMBOX1 KO mouse, LPS stimulation of aortic endothelial cells, apoptosis and autophagy assays in vivo, cytokine ELISA, in vitro gene expression analysis\",\n      \"journal\": \"Apoptosis\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo KO model with defined phenotypic readout under stress conditions, single lab\",\n      \"pmids\": [\"31583496\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"HMBOX1 inhibits hepatocellular carcinoma progression through a PTPN1/AKT1 axis; overexpression of HMBOX1 activates PTPN1 signaling which mediates regulation of AKT1 phosphorylation, inhibiting cell proliferation and migration. In vivo tumor-bearing experiments validated the HMBOX1/PTPN1/AKT1 pathway.\",\n      \"method\": \"Proteomics combined with bioinformatics, Western blot, overexpression and silencing in HCC cell lines, in vivo xenograft experiments\",\n      \"journal\": \"Oncology reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — proteomics for pathway identification, in vivo validation, gain- and loss-of-function, single lab\",\n      \"pmids\": [\"41574716\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"HMBOX1 protein is localized in both cytoplasm and nucleus in human normal tissues as detected by anti-HMBOX1 monoclonal antibodies; expression is detected in 10 human normal tissues including cerebrum, pancreas, kidney, and liver.\",\n      \"method\": \"Immunohistochemistry with anti-HMBOX1 monoclonal antibody in normal and carcinoma tissues\",\n      \"journal\": \"Cellular & molecular immunology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single immunohistochemistry method establishing localization without direct functional consequence\",\n      \"pmids\": [\"19728927\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"HMBOX1 attenuates LPS-induced injury in periodontal ligament stem cells by inhibiting CXCL10 expression via suppression of NF-κB signaling; NF-κB agonist PMA reversed HMBOX1 overexpression effects and si-CXCL10 re-rescued them, placing HMBOX1 upstream of NF-κB/CXCL10.\",\n      \"method\": \"HMBOX1 overexpression, NF-κB agonist treatment, siRNA silencing of CXCL10, qPCR and Western blot for pathway components, CCK8, ELISA, TUNEL\",\n      \"journal\": \"Experimental and therapeutic medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — epistasis-like rescue experiment placing HMBOX1 upstream of NF-κB/CXCL10, single lab\",\n      \"pmids\": [\"35222701\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"HMBOX1 is a homeobox-containing transcriptional repressor that directly binds double-stranded telomere repeats to promote telomerase recruitment and telomere elongation (including in ALT cells via APB association), suppresses NF-κB and MAPK signaling to inhibit inflammation, represses NK cell cytotoxicity by downregulating the NKG2D/DAP10 pathway and IFN-γ transcription, promotes vascular endothelial cell survival by interacting with MT2A to regulate intracellular zinc and thereby controlling autophagy/apoptosis, drives cardiac glucose metabolism by transcriptionally repressing glucokinase (Gck) under control of upstream regulator ETS1, and promotes chemosensitivity in colorectal cancer by transcriptionally activating HACE1 to drive K63-ubiquitination and degradation of ATG5; its own expression is post-transcriptionally regulated by m6A modification (written by METTL3/WTAP) and by multiple miRNAs targeting its 3'UTR.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"HMBOX1 is a homeodomain-containing transcriptional repressor with dual roles in telomere maintenance and the negative regulation of inflammatory and stress-response signaling [#0, #2, #6]. At telomeres, HMBOX1 (also termed HOT1/TAH1) directly and specifically binds double-stranded telomere repeats, associates with the active telomerase complex to promote its chromatin loading, and thereby acts as a positive regulator of telomere length [#0]; in ALT cells it localizes to PML/APB nuclear bodies and supports ALT-associated C-circle production and telomere integrity [#1]. Its repressor function depends on the homeodomain, loss of which abolishes most reporter repression [#7]. As a transcriptional regulator, HMBOX1 represses defined target genes including the IFN-\\u03b3 promoter in NK cells [#4], glucokinase (Gck) in cardiomyocytes downstream of the upstream repressor ETS1 [#13], and the glutamine transporter SLC1A5 to restrain macrophage proliferation [#16], while it activates transcription of the E3 ligase HACE1, which drives K63-ubiquitination and degradation of ATG5 to inhibit autophagy and sensitize colorectal cancer cells to 5-FU [#14]. Across multiple cell types HMBOX1 functions as a brake on NF-\\u03baB and MAPK signaling, limiting inflammatory cytokine and chemokine output and protecting cells from injury and apoptosis [#6, #12, #21]. It also restrains NK-cell cytotoxicity by downregulating the NKG2D/DAP10 pathway [#3] and supports endothelial cell survival, in part through an interaction with metallothionein MT2A that raises intracellular free zinc to modulate autophagy and apoptosis [#5, #18]. HMBOX1 expression is itself controlled post-transcriptionally by m6A modification, with WTAP destabilizing and METTL3 stabilizing its mRNA, and by 3'UTR-targeting miRNAs such as miR-885-5p [#10, #17, #15].\"\n  ,\n  \"teleology\": [\n    {\n      \"year\": 2006,\n      \"claim\": \"Established the foundational biochemical identity of HMBOX1 as a transcriptional repressor and defined its subcellular distribution, framing all subsequent functional work.\",\n      \"evidence\": \"EGFP-fusion live imaging and GAL4-fusion luciferase reporter assays in HEK-293T cells\",\n      \"pmids\": [\"16825764\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No endogenous target genes identified\", \"DNA-binding specificity not defined\", \"Repression mechanism/co-repressor partners unknown\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Mapped the determinant of repressor activity to the homeodomain, linking the protein's structural module to its molecular function.\",\n      \"evidence\": \"Characterization of the homeodomain-lacking HMBOX1b splice variant by RT-PCR and reporter assay\",\n      \"pmids\": [\"19757162\", \"19728927\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Did not identify direct DNA targets of the homeodomain\", \"Functional role of the splice variant in vivo unknown\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Placed HMBOX1 in immune regulation by showing it suppresses NK-cell cytotoxicity and IFN-\\u03b3, defining an immunosuppressive transcriptional output.\",\n      \"evidence\": \"Gain-/loss-of-function in NK cells with cytotoxicity assays and IFN-\\u03b3 promoter luciferase reporter\",\n      \"pmids\": [\"21706044\", \"21839858\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct binding of HMBOX1 to the NKG2D locus not shown\", \"Mechanism linking HMBOX1 to NKG2D/DAP10 downregulation unresolved\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Identified HMBOX1 as a sequence-specific double-stranded telomere-binding protein that recruits telomerase, resolving its core nuclear function in telomere length control and ALT.\",\n      \"evidence\": \"SILAC DNA-protein screen, in vitro binding, telomerase co-IP, fractionation; plus APB co-localization and C-circle assays in ALT cells\",\n      \"pmids\": [\"23685356\", \"23813958\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of telomere repeat recognition not solved\", \"How telomere binding relates to its repressor activity at other loci is unclear\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Connected HMBOX1 to cytoprotective metal homeostasis by identifying MT2A as a physical partner controlling intracellular zinc and downstream autophagy/apoptosis.\",\n      \"evidence\": \"Yeast two-hybrid, co-IP, zinc chelation (TPEN) and apoptosis/autophagy assays in vascular endothelial cells\",\n      \"pmids\": [\"26456220\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether the MT2A interaction is transcriptional or post-translational unclear\", \"Direct zinc-sensing role not established\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Genetically established HMBOX1 as an in vivo brake on NF-\\u03baB/MAPK inflammatory signaling, moving beyond cell-line correlations.\",\n      \"evidence\": \"Hepatocyte-specific conditional KO mice in acute liver failure model with NF-\\u03baB readouts and overexpression rescue; endothelial knockdown of NF-\\u03baB/MAPK\",\n      \"pmids\": [\"30032072\", \"30358079\", \"31583496\", \"35222701\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct transcriptional targets within the NF-\\u03baB axis not defined\", \"Mechanism by which a nuclear repressor restrains cytoplasmic signaling unresolved\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Revealed that HMBOX1 abundance is set post-transcriptionally by opposing m6A regulators and miRNAs, explaining context-dependent expression.\",\n      \"evidence\": \"MeRIP/RIP with WTAP and METTL3 manipulation; luciferase 3'UTR reporter for miR-885-5p\",\n      \"pmids\": [\"32814762\", \"36174712\", \"35345489\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Which m6A reader executes the stability change not identified\", \"Whether m6A regulation operates in vivo across tissues unknown\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Identified glucokinase as a direct repressed target and ETS1 as an upstream repressor, defining a cardiac metabolic axis controlled by HMBOX1 in vivo.\",\n      \"evidence\": \"Cardiac-specific KO mice, AAV9 knockdown, ChIP/promoter binding, Akt/mTOR/P70S6K pathway analysis in I/R injury\",\n      \"pmids\": [\"38708602\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether ETS1-HMBOX1 regulation extends beyond cardiac tissue unknown\", \"Co-repressor machinery at the Gck promoter not characterized\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Extended HMBOX1's repertoire to transcriptional activation, showing it induces HACE1 to drive K63-ubiquitination and degradation of ATG5 and control autophagy-linked chemosensitivity.\",\n      \"evidence\": \"ChIP for HACE1 transcription, co-IP for ATG5 ubiquitination, cycloheximide chase, in vitro/in vivo CRC assays; plus PTPN1/AKT1 axis in HCC\",\n      \"pmids\": [\"40126194\", \"41574716\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How HMBOX1 switches between repression and activation is unexplained\", \"Direct binding at the HACE1 promoter versus indirect activation needs further delineation\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"It remains unresolved how a single homeodomain protein integrates direct telomere binding, sequence-specific gene repression and activation, and suppression of cytoplasmic NF-\\u03baB/MAPK signaling into one coherent molecular mechanism.\",\n      \"evidence\": \"No single study reconciles the telomeric, transcriptional, and signaling roles\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No structure of HMBOX1 bound to DNA or partners\", \"Co-regulator complexes undefined\", \"Determinants of cell-type-specific target selection unknown\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [2, 4, 7, 13, 14, 16]},\n      {\"term_id\": \"GO:0003677\", \"supporting_discovery_ids\": [0, 1, 13]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [0, 1, 2, 20]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [2, 20]},\n      {\"term_id\": \"GO:0000228\", \"supporting_discovery_ids\": [0, 1]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [0, 1]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [2, 4, 13, 14]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [3, 4, 6, 12]},\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [5, 14, 18]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [6, 12, 13, 19, 21]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"MT2A\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"tie","faith_supported":7,"faith_total":7,"faith_pct":100.0}}