{"gene":"MEOX2","run_date":"2026-06-10T02:59:50","timeline":{"discoveries":[{"year":1995,"finding":"GAX/MEOX2 mRNA is rapidly down-regulated in vascular smooth muscle cells (VSMCs) in vivo in response to balloon angioplasty-induced endothelial denudation, mirroring its down-regulation by mitogens in vitro; this growth-arrest specific expression pattern suggests GAX maintains the non-proliferative contractile phenotype of VSMCs.","method":"Northern blot and in vivo balloon injury model in rat carotid arteries","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — clean in vivo loss-of-expression with defined cellular context, single lab but consistent in vitro/in vivo correlation","pmids":["7890661"],"is_preprint":false},{"year":1995,"finding":"The Gax promoter minimal core region (138 bp, −125 to +13) requires at least three positive transcriptional activators: Sp1 (binding a G/C-rich element), MEF2/RSRF (binding a MADS-box site), and a third factor HRF-1 (binding an inverted palindromic motif); MEF2A overexpression transactivates the Gax promoter, establishing a direct transcriptional link between MEF2 and Gax.","method":"Transient transfection, deletion analysis, site-directed mutagenesis, protein-DNA binding assays, MEF2A overexpression","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 1 / Strong — mutagenesis of cis-elements combined with protein-DNA binding assays and gain-of-function overexpression, multiple orthogonal methods in one study","pmids":["7623821"],"is_preprint":false},{"year":1994,"finding":"The human GAX gene was cloned and mapped by fluorescence in situ hybridization to chromosome 7p21; its coding sequence is 98% conserved with rat GAX at the amino acid level and encodes a homeodomain protein with a polyhistidine/glutamine (CAX repeat) region N-terminal to the homeodomain.","method":"Anchored PCR cloning from cardiovascular cDNA, FISH chromosomal mapping","journal":"Genomics","confidence":"High","confidence_rationale":"Tier 1 / Strong — direct molecular cloning and chromosomal mapping, foundational characterization","pmids":["7713505"],"is_preprint":false},{"year":1997,"finding":"Recombinant Gax protein microinjected into VSMCs and fibroblasts inhibited mitogen-induced S-phase entry; adenoviral overexpression of Gax caused G0/G1 arrest correlated with p53-independent upregulation of the CDK inhibitor p21, association of p21 with cdk2 complexes, and reduction in cdk2 activity; p21-deficient fibroblasts were refractory to Gax-induced growth inhibition, establishing Gax-mediated cell cycle arrest as p21-dependent.","method":"Microinjection of recombinant protein, adenoviral overexpression, cell cycle analysis, cdk2 activity assay, p21 knockout fibroblasts","journal":"Genes & development","confidence":"High","confidence_rationale":"Tier 1 / Strong — reconstitution by microinjection plus genetic epistasis with p21 KO, multiple orthogonal methods","pmids":["9224717"],"is_preprint":false},{"year":1997,"finding":"Gax protein is expressed in nuclei of cardiomyocytes during late cardiac development (when myocyte proliferation is declining) and forced precocious Gax nuclear expression via adenovirus inhibited cardiomyocyte clonal expansion and reduced PCNA positivity, resulting in abnormal heart morphology (small ventricles, thinned compact zone), establishing Gax as a negative regulator of cardiomyocyte proliferation during morphogenesis.","method":"Adenoviral overexpression in chick embryo hearts, immunohistochemistry, PCNA staining, clonal analysis","journal":"Development (Cambridge, England)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — adenoviral gain-of-function with defined proliferation and morphology readout, single lab","pmids":["9334288"],"is_preprint":false},{"year":1997,"finding":"Gax is expressed in all muscle lineages during mouse embryogenesis; immunohistochemistry and in situ hybridization placed Gax protein in lateral plate mesoderm, cardiac muscle (biphasic pattern), smooth muscle (from E9.5), and skeletal muscle (premyogenic cells and myotomes), prior to expression of myogenic bHLH and MEF2 proteins in skeletal muscle.","method":"Immunohistochemistry and in situ hybridization on mouse embryos","journal":"Circulation research","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — direct localization by immunohistochemistry and ISH, replicated across multiple tissue types, single lab","pmids":["9118475"],"is_preprint":false},{"year":1997,"finding":"Angiotensin II (via AT1 receptor) suppresses Gax mRNA expression in quiescent VSMCs, while C-type natriuretic peptide (CNP) upregulates Gax mRNA via a cGMP-dependent mechanism; simultaneous CNP administration attenuates Ang II-induced Gax down-regulation, placing Gax as a common transcriptional effector in opposing vascular growth-regulatory signaling pathways.","method":"Northern blot, pharmacological antagonism (AT1R blocker CV11974), cGMP analogue treatment","journal":"Hypertension","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — pharmacological dissection of upstream signaling, multiple agonists/antagonists tested, single lab","pmids":["9039131"],"is_preprint":false},{"year":1998,"finding":"Forced Gax expression induces apoptosis in mitogen-activated but not quiescent vascular cells via Bcl-2 down-regulation and Bax up-regulation; fibroblasts homozygous null for Bax were refractory to Gax-induced apoptosis, demonstrating that Gax-mediated cell death requires Bax and is independent of p21, p53, and cell cycle activity.","method":"Adenoviral overexpression, Bax knockout MEFs, Bcl-2/Bax Western blot, apoptosis assays with cell cycle inhibitors","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — genetic epistasis using Bax KO cells plus pharmacological cell cycle manipulation, multiple orthogonal approaches in single study","pmids":["9649428"],"is_preprint":false},{"year":1999,"finding":"Gax expression inhibits VSMC and fibroblast migration toward PDGF-BB, bFGF, and HGF; this requires p21 (p21-deficient fibroblasts were resistant but rescued by exogenous p21 or p16); Gax specifically down-regulates αvβ3 and αvβ5 integrin expression in VSMCs in vitro and in vivo after vascular injury, suggesting integrin repression as the mechanism for reduced cell motility.","method":"Adenoviral Gax transduction, transwell migration assays, p21/p53 knockout fibroblasts, flow cytometry for integrin expression, in vivo immunostaining post-balloon injury","journal":"The Journal of clinical investigation","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic epistasis with p21 KO cells, multiple migration stimuli tested, in vivo integrin down-regulation confirmed, single lab with orthogonal methods","pmids":["10562309"],"is_preprint":false},{"year":2003,"finding":"Gax is expressed in vascular endothelial cells and its adenoviral overexpression in HUVECs inhibits proliferation, mitogen-stimulated thymidine uptake, and tube formation on Matrigel, accompanied by up to 5-fold induction of p21 mRNA and 4–5-fold activation of the p21 promoter, establishing Gax as a negative regulator of the angiogenic phenotype in endothelial cells.","method":"Adenoviral overexpression, thymidine incorporation, Matrigel tube formation, Northern blot, promoter activity assay","journal":"The Journal of surgical research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional gain-of-function with multiple readouts in ECs, single lab","pmids":["12842453"],"is_preprint":false},{"year":2005,"finding":"In brain endothelial cells (BECs) from Alzheimer disease patients, MEOX2 expression is reduced independent of age; viral-mediated MEOX2 gene transfer in AD BECs stimulates angiogenesis, transcriptionally suppresses AFX1 forkhead factor-mediated apoptosis, and increases LRP1 levels at the blood-brain barrier; Meox2 knockout mice exhibit reduced brain capillary density, reduced cerebral blood flow, loss of hypoxia-induced angiogenic response, and impaired Aβ efflux due to reduced LRP levels.","method":"Transcriptional profiling of human BECs, viral-mediated gene silencing and transfer, Meox2 knockout mouse model, cerebral blood flow measurement, Aβ efflux assay","journal":"Nature medicine","confidence":"High","confidence_rationale":"Tier 2 / Strong — viral gene transfer and KO mouse model with multiple orthogonal functional readouts, replicated across in vitro and in vivo systems","pmids":["16116430"],"is_preprint":false},{"year":2005,"finding":"MEOX2 binds to RING finger protein 10 (RNF10) as determined by yeast two-hybrid screening, in vitro pull-down, and co-immunoprecipitation in mammalian cells; the minimal RNF10-binding region of MEOX2 maps to amino acids 101–185 (between the HQ-rich domain and homeodomain); RNF10 co-expression enhances MEOX2 activation of the p21WAF1 promoter.","method":"Yeast two-hybrid screen, in vitro pull-down, co-immunoprecipitation, p21 promoter reporter assay","journal":"Molecular and cellular biochemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal binding confirmed by multiple methods (Y2H, pull-down, Co-IP), domain mapping performed, single lab","pmids":["16335786"],"is_preprint":false},{"year":2006,"finding":"Meox-2 knockout mice display cleft palate (35.3% of Meox-2−/− embryos) arising from breakdown of already-fused palatal shelves (post-fusion mechanism), distinct from previously reported pre-fusion cleft palate mechanisms; Meox-2 expression marks early palatal mesenchymal cells from E11.5 and the posterior palate from E12.5–E15.5.","method":"Knockout mouse analysis, histology, in situ hybridization, timed embryo collection","journal":"Developmental dynamics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — KO mouse with specific histological phenotype analysis, single lab","pmids":["16284941"],"is_preprint":false},{"year":2006,"finding":"GAX directly activates p21WAF1/CIP1 transcription through multiple upstream ATTA-containing binding sites (~15 kb upstream of the ATG); chromatin immunoprecipitation confirmed GAX occupancy at these sites in vivo; homeodomain and N-terminal domain are required for transactivation; G0/G1 arrest ability correlates with p21 promoter transactivation ability.","method":"ChIP, GAX deletion constructs, luciferase reporter assays with p21 promoter fragments, site-directed mutagenesis of binding sites","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — ChIP confirmation of in vivo binding plus mutagenesis of binding sites plus domain deletion analysis, multiple orthogonal methods","pmids":["17074759"],"is_preprint":false},{"year":2007,"finding":"miR-130a down-regulates GAX expression through two targeting sites in a 280-bp fragment of the GAX 3′-UTR; forced miR-130a expression inhibits GAX through this specific sequence; miR-130a also targets HOXA5 3′-UTR; together, miR-130a regulates the angiogenic phenotype of endothelial cells by modulating GAX and HOXA5.","method":"Luciferase reporter assay with GAX 3′-UTR, miR-130a overexpression, promoter activity assays","journal":"Blood","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — luciferase reporter with defined UTR fragments and miRNA overexpression, single lab","pmids":["17957028"],"is_preprint":false},{"year":2007,"finding":"MEOX2 is a TGF-β/Smad target gene in epithelial cells; MEOX2 knockdown prevents TGF-β1-induced cytostatic response; ectopic MEOX2 suppresses epithelial proliferation cooperatively with TGF-β1 and induces p21 through a distal p53-binding region of the p21 promoter; MEOX2 forms protein complexes with Smads leading to cooperative p21 regulation; MEOX2 fails to induce EMT and inhibits TGF-β-induced EMT, placing MEOX2 specifically in the TGF-β tumor suppressor pathway.","method":"RNAi knockdown, ectopic expression, co-immunoprecipitation with Smads, p21 promoter deletion analysis, proliferation and EMT assays","journal":"Molecular oncology","confidence":"High","confidence_rationale":"Tier 2 / Strong — Co-IP of Smad/MEOX2 complex, RNAi epistasis, promoter analysis with multiple orthogonal approaches in single study","pmids":["19383287"],"is_preprint":false},{"year":2005,"finding":"Angiotensin II suppresses Gax expression in VSMCs via oxidative stress-activated ERK1/2 (not p38 MAPK); H2O2 mimics Ang II-induced Gax down-regulation; antioxidants (NAC, PDTC) and the ERK1/2 inhibitor PD98059 block Ang II- and H2O2-induced Gax suppression, whereas the p38 inhibitor SB203580 does not.","method":"Pharmacological inhibition of ERK1/2 and p38 MAPK, antioxidant treatment, Northern blot/RT-PCR, intracellular H2O2 measurement","journal":"Regulatory peptides","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — pharmacological epistasis with multiple inhibitors and antioxidants, single lab","pmids":["15680482"],"is_preprint":false},{"year":2009,"finding":"MEOX2 is a direct transcriptional activator of the INK4a (p16) promoter; forced MEOX2 expression induces premature senescence that is dependent on INK4a activity; ChIP confirms direct MEOX2 binding to the INK4a promoter; MEOX2 transcription is enhanced in primary cells during senescence induction.","method":"Genome-scale cDNA overexpression screen, ChIP, INK4a reporter assay, senescence assays, INK4a activity dependence testing","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP confirmation of promoter binding plus functional senescence assay, single lab","pmids":["19340300"],"is_preprint":false},{"year":2010,"finding":"MEOX2 localizes to the nuclear fraction in endothelial cells; co-immunoprecipitation shows MEOX2 binds to both p65 (RelA) and IκBβ in the nucleus; immunofluorescence confirms colocalization requiring the MEOX2 homeodomain and N-terminal domain; MEOX2 has a biphasic effect on NF-κB-dependent promoters (stimulates at low levels, represses at high levels), both effects dependent on the homeodomain and N-terminal domain.","method":"Subcellular fractionation, co-immunoprecipitation, immunofluorescence, NF-κB promoter reporter assays, MEOX2 domain deletion constructs","journal":"Cardiovascular research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP plus domain mapping plus functional promoter assays, single lab with multiple orthogonal methods","pmids":["20421348"],"is_preprint":false},{"year":2010,"finding":"miR-221 upregulates GAX expression in endothelial cells indirectly by downregulating ZEB2; ZEB2 is a repressor of GAX that binds two sites on the GAX promoter as shown by ChIP; serum upregulates ZEB2 which downregulates GAX; a mutant miR-221 fails to downregulate ZEB2 or upregulate GAX.","method":"miR-221 overexpression and inhibition, ChIP for ZEB2 binding at GAX promoter, miR-221 mutant constructs, Western blot","journal":"Molecular and cellular biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP identifying ZEB2 binding sites on GAX promoter plus functional miRNA experiments, single lab","pmids":["20516212"],"is_preprint":false},{"year":2011,"finding":"Both MEOX1 and MEOX2 induce p21CIP1/WAF1 and p16INK4a expression and cause endothelial cell cycle arrest and senescence; however, they use distinct mechanisms: MEOX1 and MEOX2 activate p16INK4a in a DNA binding-dependent manner, whereas they induce p21CIP1/WAF1 in a DNA binding-independent manner.","method":"MEOX1/MEOX2 overexpression with DNA-binding mutants, cell cycle analysis, senescence assays, p21 and p16 reporter assays","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — DNA-binding mutant constructs dissecting mechanism, multiple functional readouts, single lab","pmids":["22206000"],"is_preprint":false},{"year":2011,"finding":"The miRNA family miR-130/301/721 enhances iPSC generation from murine fibroblasts by repressing Meox2; miRNA-resistant Meox2 overexpression abrogates the pro-reprogramming effects of this miRNA family; Meox2-specific silencing mimics the miRNA family effects on reprogramming.","method":"miRNA library screen, miRNA-resistant Meox2 construct, Meox2 siRNA silencing, iPSC reprogramming efficiency assay","journal":"EMBO reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — miRNA-resistant rescue experiment plus siRNA epistasis, single lab","pmids":["21941297"],"is_preprint":false},{"year":2013,"finding":"In cardiac fibroblast-to-myofibroblast phenoconversion, Meox2 expression is reduced while Zeb2 increases; Ski overexpression restores Meox2 mRNA by suppressing Zeb2; overexpression of Meox2 (but not a DNA-binding mutant) shifts myofibroblasts back toward the fibroblast phenotype, establishing a Ski→(suppresses Zeb2)→(de-represses Meox2) pathway that regulates the cardiac myofibroblast phenotype.","method":"Overexpression and knockdown in cardiac fibroblasts, Meox2 DNA-binding mutant, Western blot, RT-PCR, myofibroblast phenotype markers","journal":"Journal of cell science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — epistasis using DNA-binding mutant plus Ski overexpression, single lab with multiple molecular readouts","pmids":["24155330"],"is_preprint":false},{"year":2015,"finding":"Meox2 and Tcf15 form heterodimers that act as transcriptional determinants of heart capillary endothelial cell identity; Meox2/Tcf15 drive endothelial CD36 and lipoprotein lipase expression to mediate fatty acid uptake in heart ECs and facilitate FA transport to cardiomyocytes; combined Meox2/Tcf15 haplodeficiency impairs cardiac FA uptake and reduces FA transfer, leading to impaired cardiac contractility.","method":"Microarray profiling of freshly isolated ECs, gain- and loss-of-function (haplodeficiency mouse model), FA uptake assays, CD36/LPL expression analysis","journal":"Circulation","confidence":"High","confidence_rationale":"Tier 2 / Strong — heterodimer identification with genetic haplodeficiency model, multiple functional readouts (FA uptake, cardiac contractility), multiple orthogonal approaches","pmids":["25561514"],"is_preprint":false},{"year":2016,"finding":"Meox2 haploinsufficiency in DBA/2J glaucoma mice significantly increases axon damage in the optic nerve head and is associated with modulation of age- and disease-specific vascular and myeloid alterations, supporting a role for Meox2 in IOP-dependent vascular remodeling and neuroinflammation that promotes axon survival.","method":"Meox2 haploinsufficient DBA/2J mouse model, axon counting, immunofluorescence, upstream regulator analysis","journal":"Investigative ophthalmology & visual science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic haploinsufficiency model with defined axon and vascular phenotype, single lab","pmids":["31369031"],"is_preprint":false},{"year":2016,"finding":"Gax overexpression in human VSMCs increases differentiation markers calponin and SM-MHC 11, suppresses proliferation and migration, and transcriptomic analysis identified Rap1A as a downstream target of Gax; Gax overexpression significantly inhibits Rap1A expression and reduces neointimal formation in carotid artery injury in mice, indicating that Gax maintains VSMC contractile phenotype partly by suppressing Rap1A.","method":"Western blot, cDNA array analysis, adenoviral overexpression and silencing, Rap1A overexpression, in vivo mouse carotid injury model","journal":"American journal of translational research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — cDNA array target identification with functional rescue by Rap1A overexpression, in vivo validation, single lab","pmids":["27508012"],"is_preprint":false},{"year":2022,"finding":"MEOX2 enhances ERK signaling in glioblastoma through a feed-forward mechanism; Ser155 (upstream of the homeodomain) is a putative ERK-dependent phosphorylation site and S155A substitution affects MEOX2 protein levels and alters its subnuclear localization; MEOX2 overexpression cooperates with p53 and PTEN loss to induce cell proliferation in cerebral organoid glioma models.","method":"ERK phosphorylation Western blot, S155A site mutagenesis, subnuclear localization imaging, cerebral organoid glioma model, RNA-seq, ACT-seq, CUT&Tag","journal":"Neuro-oncology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — mutagenesis of phosphorylation site with localization and functional consequences, single lab with multiple genomics approaches","pmids":["35468210"],"is_preprint":false},{"year":2022,"finding":"MEOX2 directly transcriptionally activates Cathepsin S (CTSS) in glioma cells, as shown by RNA-sequencing, ChIP-qPCR, and luciferase reporter assays; MEOX2 knockdown inhibits glioma cell proliferation, motility, EMT, focal adhesion formation, and F-actin assembly; MEOX2 promotes glioma tumor growth in vivo.","method":"shRNA knockdown, RNA-sequencing, ChIP-qPCR, luciferase reporter assay, intracranial mouse implantation model","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP confirmation of CTSS as direct target plus in vivo tumor model, single lab","pmids":["35436995"],"is_preprint":false},{"year":2022,"finding":"ABI2 directly interacts with MEOX2 (co-immunoprecipitation), and MEOX2 binds to the KLF4 and NANOG promoter regions to activate their transcription in hepatocellular carcinoma; this ABI2/MEOX2/KLF4-NANOG axis maintains cancer stem cell populations and drives HCC stemness, growth, and sorafenib resistance.","method":"Co-immunoprecipitation, ChIP at KLF4 and NANOG promoters, ABI2 knockdown, MEOX2 overexpression rescue, xenograft model","journal":"Liver international","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP of ABI2-MEOX2 interaction plus ChIP of downstream targets, rescue experiments, single lab","pmids":["36017822"],"is_preprint":false},{"year":2022,"finding":"MEOX2 is expressed in the nuclei of a subset of mouse DRG sensory neurons; Meox2+/− heterozygous mice show impaired nociception with altered action potential initiation; mechanistically, MEOX2 loss decreases expression of Scn9a (Nav1.7) and Scn11a (Nav1.9) voltage-gated sodium channel genes, as well as other pain-associated genes (PENK, NPY), establishing MEOX2 as a transcriptional regulator maintaining nociceptor gene programs.","method":"Heterozygous mouse model, behavioral/electrophysiological analyses, transcriptomic analysis of DRG, immunofluorescence","journal":"The FEBS journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic haploinsufficiency with electrophysiological phenotype and transcriptomic identification of downstream targets, single lab","pmids":["35029322"],"is_preprint":false},{"year":2024,"finding":"MEOX2 binds the PHLPP phosphatase promoter (by dual luciferase reporter assay) and up-regulates PHLPP transcription, leading to inhibition of AKT phosphorylation (p-AKT) in hepatic stellate cells (HSCs); MEOX2 overexpression inhibits HSC proliferation and slows liver fibrosis progression through this MEOX2→PHLPP→(inhibit AKT) axis.","method":"Dual luciferase reporter assay for PHLPP promoter, OE-MEOX2/sh-MEOX2 lentivirus, Western blot for p-AKT, CCK-8 and EdU proliferation assays","journal":"Discovery medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — luciferase reporter confirming direct promoter binding, gain/loss-of-function with signaling readout, single lab","pmids":["38926106"],"is_preprint":false},{"year":2023,"finding":"RNF10 overexpression in H9C2 cardiomyocytes promotes MEOX2 expression and inhibits AP-1 activation, alleviating pirarubicin-induced apoptosis; RNF10 knockdown produces the opposite effect; in vivo, THP-induced CRC is associated with decreased RNF10 and Meox2 and activated AP-1, placing RNF10 upstream of MEOX2 in the AP-1/Meox2 pathway modulating cardiomyocyte apoptosis.","method":"siRNA knockdown, lentiviral overexpression, Western blot, flow cytometry for apoptosis, rat in vivo CRC model","journal":"Oxidative medicine and cellular longevity","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal gain/loss-of-function with in vivo validation, single lab","pmids":["36713029"],"is_preprint":false},{"year":2025,"finding":"NAT10-mediated ac4C modification of MEOX2 mRNA at nucleotides 409–423 stabilizes MEOX2 mRNA and increases its expression; NAT10 knockdown reduces ac4C modification at this site, decreases MEOX2 mRNA stability and protein expression, and consequently enhances HUVEC migration, invasion, and tube formation in high-glucose conditions; MEOX2 overexpression reverses these effects.","method":"MeRIP-qPCR for ac4C modification, RIP, RNA stability assay, NAT10 knockdown, MEOX2 overexpression rescue, functional HUVEC assays","journal":"Applied biochemistry and biotechnology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct measurement of ac4C modification at specific mRNA site plus RNA stability assay and rescue experiments, single lab","pmids":["41082000"],"is_preprint":false},{"year":2026,"finding":"MEOX2 promotes DNA damage repair in glioblastoma stem-like cells; co-immunoprecipitation and mass spectrometry identified PARP1 as a direct MEOX2 interactor; MEOX2 depletion reduces PARylation levels and sensitizes GSCs to the PARP1 inhibitor Talazoparib; MEOX2 knockdown in a GLICO model impairs tumor growth and increases sensitivity to temozolomide.","method":"Co-immunoprecipitation, mass spectrometry, GLICO organoid model, shRNA knockdown, Talazoparib sensitivity assay, PARylation measurement","journal":"Cancer letters","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP/MS identification of PARP1 interaction plus functional DNA repair and drug sensitivity assays, single lab","pmids":["41620199"],"is_preprint":false}],"current_model":"MEOX2/GAX is a homeodomain transcription factor that, in quiescent vascular cells, enforces cell cycle arrest by directly activating p21CIP1 (through upstream ATTA-binding sites) and p16INK4a (DNA binding-dependent), and inhibits proliferation, migration (via αvβ3/αvβ5 integrin down-regulation), and apoptosis (via Bax up-regulation/Bcl-2 down-regulation) in a p21-dependent manner; in endothelial cells it suppresses the angiogenic phenotype partly by interacting with NF-κB components (p65 and IκBβ) and by forming heterodimers with TCF15 to regulate fatty acid transport; its transcription is activated by MEF2, repressed by ZEB2 (relieved by miR-221) and by Ang II/ROS/ERK1/2 signaling, and post-transcriptionally silenced by miR-130a/301/721 family members; in the brain vasculature MEOX2 maintains blood-brain barrier LRP1 levels and cerebral perfusion relevant to Alzheimer disease, while in glioblastoma it paradoxically acts as an oncogene by enhancing ERK signaling, interacting with PARP1 to promote DNA repair, and directly activating targets such as Cathepsin S."},"narrative":{"mechanistic_narrative":"MEOX2 (GAX) is a homeodomain transcription factor that enforces the quiescent, non-proliferative state of vascular and muscle cells and is rapidly down-regulated when these cells are stimulated to proliferate [PMID:7890661]. Its core mechanism is direct transcriptional activation of cyclin-dependent kinase inhibitors: it occupies upstream ATTA-containing sites of the p21CIP1/WAF1 promoter to induce p21, drive its association with cdk2 and impose G0/G1 arrest, with p21-null cells being refractory to this effect [PMID:9224717, PMID:17074759], and it directly binds and activates the INK4a (p16) promoter to trigger senescence [PMID:19340300]. MEOX1 and MEOX2 distinguish these two targets mechanistically, activating p16INK4a in a DNA-binding-dependent manner while inducing p21 independently of DNA binding [PMID:22206000]. Through this growth-suppressive program MEOX2 blocks proliferation, migration—partly by down-regulating αvβ3/αvβ5 integrins in a p21-dependent fashion [PMID:10562309]—and promotes Bax-dependent, p21/p53-independent apoptosis in mitogen-activated cells [PMID:9649428]; in endothelial cells it suppresses the angiogenic phenotype and tube formation [PMID:12842453]. Beyond cell-cycle control, MEOX2 functions as a transcriptional determinant in tissue-specific contexts: it forms heterodimers with TCF15 to drive CD36/lipoprotein lipase expression and fatty acid uptake in heart capillary endothelium [PMID:25561514], maintains blood-brain-barrier LRP1 levels and cerebral perfusion relevant to Alzheimer disease [PMID:16116430], and sustains nociceptor sodium-channel gene programs (Scn9a/Scn11a) in sensory neurons [PMID:35029322]. Its expression is gated by a MEF2/Sp1-dependent promoter [PMID:7623821], repressed by ZEB2 (relieved by miR-221) [PMID:20516212] and by Angiotensin II acting through oxidative-stress-driven ERK1/2 signaling [PMID:15680482], and silenced post-transcriptionally by the miR-130a/301 family [PMID:17957028, PMID:21941297]. MEOX2 physically associates with NF-κB components p65 and IκBβ [PMID:20421348], with TGF-β/Smad complexes to cooperatively induce p21 within the TGF-β tumor-suppressor pathway [PMID:19383287], and with RNF10, which enhances its p21 activation [PMID:16335786]. In glioblastoma and other cancers MEOX2 paradoxically acts as an oncogene, enhancing ERK signaling via Ser155 phosphorylation [PMID:35468210], interacting with PARP1 to promote DNA-damage repair and PARP-inhibitor resistance [PMID:41620199], and directly activating targets such as Cathepsin S to drive tumor growth [PMID:35436995].","teleology":[{"year":1995,"claim":"Established MEOX2/GAX as a growth-arrest-specific gene whose loss accompanies the switch of vascular smooth muscle cells to a proliferative phenotype, framing it as a candidate enforcer of quiescence.","evidence":"Northern blot and in vivo balloon-injury model in rat carotid arteries","pmids":["7890661"],"confidence":"Medium","gaps":["Correlative loss-of-expression does not show GAX is sufficient or required for arrest","No direct transcriptional target identified at this stage"]},{"year":1994,"claim":"Provided the foundational molecular identity of human GAX as a chromosome 7p21 homeodomain protein with an N-terminal polyhistidine/glutamine region, enabling all subsequent functional dissection.","evidence":"Anchored PCR cloning and FISH chromosomal mapping","pmids":["7713505"],"confidence":"High","gaps":["Cloning alone does not assign function or DNA-binding specificity"]},{"year":1995,"claim":"Defined how GAX transcription is itself driven, identifying Sp1, MEF2/RSRF and HRF-1 as positive regulators and establishing a direct MEF2→Gax link.","evidence":"Transient transfection, promoter deletion/mutagenesis, protein-DNA binding, MEF2A overexpression","pmids":["7623821"],"confidence":"High","gaps":["HRF-1 not molecularly identified","Does not address signals controlling MEF2 in vivo"]},{"year":1997,"claim":"Demonstrated GAX is sufficient to arrest the cell cycle and pinned the mechanism on p21 induction, with genetic epistasis proving p21-dependence.","evidence":"Recombinant protein microinjection, adenoviral overexpression, cdk2 activity assay, p21-knockout fibroblasts","pmids":["9224717"],"confidence":"High","gaps":["Did not show whether p21 induction is via direct promoter binding","Mechanism of p53-independence not resolved"]},{"year":1997,"claim":"Extended the anti-proliferative role to development, showing GAX restrains cardiomyocyte proliferation during heart morphogenesis and is broadly expressed across muscle lineages.","evidence":"Adenoviral overexpression in chick hearts, IHC/ISH on mouse embryos, PCNA staining","pmids":["9334288","9118475"],"confidence":"Medium","gaps":["Forced expression does not establish endogenous requirement","No transcriptional targets identified in cardiac context"]},{"year":1997,"claim":"Placed GAX downstream of opposing vascular signals, with Angiotensin II suppressing and CNP/cGMP inducing its expression.","evidence":"Northern blot with AT1R antagonist and cGMP analogue treatment","pmids":["9039131"],"confidence":"Medium","gaps":["Intermediate signaling steps not defined at this stage"]},{"year":1998,"claim":"Separated GAX's apoptotic function from its cell-cycle function, showing it triggers Bax-dependent death only in cycling cells, independent of p21/p53.","evidence":"Adenoviral overexpression, Bax-knockout MEFs, Bcl-2/Bax Western, cell-cycle inhibitors","pmids":["9649428"],"confidence":"High","gaps":["Whether Bax/Bcl-2 changes are direct transcriptional effects unknown"]},{"year":1999,"claim":"Identified integrin repression (αvβ3/αvβ5) as the mechanism for GAX-mediated inhibition of migration and showed this too is p21-dependent.","evidence":"Adenoviral transduction, transwell migration, p21/p53-knockout fibroblasts, flow cytometry, in vivo immunostaining","pmids":["10562309"],"confidence":"High","gaps":["Whether GAX directly regulates integrin promoters not shown"]},{"year":2003,"claim":"Extended the growth-suppressive program to endothelial cells, showing GAX inhibits proliferation and tube formation while inducing p21.","evidence":"Adenoviral overexpression in HUVECs, thymidine uptake, Matrigel tube formation, p21 promoter assay","pmids":["12842453"],"confidence":"Medium","gaps":["Anti-angiogenic mechanism beyond p21 not defined"]},{"year":2005,"claim":"Connected MEOX2 to brain-vascular homeostasis and Alzheimer disease, showing it maintains capillary density, cerebral blood flow and LRP1-mediated Aβ efflux.","evidence":"Human BEC profiling, viral gene transfer/silencing, Meox2 knockout mice, cerebral blood flow and Aβ efflux assays","pmids":["16116430"],"confidence":"High","gaps":["Direct transcriptional targets in BECs (e.g. LRP1 regulation) not mapped","Reconciliation with anti-angiogenic role in other vessels unresolved"]},{"year":2005,"claim":"Resolved the upstream pathway by which Angiotensin II suppresses Gax, implicating oxidative-stress-activated ERK1/2 rather than p38.","evidence":"Pharmacological ERK1/2 and p38 inhibition, antioxidant treatment, H2O2 measurement, Northern/RT-PCR","pmids":["15680482"],"confidence":"Medium","gaps":["Transcription factor mediating ERK-dependent repression not identified"]},{"year":2006,"claim":"Revealed a distinct developmental requirement—post-fusion palatal shelf integrity—via the knockout cleft-palate phenotype.","evidence":"Knockout mouse histology, ISH, timed embryo collection","pmids":["16284941"],"confidence":"Medium","gaps":["Molecular targets maintaining palatal tissue not identified"]},{"year":2005,"claim":"Identified RNF10 as a direct MEOX2 partner that potentiates its p21 activation, mapping the interaction region between the HQ domain and homeodomain.","evidence":"Yeast two-hybrid, in vitro pull-down, co-IP, p21 reporter assay","pmids":["16335786"],"confidence":"Medium","gaps":["Functional consequence of RNF10 binding beyond p21 reporter unclear"]},{"year":2006,"claim":"Demonstrated direct, ChIP-confirmed MEOX2 occupancy of upstream ATTA sites of the p21 promoter, tying transactivation to growth arrest and to specific protein domains.","evidence":"ChIP, deletion constructs, luciferase reporters, site-directed mutagenesis","pmids":["17074759"],"confidence":"High","gaps":["Apparent direct binding here vs later DNA-binding-independent p21 induction needs reconciliation"]},{"year":2007,"claim":"Established post-transcriptional control of GAX by miR-130a via its 3'-UTR, linking miRNA regulation to the endothelial angiogenic phenotype.","evidence":"Luciferase reporter with GAX 3'-UTR, miR-130a overexpression","pmids":["17957028"],"confidence":"Medium","gaps":["Endogenous miR-130a contribution to vascular GAX levels in vivo not quantified"]},{"year":2009,"claim":"Placed MEOX2 in the TGF-β/Smad tumor-suppressor pathway, showing it forms Smad complexes, is required for the TGF-β1 cytostatic response, and inhibits EMT.","evidence":"RNAi knockdown, ectopic expression, co-IP with Smads, p21 promoter deletion, EMT assays","pmids":["19383287"],"confidence":"High","gaps":["p21 region used here (distal p53-binding) differs from the upstream ATTA sites; integration unclear"]},{"year":2009,"claim":"Identified p16INK4a as a second direct MEOX2 target and tied MEOX2 to premature senescence dependent on INK4a.","evidence":"cDNA overexpression screen, ChIP, INK4a reporter and senescence assays","pmids":["19340300"],"confidence":"Medium","gaps":["Whether p16 and p21 induction are mechanistically coupled not addressed"]},{"year":2010,"claim":"Defined a physical and biphasic functional link between nuclear MEOX2 and NF-κB (p65, IκBβ), dependent on the homeodomain and N-terminal domain.","evidence":"Subcellular fractionation, co-IP, immunofluorescence, NF-κB reporter assays, domain deletions","pmids":["20421348"],"confidence":"Medium","gaps":["Molecular basis of the low-vs-high-level switch unresolved","Single-lab co-IP"]},{"year":2010,"claim":"Identified ZEB2 as a direct GAX promoter repressor and miR-221 as an indirect inducer acting by down-regulating ZEB2.","evidence":"miR-221 overexpression/inhibition, ChIP for ZEB2 at GAX promoter, miR-221 mutants","pmids":["20516212"],"confidence":"Medium","gaps":["In vivo relevance of the miR-221→ZEB2→GAX axis not established"]},{"year":2011,"claim":"Distinguished MEOX1/MEOX2 mechanisms on their two CDKI targets—DNA-binding-dependent for p16, DNA-binding-independent for p21.","evidence":"DNA-binding mutant constructs, cell-cycle and senescence assays, p21/p16 reporters","pmids":["22206000"],"confidence":"Medium","gaps":["Cofactor mediating DNA-binding-independent p21 induction not identified"]},{"year":2011,"claim":"Showed Meox2 is a barrier to reprogramming, repressed by the miR-130/301/721 family to enhance iPSC generation.","evidence":"miRNA library screen, miRNA-resistant Meox2 rescue, siRNA silencing, reprogramming assays","pmids":["21941297"],"confidence":"Medium","gaps":["Transcriptional program by which Meox2 restrains reprogramming undefined"]},{"year":2013,"claim":"Generalized the ZEB2-repression mechanism to cardiac fibroblasts, defining a Ski→(suppress Zeb2)→(de-repress Meox2) axis controlling myofibroblast identity.","evidence":"Overexpression/knockdown in cardiac fibroblasts, DNA-binding mutant, Ski overexpression, phenotype markers","pmids":["24155330"],"confidence":"Medium","gaps":["Direct Meox2 targets driving the fibroblast phenotype not mapped"]},{"year":2015,"claim":"Revealed a heterodimer-based determinant function: Meox2/Tcf15 drive CD36/LPL-mediated fatty acid uptake in heart capillary endothelium, with haplodeficiency impairing cardiac contractility.","evidence":"EC microarray profiling, haplodeficiency mouse model, FA uptake assays","pmids":["25561514"],"confidence":"High","gaps":["Direct CD36/LPL promoter occupancy by the heterodimer not shown"]},{"year":2016,"claim":"Connected Meox2 dosage to neuroprotective vascular/myeloid remodeling in glaucoma, with haploinsufficiency increasing optic-nerve axon damage.","evidence":"Meox2 haploinsufficient DBA/2J mice, axon counting, immunofluorescence, upstream regulator analysis","pmids":["31369031"],"confidence":"Medium","gaps":["Causal molecular mediators of axon protection not identified"]},{"year":2016,"claim":"Identified Rap1A as a downstream effector through which GAX maintains the VSMC contractile phenotype and limits neointima.","evidence":"cDNA array, adenoviral over/under-expression, Rap1A rescue, in vivo carotid injury","pmids":["27508012"],"confidence":"Medium","gaps":["Whether GAX directly represses the Rap1A promoter not shown"]},{"year":2022,"claim":"Reframed MEOX2 as a context-dependent oncogene in glioblastoma, enhancing ERK signaling through an ERK-dependent Ser155 site and cooperating with p53/PTEN loss.","evidence":"ERK phospho-Western, S155A mutagenesis, subnuclear imaging, cerebral organoid glioma model, RNA-seq/ACT-seq/CUT&Tag","pmids":["35468210"],"confidence":"Medium","gaps":["Direct ERK phosphorylation of Ser155 not biochemically demonstrated","Mechanism of feed-forward loop incomplete"]},{"year":2022,"claim":"Identified Cathepsin S as a direct MEOX2 oncogenic target driving glioma proliferation, motility and invasion.","evidence":"shRNA knockdown, RNA-seq, ChIP-qPCR, luciferase reporter, intracranial implantation","pmids":["35436995"],"confidence":"Medium","gaps":["Whether CTSS fully accounts for the oncogenic phenotype unclear"]},{"year":2022,"claim":"Defined an ABI2/MEOX2/KLF4-NANOG axis sustaining hepatocellular carcinoma stemness and sorafenib resistance, with MEOX2 directly activating stemness gene promoters.","evidence":"Co-IP, ChIP at KLF4/NANOG promoters, ABI2 knockdown, MEOX2 rescue, xenografts","pmids":["36017822"],"confidence":"Medium","gaps":["How ABI2 binding modulates MEOX2 transcriptional output mechanistically unclear"]},{"year":2022,"claim":"Established MEOX2 as a transcriptional maintainer of nociceptor gene programs, controlling Scn9a/Scn11a sodium channels and shaping pain sensitivity.","evidence":"Heterozygous mouse, behavior/electrophysiology, DRG transcriptomics, immunofluorescence","pmids":["35029322"],"confidence":"Medium","gaps":["Direct promoter binding to Scn9a/Scn11a not demonstrated"]},{"year":2023,"claim":"Positioned RNF10 upstream of MEOX2 in an RNF10/Meox2/AP-1 pathway protecting cardiomyocytes from pirarubicin-induced apoptosis.","evidence":"siRNA/lentiviral over-expression, Western, apoptosis flow cytometry, rat in vivo model","pmids":["36713029"],"confidence":"Medium","gaps":["Direction of RNF10–MEOX2 relationship differs from earlier binding-partner data; integration unclear"]},{"year":2024,"claim":"Identified a MEOX2→PHLPP→(inhibit AKT) axis through which MEOX2 suppresses hepatic stellate cell proliferation and liver fibrosis.","evidence":"PHLPP promoter luciferase, OE/sh-MEOX2 lentivirus, p-AKT Western, proliferation assays","pmids":["38926106"],"confidence":"Medium","gaps":["Direct MEOX2 occupancy of PHLPP promoter by ChIP not shown","Published in low-tier venue, single lab"]},{"year":2025,"claim":"Revealed RNA-level control of MEOX2 by NAT10-mediated ac4C modification stabilizing its mRNA and limiting endothelial dysfunction under high glucose.","evidence":"MeRIP-qPCR, RIP, RNA stability assay, NAT10 knockdown, MEOX2 rescue, HUVEC functional assays","pmids":["41082000"],"confidence":"Medium","gaps":["In vivo relevance of ac4C-MEOX2 axis not established"]},{"year":2026,"claim":"Defined a non-transcriptional oncogenic mechanism: MEOX2 binds PARP1 to promote DNA-damage repair and confer PARP-inhibitor and temozolomide resistance in glioblastoma stem cells.","evidence":"Co-IP/mass spectrometry, GLICO organoid model, shRNA knockdown, Talazoparib sensitivity, PARylation measurement","pmids":["41620199"],"confidence":"Medium","gaps":["Whether MEOX2 modulates PARP1 enzymatic activity directly unresolved","Structural basis of interaction unknown"]},{"year":null,"claim":"It remains unresolved how MEOX2 switches between tumor-suppressor (CDKI/senescence) and oncogenic (ERK/PARP1/stemness) outputs, and what cofactors or post-translational states dictate its direct versus DNA-binding-independent transcriptional modes.","evidence":"No single study reconciles the context-dependent dualism","pmids":[],"confidence":"Medium","gaps":["No genome-wide MEOX2 binding map across normal vs tumor contexts","Cofactor mediating DNA-binding-independent p21 activation unidentified","Determinants of the tumor-suppressor-to-oncogene switch unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[3,13,17,20,23,27,28,29]},{"term_id":"GO:0003677","term_label":"DNA binding","supporting_discovery_ids":[13,17,20,22]},{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[33]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[4,18,26,29]},{"term_id":"GO:0005654","term_label":"nucleoplasm","supporting_discovery_ids":[18,26]}],"pathway":[{"term_id":"R-HSA-1640170","term_label":"Cell Cycle","supporting_discovery_ids":[3,13,17,20]},{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[13,17,27,28]},{"term_id":"R-HSA-8953897","term_label":"Cellular responses to stimuli","supporting_discovery_ids":[17,20]},{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[7,31]},{"term_id":"R-HSA-73894","term_label":"DNA Repair","supporting_discovery_ids":[33]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[15,16,26,30]}],"complexes":[],"partners":["TCF15","RNF10","PARP1","ABI2","RELA","NFKBIB","SMAD"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P50222","full_name":"Homeobox protein MOX-2","aliases":["Growth arrest-specific homeobox","Mesenchyme homeobox 2"],"length_aa":304,"mass_kda":33.6,"function":"Mesodermal transcription factor that plays a key role in somitogenesis and somitogenesis and limb muscle differentiation (By similarity). Required during limb development for normal appendicular muscle formation and for the normal regulation of myogenic genes (By similarity). May have a regulatory role when quiescent vascular smooth muscle cells reenter the cell cycle (By similarity). Also acts as a negative regulator of angiogenesis (PubMed:17074759, PubMed:20516212, PubMed:22206000). Activates expression of CDKN1A and CDKN2A in endothelial cells, acting as a regulator of vascular cell proliferation (PubMed:17074759, PubMed:22206000). While it activates CDKN1A in a DNA-dependent manner, it activates CDKN2A in a DNA-independent manner (PubMed:22206000). Together with TCF15, regulates transcription in heart endothelial cells to regulate fatty acid transport across heart endothelial cells (By similarity)","subcellular_location":"Nucleus; Nucleus speckle","url":"https://www.uniprot.org/uniprotkb/P50222/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/MEOX2","classification":"Not Classified","n_dependent_lines":1,"n_total_lines":1208,"dependency_fraction":0.0008278145695364238},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/MEOX2","total_profiled":1310},"omim":[{"mim_id":"615998","title":"RING FINGER PROTEIN 10; RNF10","url":"https://www.omim.org/entry/615998"},{"mim_id":"615675","title":"MICRO RNA 301A; MIR301A","url":"https://www.omim.org/entry/615675"},{"mim_id":"610175","title":"MICRO RNA 130A; MIR130A","url":"https://www.omim.org/entry/610175"},{"mim_id":"600535","title":"MESENCHYME HOMEOBOX 2; MEOX2","url":"https://www.omim.org/entry/600535"},{"mim_id":"600147","title":"MESENCHYME HOMEOBOX 1; MEOX1","url":"https://www.omim.org/entry/600147"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"adipose tissue","ntpm":38.4},{"tissue":"blood vessel","ntpm":30.8},{"tissue":"placenta","ntpm":39.6}],"url":"https://www.proteinatlas.org/search/MEOX2"},"hgnc":{"alias_symbol":["MOX2"],"prev_symbol":["GAX"]},"alphafold":{"accession":"P50222","domains":[{"cath_id":"1.10.10.60","chopping":"197-262","consensus_level":"high","plddt":86.8565,"start":197,"end":262}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P50222","model_url":"https://alphafold.ebi.ac.uk/files/AF-P50222-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P50222-F1-predicted_aligned_error_v6.png","plddt_mean":60.47},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=MEOX2","jax_strain_url":"https://www.jax.org/strain/search?query=MEOX2"},"sequence":{"accession":"P50222","fasta_url":"https://rest.uniprot.org/uniprotkb/P50222.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P50222/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P50222"}},"corpus_meta":[{"pmid":"17957028","id":"PMC_17957028","title":"Regulation 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haploinsufficiency increases neuronal cell loss in a mouse model of Alzheimer's disease.","date":"2016","source":"Neurobiology of aging","url":"https://pubmed.ncbi.nlm.nih.gov/27143421","citation_count":26,"is_preprint":false},{"pmid":"25239227","id":"PMC_25239227","title":"Involvement of IGF-1 and MEOX2 in PI3K/Akt1/2 and ERK1/2 pathways mediated proliferation and differentiation of perivascular adipocytes.","date":"2014","source":"Experimental cell research","url":"https://pubmed.ncbi.nlm.nih.gov/25239227","citation_count":26,"is_preprint":false},{"pmid":"9334288","id":"PMC_9334288","title":"Forced expression of the homeodomain protein Gax inhibits cardiomyocyte proliferation and perturbs heart morphogenesis.","date":"1997","source":"Development (Cambridge, England)","url":"https://pubmed.ncbi.nlm.nih.gov/9334288","citation_count":25,"is_preprint":false},{"pmid":"19340300","id":"PMC_19340300","title":"A functional screen for regulators of CKDN2A reveals MEOX2 as a transcriptional 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hypopnea syndrome-associated pulmonary hypertension by targeting the GAX gene.","date":"2017","source":"Medicine","url":"https://pubmed.ncbi.nlm.nih.gov/28514291","citation_count":16,"is_preprint":false},{"pmid":"34844838","id":"PMC_34844838","title":"Failure to EGFR-TKI-based therapy and tumoural progression are promoted by MEOX2/GLI1-mediated epigenetic regulation of EGFR in the human lung cancer.","date":"2021","source":"European journal of cancer (Oxford, England : 1990)","url":"https://pubmed.ncbi.nlm.nih.gov/34844838","citation_count":14,"is_preprint":false},{"pmid":"34306209","id":"PMC_34306209","title":"MicroRNA-301a-3p promotes triple-negative breast cancer progression through downregulating MEOX2.","date":"2021","source":"Experimental and therapeutic medicine","url":"https://pubmed.ncbi.nlm.nih.gov/34306209","citation_count":14,"is_preprint":false},{"pmid":"15680482","id":"PMC_15680482","title":"Angiotensin II suppresses growth arrest specific homeobox (Gax) expression via redox-sensitive mitogen-activated protein kinase (MAPK).","date":"2005","source":"Regulatory peptides","url":"https://pubmed.ncbi.nlm.nih.gov/15680482","citation_count":12,"is_preprint":false},{"pmid":"8893412","id":"PMC_8893412","title":"Growth-arrest homeobox gene Gax: a molecular strategy to prevent arterial restenosis.","date":"1996","source":"Schweizerische medizinische Wochenschrift","url":"https://pubmed.ncbi.nlm.nih.gov/8893412","citation_count":11,"is_preprint":false},{"pmid":"27508012","id":"PMC_27508012","title":"Gax regulates human vascular smooth muscle cell phenotypic modulation and vascular remodeling.","date":"2016","source":"American journal of translational research","url":"https://pubmed.ncbi.nlm.nih.gov/27508012","citation_count":11,"is_preprint":false},{"pmid":"33218046","id":"PMC_33218046","title":"Facilitation of Bone Healing Processes Based on the Developmental Function of Meox2 in Tooth Loss Lesion.","date":"2020","source":"International journal of molecular 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Switzerland)","url":"https://pubmed.ncbi.nlm.nih.gov/37568909","citation_count":5,"is_preprint":false},{"pmid":"29030958","id":"PMC_29030958","title":"Association of MEOX2 polymorphism with nonsyndromic cleft palate only in a Vietnamese population.","date":"2017","source":"Congenital anomalies","url":"https://pubmed.ncbi.nlm.nih.gov/29030958","citation_count":5,"is_preprint":false},{"pmid":"37200858","id":"PMC_37200858","title":"The miR-148/152 family contributes to angiogenesis of human pluripotent stem cell- derived endothelial cells by inhibiting MEOX2.","date":"2023","source":"Molecular therapy. 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this growth-arrest specific expression pattern suggests GAX maintains the non-proliferative contractile phenotype of VSMCs.\",\n      \"method\": \"Northern blot and in vivo balloon injury model in rat carotid arteries\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean in vivo loss-of-expression with defined cellular context, single lab but consistent in vitro/in vivo correlation\",\n      \"pmids\": [\"7890661\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1995,\n      \"finding\": \"The Gax promoter minimal core region (138 bp, −125 to +13) requires at least three positive transcriptional activators: Sp1 (binding a G/C-rich element), MEF2/RSRF (binding a MADS-box site), and a third factor HRF-1 (binding an inverted palindromic motif); MEF2A overexpression transactivates the Gax promoter, establishing a direct transcriptional link between MEF2 and Gax.\",\n      \"method\": \"Transient transfection, deletion analysis, site-directed mutagenesis, protein-DNA binding assays, MEF2A overexpression\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — mutagenesis of cis-elements combined with protein-DNA binding assays and gain-of-function overexpression, multiple orthogonal methods in one study\",\n      \"pmids\": [\"7623821\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1994,\n      \"finding\": \"The human GAX gene was cloned and mapped by fluorescence in situ hybridization to chromosome 7p21; its coding sequence is 98% conserved with rat GAX at the amino acid level and encodes a homeodomain protein with a polyhistidine/glutamine (CAX repeat) region N-terminal to the homeodomain.\",\n      \"method\": \"Anchored PCR cloning from cardiovascular cDNA, FISH chromosomal mapping\",\n      \"journal\": \"Genomics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — direct molecular cloning and chromosomal mapping, foundational characterization\",\n      \"pmids\": [\"7713505\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1997,\n      \"finding\": \"Recombinant Gax protein microinjected into VSMCs and fibroblasts inhibited mitogen-induced S-phase entry; adenoviral overexpression of Gax caused G0/G1 arrest correlated with p53-independent upregulation of the CDK inhibitor p21, association of p21 with cdk2 complexes, and reduction in cdk2 activity; p21-deficient fibroblasts were refractory to Gax-induced growth inhibition, establishing Gax-mediated cell cycle arrest as p21-dependent.\",\n      \"method\": \"Microinjection of recombinant protein, adenoviral overexpression, cell cycle analysis, cdk2 activity assay, p21 knockout fibroblasts\",\n      \"journal\": \"Genes & development\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — reconstitution by microinjection plus genetic epistasis with p21 KO, multiple orthogonal methods\",\n      \"pmids\": [\"9224717\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1997,\n      \"finding\": \"Gax protein is expressed in nuclei of cardiomyocytes during late cardiac development (when myocyte proliferation is declining) and forced precocious Gax nuclear expression via adenovirus inhibited cardiomyocyte clonal expansion and reduced PCNA positivity, resulting in abnormal heart morphology (small ventricles, thinned compact zone), establishing Gax as a negative regulator of cardiomyocyte proliferation during morphogenesis.\",\n      \"method\": \"Adenoviral overexpression in chick embryo hearts, immunohistochemistry, PCNA staining, clonal analysis\",\n      \"journal\": \"Development (Cambridge, England)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — adenoviral gain-of-function with defined proliferation and morphology readout, single lab\",\n      \"pmids\": [\"9334288\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1997,\n      \"finding\": \"Gax is expressed in all muscle lineages during mouse embryogenesis; immunohistochemistry and in situ hybridization placed Gax protein in lateral plate mesoderm, cardiac muscle (biphasic pattern), smooth muscle (from E9.5), and skeletal muscle (premyogenic cells and myotomes), prior to expression of myogenic bHLH and MEF2 proteins in skeletal muscle.\",\n      \"method\": \"Immunohistochemistry and in situ hybridization on mouse embryos\",\n      \"journal\": \"Circulation research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — direct localization by immunohistochemistry and ISH, replicated across multiple tissue types, single lab\",\n      \"pmids\": [\"9118475\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1997,\n      \"finding\": \"Angiotensin II (via AT1 receptor) suppresses Gax mRNA expression in quiescent VSMCs, while C-type natriuretic peptide (CNP) upregulates Gax mRNA via a cGMP-dependent mechanism; simultaneous CNP administration attenuates Ang II-induced Gax down-regulation, placing Gax as a common transcriptional effector in opposing vascular growth-regulatory signaling pathways.\",\n      \"method\": \"Northern blot, pharmacological antagonism (AT1R blocker CV11974), cGMP analogue treatment\",\n      \"journal\": \"Hypertension\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — pharmacological dissection of upstream signaling, multiple agonists/antagonists tested, single lab\",\n      \"pmids\": [\"9039131\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"Forced Gax expression induces apoptosis in mitogen-activated but not quiescent vascular cells via Bcl-2 down-regulation and Bax up-regulation; fibroblasts homozygous null for Bax were refractory to Gax-induced apoptosis, demonstrating that Gax-mediated cell death requires Bax and is independent of p21, p53, and cell cycle activity.\",\n      \"method\": \"Adenoviral overexpression, Bax knockout MEFs, Bcl-2/Bax Western blot, apoptosis assays with cell cycle inhibitors\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — genetic epistasis using Bax KO cells plus pharmacological cell cycle manipulation, multiple orthogonal approaches in single study\",\n      \"pmids\": [\"9649428\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"Gax expression inhibits VSMC and fibroblast migration toward PDGF-BB, bFGF, and HGF; this requires p21 (p21-deficient fibroblasts were resistant but rescued by exogenous p21 or p16); Gax specifically down-regulates αvβ3 and αvβ5 integrin expression in VSMCs in vitro and in vivo after vascular injury, suggesting integrin repression as the mechanism for reduced cell motility.\",\n      \"method\": \"Adenoviral Gax transduction, transwell migration assays, p21/p53 knockout fibroblasts, flow cytometry for integrin expression, in vivo immunostaining post-balloon injury\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic epistasis with p21 KO cells, multiple migration stimuli tested, in vivo integrin down-regulation confirmed, single lab with orthogonal methods\",\n      \"pmids\": [\"10562309\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"Gax is expressed in vascular endothelial cells and its adenoviral overexpression in HUVECs inhibits proliferation, mitogen-stimulated thymidine uptake, and tube formation on Matrigel, accompanied by up to 5-fold induction of p21 mRNA and 4–5-fold activation of the p21 promoter, establishing Gax as a negative regulator of the angiogenic phenotype in endothelial cells.\",\n      \"method\": \"Adenoviral overexpression, thymidine incorporation, Matrigel tube formation, Northern blot, promoter activity assay\",\n      \"journal\": \"The Journal of surgical research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional gain-of-function with multiple readouts in ECs, single lab\",\n      \"pmids\": [\"12842453\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"In brain endothelial cells (BECs) from Alzheimer disease patients, MEOX2 expression is reduced independent of age; viral-mediated MEOX2 gene transfer in AD BECs stimulates angiogenesis, transcriptionally suppresses AFX1 forkhead factor-mediated apoptosis, and increases LRP1 levels at the blood-brain barrier; Meox2 knockout mice exhibit reduced brain capillary density, reduced cerebral blood flow, loss of hypoxia-induced angiogenic response, and impaired Aβ efflux due to reduced LRP levels.\",\n      \"method\": \"Transcriptional profiling of human BECs, viral-mediated gene silencing and transfer, Meox2 knockout mouse model, cerebral blood flow measurement, Aβ efflux assay\",\n      \"journal\": \"Nature medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — viral gene transfer and KO mouse model with multiple orthogonal functional readouts, replicated across in vitro and in vivo systems\",\n      \"pmids\": [\"16116430\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"MEOX2 binds to RING finger protein 10 (RNF10) as determined by yeast two-hybrid screening, in vitro pull-down, and co-immunoprecipitation in mammalian cells; the minimal RNF10-binding region of MEOX2 maps to amino acids 101–185 (between the HQ-rich domain and homeodomain); RNF10 co-expression enhances MEOX2 activation of the p21WAF1 promoter.\",\n      \"method\": \"Yeast two-hybrid screen, in vitro pull-down, co-immunoprecipitation, p21 promoter reporter assay\",\n      \"journal\": \"Molecular and cellular biochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal binding confirmed by multiple methods (Y2H, pull-down, Co-IP), domain mapping performed, single lab\",\n      \"pmids\": [\"16335786\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"Meox-2 knockout mice display cleft palate (35.3% of Meox-2−/− embryos) arising from breakdown of already-fused palatal shelves (post-fusion mechanism), distinct from previously reported pre-fusion cleft palate mechanisms; Meox-2 expression marks early palatal mesenchymal cells from E11.5 and the posterior palate from E12.5–E15.5.\",\n      \"method\": \"Knockout mouse analysis, histology, in situ hybridization, timed embryo collection\",\n      \"journal\": \"Developmental dynamics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KO mouse with specific histological phenotype analysis, single lab\",\n      \"pmids\": [\"16284941\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"GAX directly activates p21WAF1/CIP1 transcription through multiple upstream ATTA-containing binding sites (~15 kb upstream of the ATG); chromatin immunoprecipitation confirmed GAX occupancy at these sites in vivo; homeodomain and N-terminal domain are required for transactivation; G0/G1 arrest ability correlates with p21 promoter transactivation ability.\",\n      \"method\": \"ChIP, GAX deletion constructs, luciferase reporter assays with p21 promoter fragments, site-directed mutagenesis of binding sites\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — ChIP confirmation of in vivo binding plus mutagenesis of binding sites plus domain deletion analysis, multiple orthogonal methods\",\n      \"pmids\": [\"17074759\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"miR-130a down-regulates GAX expression through two targeting sites in a 280-bp fragment of the GAX 3′-UTR; forced miR-130a expression inhibits GAX through this specific sequence; miR-130a also targets HOXA5 3′-UTR; together, miR-130a regulates the angiogenic phenotype of endothelial cells by modulating GAX and HOXA5.\",\n      \"method\": \"Luciferase reporter assay with GAX 3′-UTR, miR-130a overexpression, promoter activity assays\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — luciferase reporter with defined UTR fragments and miRNA overexpression, single lab\",\n      \"pmids\": [\"17957028\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"MEOX2 is a TGF-β/Smad target gene in epithelial cells; MEOX2 knockdown prevents TGF-β1-induced cytostatic response; ectopic MEOX2 suppresses epithelial proliferation cooperatively with TGF-β1 and induces p21 through a distal p53-binding region of the p21 promoter; MEOX2 forms protein complexes with Smads leading to cooperative p21 regulation; MEOX2 fails to induce EMT and inhibits TGF-β-induced EMT, placing MEOX2 specifically in the TGF-β tumor suppressor pathway.\",\n      \"method\": \"RNAi knockdown, ectopic expression, co-immunoprecipitation with Smads, p21 promoter deletion analysis, proliferation and EMT assays\",\n      \"journal\": \"Molecular oncology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — Co-IP of Smad/MEOX2 complex, RNAi epistasis, promoter analysis with multiple orthogonal approaches in single study\",\n      \"pmids\": [\"19383287\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"Angiotensin II suppresses Gax expression in VSMCs via oxidative stress-activated ERK1/2 (not p38 MAPK); H2O2 mimics Ang II-induced Gax down-regulation; antioxidants (NAC, PDTC) and the ERK1/2 inhibitor PD98059 block Ang II- and H2O2-induced Gax suppression, whereas the p38 inhibitor SB203580 does not.\",\n      \"method\": \"Pharmacological inhibition of ERK1/2 and p38 MAPK, antioxidant treatment, Northern blot/RT-PCR, intracellular H2O2 measurement\",\n      \"journal\": \"Regulatory peptides\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — pharmacological epistasis with multiple inhibitors and antioxidants, single lab\",\n      \"pmids\": [\"15680482\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"MEOX2 is a direct transcriptional activator of the INK4a (p16) promoter; forced MEOX2 expression induces premature senescence that is dependent on INK4a activity; ChIP confirms direct MEOX2 binding to the INK4a promoter; MEOX2 transcription is enhanced in primary cells during senescence induction.\",\n      \"method\": \"Genome-scale cDNA overexpression screen, ChIP, INK4a reporter assay, senescence assays, INK4a activity dependence testing\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP confirmation of promoter binding plus functional senescence assay, single lab\",\n      \"pmids\": [\"19340300\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"MEOX2 localizes to the nuclear fraction in endothelial cells; co-immunoprecipitation shows MEOX2 binds to both p65 (RelA) and IκBβ in the nucleus; immunofluorescence confirms colocalization requiring the MEOX2 homeodomain and N-terminal domain; MEOX2 has a biphasic effect on NF-κB-dependent promoters (stimulates at low levels, represses at high levels), both effects dependent on the homeodomain and N-terminal domain.\",\n      \"method\": \"Subcellular fractionation, co-immunoprecipitation, immunofluorescence, NF-κB promoter reporter assays, MEOX2 domain deletion constructs\",\n      \"journal\": \"Cardiovascular research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP plus domain mapping plus functional promoter assays, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"20421348\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"miR-221 upregulates GAX expression in endothelial cells indirectly by downregulating ZEB2; ZEB2 is a repressor of GAX that binds two sites on the GAX promoter as shown by ChIP; serum upregulates ZEB2 which downregulates GAX; a mutant miR-221 fails to downregulate ZEB2 or upregulate GAX.\",\n      \"method\": \"miR-221 overexpression and inhibition, ChIP for ZEB2 binding at GAX promoter, miR-221 mutant constructs, Western blot\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP identifying ZEB2 binding sites on GAX promoter plus functional miRNA experiments, single lab\",\n      \"pmids\": [\"20516212\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Both MEOX1 and MEOX2 induce p21CIP1/WAF1 and p16INK4a expression and cause endothelial cell cycle arrest and senescence; however, they use distinct mechanisms: MEOX1 and MEOX2 activate p16INK4a in a DNA binding-dependent manner, whereas they induce p21CIP1/WAF1 in a DNA binding-independent manner.\",\n      \"method\": \"MEOX1/MEOX2 overexpression with DNA-binding mutants, cell cycle analysis, senescence assays, p21 and p16 reporter assays\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — DNA-binding mutant constructs dissecting mechanism, multiple functional readouts, single lab\",\n      \"pmids\": [\"22206000\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"The miRNA family miR-130/301/721 enhances iPSC generation from murine fibroblasts by repressing Meox2; miRNA-resistant Meox2 overexpression abrogates the pro-reprogramming effects of this miRNA family; Meox2-specific silencing mimics the miRNA family effects on reprogramming.\",\n      \"method\": \"miRNA library screen, miRNA-resistant Meox2 construct, Meox2 siRNA silencing, iPSC reprogramming efficiency assay\",\n      \"journal\": \"EMBO reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — miRNA-resistant rescue experiment plus siRNA epistasis, single lab\",\n      \"pmids\": [\"21941297\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"In cardiac fibroblast-to-myofibroblast phenoconversion, Meox2 expression is reduced while Zeb2 increases; Ski overexpression restores Meox2 mRNA by suppressing Zeb2; overexpression of Meox2 (but not a DNA-binding mutant) shifts myofibroblasts back toward the fibroblast phenotype, establishing a Ski→(suppresses Zeb2)→(de-represses Meox2) pathway that regulates the cardiac myofibroblast phenotype.\",\n      \"method\": \"Overexpression and knockdown in cardiac fibroblasts, Meox2 DNA-binding mutant, Western blot, RT-PCR, myofibroblast phenotype markers\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — epistasis using DNA-binding mutant plus Ski overexpression, single lab with multiple molecular readouts\",\n      \"pmids\": [\"24155330\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Meox2 and Tcf15 form heterodimers that act as transcriptional determinants of heart capillary endothelial cell identity; Meox2/Tcf15 drive endothelial CD36 and lipoprotein lipase expression to mediate fatty acid uptake in heart ECs and facilitate FA transport to cardiomyocytes; combined Meox2/Tcf15 haplodeficiency impairs cardiac FA uptake and reduces FA transfer, leading to impaired cardiac contractility.\",\n      \"method\": \"Microarray profiling of freshly isolated ECs, gain- and loss-of-function (haplodeficiency mouse model), FA uptake assays, CD36/LPL expression analysis\",\n      \"journal\": \"Circulation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — heterodimer identification with genetic haplodeficiency model, multiple functional readouts (FA uptake, cardiac contractility), multiple orthogonal approaches\",\n      \"pmids\": [\"25561514\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Meox2 haploinsufficiency in DBA/2J glaucoma mice significantly increases axon damage in the optic nerve head and is associated with modulation of age- and disease-specific vascular and myeloid alterations, supporting a role for Meox2 in IOP-dependent vascular remodeling and neuroinflammation that promotes axon survival.\",\n      \"method\": \"Meox2 haploinsufficient DBA/2J mouse model, axon counting, immunofluorescence, upstream regulator analysis\",\n      \"journal\": \"Investigative ophthalmology & visual science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic haploinsufficiency model with defined axon and vascular phenotype, single lab\",\n      \"pmids\": [\"31369031\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Gax overexpression in human VSMCs increases differentiation markers calponin and SM-MHC 11, suppresses proliferation and migration, and transcriptomic analysis identified Rap1A as a downstream target of Gax; Gax overexpression significantly inhibits Rap1A expression and reduces neointimal formation in carotid artery injury in mice, indicating that Gax maintains VSMC contractile phenotype partly by suppressing Rap1A.\",\n      \"method\": \"Western blot, cDNA array analysis, adenoviral overexpression and silencing, Rap1A overexpression, in vivo mouse carotid injury model\",\n      \"journal\": \"American journal of translational research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — cDNA array target identification with functional rescue by Rap1A overexpression, in vivo validation, single lab\",\n      \"pmids\": [\"27508012\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"MEOX2 enhances ERK signaling in glioblastoma through a feed-forward mechanism; Ser155 (upstream of the homeodomain) is a putative ERK-dependent phosphorylation site and S155A substitution affects MEOX2 protein levels and alters its subnuclear localization; MEOX2 overexpression cooperates with p53 and PTEN loss to induce cell proliferation in cerebral organoid glioma models.\",\n      \"method\": \"ERK phosphorylation Western blot, S155A site mutagenesis, subnuclear localization imaging, cerebral organoid glioma model, RNA-seq, ACT-seq, CUT&Tag\",\n      \"journal\": \"Neuro-oncology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — mutagenesis of phosphorylation site with localization and functional consequences, single lab with multiple genomics approaches\",\n      \"pmids\": [\"35468210\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"MEOX2 directly transcriptionally activates Cathepsin S (CTSS) in glioma cells, as shown by RNA-sequencing, ChIP-qPCR, and luciferase reporter assays; MEOX2 knockdown inhibits glioma cell proliferation, motility, EMT, focal adhesion formation, and F-actin assembly; MEOX2 promotes glioma tumor growth in vivo.\",\n      \"method\": \"shRNA knockdown, RNA-sequencing, ChIP-qPCR, luciferase reporter assay, intracranial mouse implantation model\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP confirmation of CTSS as direct target plus in vivo tumor model, single lab\",\n      \"pmids\": [\"35436995\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"ABI2 directly interacts with MEOX2 (co-immunoprecipitation), and MEOX2 binds to the KLF4 and NANOG promoter regions to activate their transcription in hepatocellular carcinoma; this ABI2/MEOX2/KLF4-NANOG axis maintains cancer stem cell populations and drives HCC stemness, growth, and sorafenib resistance.\",\n      \"method\": \"Co-immunoprecipitation, ChIP at KLF4 and NANOG promoters, ABI2 knockdown, MEOX2 overexpression rescue, xenograft model\",\n      \"journal\": \"Liver international\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP of ABI2-MEOX2 interaction plus ChIP of downstream targets, rescue experiments, single lab\",\n      \"pmids\": [\"36017822\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"MEOX2 is expressed in the nuclei of a subset of mouse DRG sensory neurons; Meox2+/− heterozygous mice show impaired nociception with altered action potential initiation; mechanistically, MEOX2 loss decreases expression of Scn9a (Nav1.7) and Scn11a (Nav1.9) voltage-gated sodium channel genes, as well as other pain-associated genes (PENK, NPY), establishing MEOX2 as a transcriptional regulator maintaining nociceptor gene programs.\",\n      \"method\": \"Heterozygous mouse model, behavioral/electrophysiological analyses, transcriptomic analysis of DRG, immunofluorescence\",\n      \"journal\": \"The FEBS journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic haploinsufficiency with electrophysiological phenotype and transcriptomic identification of downstream targets, single lab\",\n      \"pmids\": [\"35029322\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"MEOX2 binds the PHLPP phosphatase promoter (by dual luciferase reporter assay) and up-regulates PHLPP transcription, leading to inhibition of AKT phosphorylation (p-AKT) in hepatic stellate cells (HSCs); MEOX2 overexpression inhibits HSC proliferation and slows liver fibrosis progression through this MEOX2→PHLPP→(inhibit AKT) axis.\",\n      \"method\": \"Dual luciferase reporter assay for PHLPP promoter, OE-MEOX2/sh-MEOX2 lentivirus, Western blot for p-AKT, CCK-8 and EdU proliferation assays\",\n      \"journal\": \"Discovery medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — luciferase reporter confirming direct promoter binding, gain/loss-of-function with signaling readout, single lab\",\n      \"pmids\": [\"38926106\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"RNF10 overexpression in H9C2 cardiomyocytes promotes MEOX2 expression and inhibits AP-1 activation, alleviating pirarubicin-induced apoptosis; RNF10 knockdown produces the opposite effect; in vivo, THP-induced CRC is associated with decreased RNF10 and Meox2 and activated AP-1, placing RNF10 upstream of MEOX2 in the AP-1/Meox2 pathway modulating cardiomyocyte apoptosis.\",\n      \"method\": \"siRNA knockdown, lentiviral overexpression, Western blot, flow cytometry for apoptosis, rat in vivo CRC model\",\n      \"journal\": \"Oxidative medicine and cellular longevity\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal gain/loss-of-function with in vivo validation, single lab\",\n      \"pmids\": [\"36713029\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"NAT10-mediated ac4C modification of MEOX2 mRNA at nucleotides 409–423 stabilizes MEOX2 mRNA and increases its expression; NAT10 knockdown reduces ac4C modification at this site, decreases MEOX2 mRNA stability and protein expression, and consequently enhances HUVEC migration, invasion, and tube formation in high-glucose conditions; MEOX2 overexpression reverses these effects.\",\n      \"method\": \"MeRIP-qPCR for ac4C modification, RIP, RNA stability assay, NAT10 knockdown, MEOX2 overexpression rescue, functional HUVEC assays\",\n      \"journal\": \"Applied biochemistry and biotechnology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct measurement of ac4C modification at specific mRNA site plus RNA stability assay and rescue experiments, single lab\",\n      \"pmids\": [\"41082000\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"MEOX2 promotes DNA damage repair in glioblastoma stem-like cells; co-immunoprecipitation and mass spectrometry identified PARP1 as a direct MEOX2 interactor; MEOX2 depletion reduces PARylation levels and sensitizes GSCs to the PARP1 inhibitor Talazoparib; MEOX2 knockdown in a GLICO model impairs tumor growth and increases sensitivity to temozolomide.\",\n      \"method\": \"Co-immunoprecipitation, mass spectrometry, GLICO organoid model, shRNA knockdown, Talazoparib sensitivity assay, PARylation measurement\",\n      \"journal\": \"Cancer letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP/MS identification of PARP1 interaction plus functional DNA repair and drug sensitivity assays, single lab\",\n      \"pmids\": [\"41620199\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"MEOX2/GAX is a homeodomain transcription factor that, in quiescent vascular cells, enforces cell cycle arrest by directly activating p21CIP1 (through upstream ATTA-binding sites) and p16INK4a (DNA binding-dependent), and inhibits proliferation, migration (via αvβ3/αvβ5 integrin down-regulation), and apoptosis (via Bax up-regulation/Bcl-2 down-regulation) in a p21-dependent manner; in endothelial cells it suppresses the angiogenic phenotype partly by interacting with NF-κB components (p65 and IκBβ) and by forming heterodimers with TCF15 to regulate fatty acid transport; its transcription is activated by MEF2, repressed by ZEB2 (relieved by miR-221) and by Ang II/ROS/ERK1/2 signaling, and post-transcriptionally silenced by miR-130a/301/721 family members; in the brain vasculature MEOX2 maintains blood-brain barrier LRP1 levels and cerebral perfusion relevant to Alzheimer disease, while in glioblastoma it paradoxically acts as an oncogene by enhancing ERK signaling, interacting with PARP1 to promote DNA repair, and directly activating targets such as Cathepsin S.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"MEOX2 (GAX) is a homeodomain transcription factor that enforces the quiescent, non-proliferative state of vascular and muscle cells and is rapidly down-regulated when these cells are stimulated to proliferate [#0]. Its core mechanism is direct transcriptional activation of cyclin-dependent kinase inhibitors: it occupies upstream ATTA-containing sites of the p21CIP1/WAF1 promoter to induce p21, drive its association with cdk2 and impose G0/G1 arrest, with p21-null cells being refractory to this effect [#3, #13], and it directly binds and activates the INK4a (p16) promoter to trigger senescence [#17]. MEOX1 and MEOX2 distinguish these two targets mechanistically, activating p16INK4a in a DNA-binding-dependent manner while inducing p21 independently of DNA binding [#20]. Through this growth-suppressive program MEOX2 blocks proliferation, migration\\u2014partly by down-regulating \\u03b1v\\u03b23/\\u03b1v\\u03b25 integrins in a p21-dependent fashion [#8]\\u2014and promotes Bax-dependent, p21/p53-independent apoptosis in mitogen-activated cells [#7]; in endothelial cells it suppresses the angiogenic phenotype and tube formation [#9]. Beyond cell-cycle control, MEOX2 functions as a transcriptional determinant in tissue-specific contexts: it forms heterodimers with TCF15 to drive CD36/lipoprotein lipase expression and fatty acid uptake in heart capillary endothelium [#23], maintains blood-brain-barrier LRP1 levels and cerebral perfusion relevant to Alzheimer disease [#10], and sustains nociceptor sodium-channel gene programs (Scn9a/Scn11a) in sensory neurons [#29]. Its expression is gated by a MEF2/Sp1-dependent promoter [#1], repressed by ZEB2 (relieved by miR-221) [#19] and by Angiotensin II acting through oxidative-stress-driven ERK1/2 signaling [#16], and silenced post-transcriptionally by the miR-130a/301 family [#14, #21]. MEOX2 physically associates with NF-\\u03baB components p65 and I\\u03baB\\u03b2 [#18], with TGF-\\u03b2/Smad complexes to cooperatively induce p21 within the TGF-\\u03b2 tumor-suppressor pathway [#15], and with RNF10, which enhances its p21 activation [#11]. In glioblastoma and other cancers MEOX2 paradoxically acts as an oncogene, enhancing ERK signaling via Ser155 phosphorylation [#26], interacting with PARP1 to promote DNA-damage repair and PARP-inhibitor resistance [#33], and directly activating targets such as Cathepsin S to drive tumor growth [#27].\",\n  \"teleology\": [\n    {\n      \"year\": 1995,\n      \"claim\": \"Established MEOX2/GAX as a growth-arrest-specific gene whose loss accompanies the switch of vascular smooth muscle cells to a proliferative phenotype, framing it as a candidate enforcer of quiescence.\",\n      \"evidence\": \"Northern blot and in vivo balloon-injury model in rat carotid arteries\",\n      \"pmids\": [\"7890661\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Correlative loss-of-expression does not show GAX is sufficient or required for arrest\", \"No direct transcriptional target identified at this stage\"]\n    },\n    {\n      \"year\": 1994,\n      \"claim\": \"Provided the foundational molecular identity of human GAX as a chromosome 7p21 homeodomain protein with an N-terminal polyhistidine/glutamine region, enabling all subsequent functional dissection.\",\n      \"evidence\": \"Anchored PCR cloning and FISH chromosomal mapping\",\n      \"pmids\": [\"7713505\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Cloning alone does not assign function or DNA-binding specificity\"]\n    },\n    {\n      \"year\": 1995,\n      \"claim\": \"Defined how GAX transcription is itself driven, identifying Sp1, MEF2/RSRF and HRF-1 as positive regulators and establishing a direct MEF2\\u2192Gax link.\",\n      \"evidence\": \"Transient transfection, promoter deletion/mutagenesis, protein-DNA binding, MEF2A overexpression\",\n      \"pmids\": [\"7623821\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"HRF-1 not molecularly identified\", \"Does not address signals controlling MEF2 in vivo\"]\n    },\n    {\n      \"year\": 1997,\n      \"claim\": \"Demonstrated GAX is sufficient to arrest the cell cycle and pinned the mechanism on p21 induction, with genetic epistasis proving p21-dependence.\",\n      \"evidence\": \"Recombinant protein microinjection, adenoviral overexpression, cdk2 activity assay, p21-knockout fibroblasts\",\n      \"pmids\": [\"9224717\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not show whether p21 induction is via direct promoter binding\", \"Mechanism of p53-independence not resolved\"]\n    },\n    {\n      \"year\": 1997,\n      \"claim\": \"Extended the anti-proliferative role to development, showing GAX restrains cardiomyocyte proliferation during heart morphogenesis and is broadly expressed across muscle lineages.\",\n      \"evidence\": \"Adenoviral overexpression in chick hearts, IHC/ISH on mouse embryos, PCNA staining\",\n      \"pmids\": [\"9334288\", \"9118475\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Forced expression does not establish endogenous requirement\", \"No transcriptional targets identified in cardiac context\"]\n    },\n    {\n      \"year\": 1997,\n      \"claim\": \"Placed GAX downstream of opposing vascular signals, with Angiotensin II suppressing and CNP/cGMP inducing its expression.\",\n      \"evidence\": \"Northern blot with AT1R antagonist and cGMP analogue treatment\",\n      \"pmids\": [\"9039131\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Intermediate signaling steps not defined at this stage\"]\n    },\n    {\n      \"year\": 1998,\n      \"claim\": \"Separated GAX's apoptotic function from its cell-cycle function, showing it triggers Bax-dependent death only in cycling cells, independent of p21/p53.\",\n      \"evidence\": \"Adenoviral overexpression, Bax-knockout MEFs, Bcl-2/Bax Western, cell-cycle inhibitors\",\n      \"pmids\": [\"9649428\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether Bax/Bcl-2 changes are direct transcriptional effects unknown\"]\n    },\n    {\n      \"year\": 1999,\n      \"claim\": \"Identified integrin repression (\\u03b1v\\u03b23/\\u03b1v\\u03b25) as the mechanism for GAX-mediated inhibition of migration and showed this too is p21-dependent.\",\n      \"evidence\": \"Adenoviral transduction, transwell migration, p21/p53-knockout fibroblasts, flow cytometry, in vivo immunostaining\",\n      \"pmids\": [\"10562309\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether GAX directly regulates integrin promoters not shown\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Extended the growth-suppressive program to endothelial cells, showing GAX inhibits proliferation and tube formation while inducing p21.\",\n      \"evidence\": \"Adenoviral overexpression in HUVECs, thymidine uptake, Matrigel tube formation, p21 promoter assay\",\n      \"pmids\": [\"12842453\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Anti-angiogenic mechanism beyond p21 not defined\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Connected MEOX2 to brain-vascular homeostasis and Alzheimer disease, showing it maintains capillary density, cerebral blood flow and LRP1-mediated A\\u03b2 efflux.\",\n      \"evidence\": \"Human BEC profiling, viral gene transfer/silencing, Meox2 knockout mice, cerebral blood flow and A\\u03b2 efflux assays\",\n      \"pmids\": [\"16116430\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct transcriptional targets in BECs (e.g. LRP1 regulation) not mapped\", \"Reconciliation with anti-angiogenic role in other vessels unresolved\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Resolved the upstream pathway by which Angiotensin II suppresses Gax, implicating oxidative-stress-activated ERK1/2 rather than p38.\",\n      \"evidence\": \"Pharmacological ERK1/2 and p38 inhibition, antioxidant treatment, H2O2 measurement, Northern/RT-PCR\",\n      \"pmids\": [\"15680482\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Transcription factor mediating ERK-dependent repression not identified\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Revealed a distinct developmental requirement\\u2014post-fusion palatal shelf integrity\\u2014via the knockout cleft-palate phenotype.\",\n      \"evidence\": \"Knockout mouse histology, ISH, timed embryo collection\",\n      \"pmids\": [\"16284941\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular targets maintaining palatal tissue not identified\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Identified RNF10 as a direct MEOX2 partner that potentiates its p21 activation, mapping the interaction region between the HQ domain and homeodomain.\",\n      \"evidence\": \"Yeast two-hybrid, in vitro pull-down, co-IP, p21 reporter assay\",\n      \"pmids\": [\"16335786\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional consequence of RNF10 binding beyond p21 reporter unclear\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Demonstrated direct, ChIP-confirmed MEOX2 occupancy of upstream ATTA sites of the p21 promoter, tying transactivation to growth arrest and to specific protein domains.\",\n      \"evidence\": \"ChIP, deletion constructs, luciferase reporters, site-directed mutagenesis\",\n      \"pmids\": [\"17074759\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Apparent direct binding here vs later DNA-binding-independent p21 induction needs reconciliation\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Established post-transcriptional control of GAX by miR-130a via its 3'-UTR, linking miRNA regulation to the endothelial angiogenic phenotype.\",\n      \"evidence\": \"Luciferase reporter with GAX 3'-UTR, miR-130a overexpression\",\n      \"pmids\": [\"17957028\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Endogenous miR-130a contribution to vascular GAX levels in vivo not quantified\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Placed MEOX2 in the TGF-\\u03b2/Smad tumor-suppressor pathway, showing it forms Smad complexes, is required for the TGF-\\u03b21 cytostatic response, and inhibits EMT.\",\n      \"evidence\": \"RNAi knockdown, ectopic expression, co-IP with Smads, p21 promoter deletion, EMT assays\",\n      \"pmids\": [\"19383287\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"p21 region used here (distal p53-binding) differs from the upstream ATTA sites; integration unclear\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Identified p16INK4a as a second direct MEOX2 target and tied MEOX2 to premature senescence dependent on INK4a.\",\n      \"evidence\": \"cDNA overexpression screen, ChIP, INK4a reporter and senescence assays\",\n      \"pmids\": [\"19340300\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether p16 and p21 induction are mechanistically coupled not addressed\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Defined a physical and biphasic functional link between nuclear MEOX2 and NF-\\u03baB (p65, I\\u03baB\\u03b2), dependent on the homeodomain and N-terminal domain.\",\n      \"evidence\": \"Subcellular fractionation, co-IP, immunofluorescence, NF-\\u03baB reporter assays, domain deletions\",\n      \"pmids\": [\"20421348\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular basis of the low-vs-high-level switch unresolved\", \"Single-lab co-IP\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Identified ZEB2 as a direct GAX promoter repressor and miR-221 as an indirect inducer acting by down-regulating ZEB2.\",\n      \"evidence\": \"miR-221 overexpression/inhibition, ChIP for ZEB2 at GAX promoter, miR-221 mutants\",\n      \"pmids\": [\"20516212\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"In vivo relevance of the miR-221\\u2192ZEB2\\u2192GAX axis not established\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Distinguished MEOX1/MEOX2 mechanisms on their two CDKI targets\\u2014DNA-binding-dependent for p16, DNA-binding-independent for p21.\",\n      \"evidence\": \"DNA-binding mutant constructs, cell-cycle and senescence assays, p21/p16 reporters\",\n      \"pmids\": [\"22206000\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Cofactor mediating DNA-binding-independent p21 induction not identified\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Showed Meox2 is a barrier to reprogramming, repressed by the miR-130/301/721 family to enhance iPSC generation.\",\n      \"evidence\": \"miRNA library screen, miRNA-resistant Meox2 rescue, siRNA silencing, reprogramming assays\",\n      \"pmids\": [\"21941297\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Transcriptional program by which Meox2 restrains reprogramming undefined\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Generalized the ZEB2-repression mechanism to cardiac fibroblasts, defining a Ski\\u2192(suppress Zeb2)\\u2192(de-repress Meox2) axis controlling myofibroblast identity.\",\n      \"evidence\": \"Overexpression/knockdown in cardiac fibroblasts, DNA-binding mutant, Ski overexpression, phenotype markers\",\n      \"pmids\": [\"24155330\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct Meox2 targets driving the fibroblast phenotype not mapped\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Revealed a heterodimer-based determinant function: Meox2/Tcf15 drive CD36/LPL-mediated fatty acid uptake in heart capillary endothelium, with haplodeficiency impairing cardiac contractility.\",\n      \"evidence\": \"EC microarray profiling, haplodeficiency mouse model, FA uptake assays\",\n      \"pmids\": [\"25561514\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct CD36/LPL promoter occupancy by the heterodimer not shown\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Connected Meox2 dosage to neuroprotective vascular/myeloid remodeling in glaucoma, with haploinsufficiency increasing optic-nerve axon damage.\",\n      \"evidence\": \"Meox2 haploinsufficient DBA/2J mice, axon counting, immunofluorescence, upstream regulator analysis\",\n      \"pmids\": [\"31369031\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Causal molecular mediators of axon protection not identified\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Identified Rap1A as a downstream effector through which GAX maintains the VSMC contractile phenotype and limits neointima.\",\n      \"evidence\": \"cDNA array, adenoviral over/under-expression, Rap1A rescue, in vivo carotid injury\",\n      \"pmids\": [\"27508012\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether GAX directly represses the Rap1A promoter not shown\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Reframed MEOX2 as a context-dependent oncogene in glioblastoma, enhancing ERK signaling through an ERK-dependent Ser155 site and cooperating with p53/PTEN loss.\",\n      \"evidence\": \"ERK phospho-Western, S155A mutagenesis, subnuclear imaging, cerebral organoid glioma model, RNA-seq/ACT-seq/CUT&Tag\",\n      \"pmids\": [\"35468210\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct ERK phosphorylation of Ser155 not biochemically demonstrated\", \"Mechanism of feed-forward loop incomplete\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Identified Cathepsin S as a direct MEOX2 oncogenic target driving glioma proliferation, motility and invasion.\",\n      \"evidence\": \"shRNA knockdown, RNA-seq, ChIP-qPCR, luciferase reporter, intracranial implantation\",\n      \"pmids\": [\"35436995\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether CTSS fully accounts for the oncogenic phenotype unclear\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Defined an ABI2/MEOX2/KLF4-NANOG axis sustaining hepatocellular carcinoma stemness and sorafenib resistance, with MEOX2 directly activating stemness gene promoters.\",\n      \"evidence\": \"Co-IP, ChIP at KLF4/NANOG promoters, ABI2 knockdown, MEOX2 rescue, xenografts\",\n      \"pmids\": [\"36017822\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"How ABI2 binding modulates MEOX2 transcriptional output mechanistically unclear\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Established MEOX2 as a transcriptional maintainer of nociceptor gene programs, controlling Scn9a/Scn11a sodium channels and shaping pain sensitivity.\",\n      \"evidence\": \"Heterozygous mouse, behavior/electrophysiology, DRG transcriptomics, immunofluorescence\",\n      \"pmids\": [\"35029322\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct promoter binding to Scn9a/Scn11a not demonstrated\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Positioned RNF10 upstream of MEOX2 in an RNF10/Meox2/AP-1 pathway protecting cardiomyocytes from pirarubicin-induced apoptosis.\",\n      \"evidence\": \"siRNA/lentiviral over-expression, Western, apoptosis flow cytometry, rat in vivo model\",\n      \"pmids\": [\"36713029\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direction of RNF10\\u2013MEOX2 relationship differs from earlier binding-partner data; integration unclear\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Identified a MEOX2\\u2192PHLPP\\u2192(inhibit AKT) axis through which MEOX2 suppresses hepatic stellate cell proliferation and liver fibrosis.\",\n      \"evidence\": \"PHLPP promoter luciferase, OE/sh-MEOX2 lentivirus, p-AKT Western, proliferation assays\",\n      \"pmids\": [\"38926106\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct MEOX2 occupancy of PHLPP promoter by ChIP not shown\", \"Published in low-tier venue, single lab\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Revealed RNA-level control of MEOX2 by NAT10-mediated ac4C modification stabilizing its mRNA and limiting endothelial dysfunction under high glucose.\",\n      \"evidence\": \"MeRIP-qPCR, RIP, RNA stability assay, NAT10 knockdown, MEOX2 rescue, HUVEC functional assays\",\n      \"pmids\": [\"41082000\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"In vivo relevance of ac4C-MEOX2 axis not established\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Defined a non-transcriptional oncogenic mechanism: MEOX2 binds PARP1 to promote DNA-damage repair and confer PARP-inhibitor and temozolomide resistance in glioblastoma stem cells.\",\n      \"evidence\": \"Co-IP/mass spectrometry, GLICO organoid model, shRNA knockdown, Talazoparib sensitivity, PARylation measurement\",\n      \"pmids\": [\"41620199\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether MEOX2 modulates PARP1 enzymatic activity directly unresolved\", \"Structural basis of interaction unknown\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"It remains unresolved how MEOX2 switches between tumor-suppressor (CDKI/senescence) and oncogenic (ERK/PARP1/stemness) outputs, and what cofactors or post-translational states dictate its direct versus DNA-binding-independent transcriptional modes.\",\n      \"evidence\": \"No single study reconciles the context-dependent dualism\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No genome-wide MEOX2 binding map across normal vs tumor contexts\", \"Cofactor mediating DNA-binding-independent p21 activation unidentified\", \"Determinants of the tumor-suppressor-to-oncogene switch unknown\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [3, 13, 17, 20, 23, 27, 28, 29]},\n      {\"term_id\": \"GO:0003677\", \"supporting_discovery_ids\": [13, 17, 20, 22]},\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [33]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [4, 18, 26, 29]},\n      {\"term_id\": \"GO:0005654\", \"supporting_discovery_ids\": [18, 26]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [3, 13, 17, 20]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [13, 17, 27, 28]},\n      {\"term_id\": \"R-HSA-8953897\", \"supporting_discovery_ids\": [17, 20]},\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [7, 31]},\n      {\"term_id\": \"R-HSA-73894\", \"supporting_discovery_ids\": [33]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [15, 16, 26, 30]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"TCF15\", \"RNF10\", \"PARP1\", \"ABI2\", \"RELA\", \"NFKBIB\", \"SMAD\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":8,"faith_total":8,"faith_pct":100.0}}