{"gene":"CDX1","run_date":"2026-04-28T17:28:52","timeline":{"discoveries":[{"year":1995,"finding":"Cdx1 loss-of-function (homologous recombination knockout) causes anterior homeotic transformations of vertebrae, accompanied by posterior shifts of Hox gene expression domains in somitic mesoderm; putative Cdx1-binding sites were identified in Hox gene control regions, and in vitro transactivation of Hoxa-7 was demonstrated, indicating direct regulation of Hox genes by Cdx1.","method":"Homologous recombination knockout, in vitro transactivation assay, in situ hybridization of Hox expression domains","journal":"Cell","confidence":"High","confidence_rationale":"Tier 1-2 — reconstitution of Hox transactivation in vitro plus definitive loss-of-function with clear skeletal phenotype, foundational paper with 291 citations","pmids":["7585967"],"is_preprint":false},{"year":2000,"finding":"Cdx1 is a direct transcriptional target of the Wnt/β-catenin signaling pathway; the Cdx1 promoter contains functional TCF/LEF-binding motifs that bind TCF/LEF1/β-catenin complexes and mediate β-catenin-dependent transactivation; Tcf4-deficient mice lose Cdx1 protein in small intestinal epithelium.","method":"Promoter reporter assays, gel shift (EMSA), in vivo Wnt stimulation of ES cells and embryonic endoderm, Tcf4 knockout mice analysis","journal":"Development (Cambridge, England)","confidence":"High","confidence_rationale":"Tier 1-2 — multiple orthogonal methods (reporter assay, EMSA, in vivo genetic model), Strong evidence replicated in subsequent studies","pmids":["10934025"],"is_preprint":false},{"year":2000,"finding":"Cdx1 is a direct retinoic acid (RA) target gene; an atypical RA response element (RARE) in the proximal Cdx1 promoter mediates retinoid-dependent activation, providing an indirect pathway for RA to regulate Hox gene expression and vertebral patterning.","method":"Promoter reporter assay, RARE mutagenesis, retinoid receptor loss-of-function genetics","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 1-2 — promoter mutagenesis and in vivo genetic validation, independently confirmed by RARE-null mouse line in 2003","pmids":["10938132"],"is_preprint":false},{"year":2000,"finding":"Cdx1 inhibits intestinal epithelial cell proliferation by arresting cells in G0/G1, specifically by reducing cyclin D1 and D2 protein levels (without affecting other cyclins or CDK inhibitors), leading to increased hypophosphorylated Rb and p130.","method":"Stable transfection and adenoviral induction of Cdx1 in rat IEC-6 cells, flow cytometry, Western blot for cyclins and Rb","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 — clean inducible system with multiple molecular readouts, specific mechanistic dissection of cyclin targets","pmids":["10660624"],"is_preprint":false},{"year":2001,"finding":"Cdx1 expression is regulated by both Wnt3a signaling (through functional LEF/TCF response elements) and by an autoregulatory loop; Wnt3a and retinoic acid synergize strongly to activate Cdx1, and Cdx1 positively regulates its own expression.","method":"LEF/TCF motif mutagenesis in promoter reporters, Wnt3a hypomorph (vestigial tail) mouse analysis, EMSA, compound mutant analysis","journal":"Developmental biology","confidence":"High","confidence_rationale":"Tier 1-2 — promoter mutagenesis, in vivo genetic model, multiple orthogonal methods","pmids":["11784033"],"is_preprint":false},{"year":2001,"finding":"CDX1 regulates PAP I (Pancreatitis Associated Protein I) gene expression in intestinal cells by directly binding the PAP I promoter; PAP I acts downstream of Cdx1 to promote intestinal cell proliferation via an autocrine/paracrine mechanism.","method":"Stable transfection of Cdx1 in IEC-6 cells, promoter binding/deletion assay, adenoviral PAP I expression, antisense inhibition of PAP I","journal":"European journal of cell biology","confidence":"Medium","confidence_rationale":"Tier 2 — direct promoter binding demonstrated with deletion analysis, functional rescue/antisense experiments, single lab","pmids":["11302520"],"is_preprint":false},{"year":2001,"finding":"Wnt-3a is required for Cdx1 expression in the primitive streak and tail bud; Wnt-3a mutant mice show reduced Cdx1 expression concomitant with vertebral homeotic transformations, placing Wnt-3a upstream of Cdx1 in the axial patterning pathway.","method":"Wnt-3a mutant mouse analysis, in situ hybridization, skeletal phenotyping","journal":"Mechanisms of development","confidence":"High","confidence_rationale":"Tier 2 — genetic epistasis in vivo with clear pathway placement, consistent with complementary studies","pmids":["11335109"],"is_preprint":false},{"year":2001,"finding":"Cdx1 expression in intestinal epithelial IEC-6 cells activates Ras (increased GTP-bound Ras), modulates Cdc42 and RhoA activities, and accumulates PI3-kinase products; combined inhibition of Ras/Rho and PI3K signaling blocked Cdx1-induced anchorage-independent growth and tumorigenesis.","method":"Stable transfection, Ras GTP-loading assay, Rho activity assay, PI3K lipid product measurement, pharmacological inhibition, soft agar and xenograft assays","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 — multiple signaling pathway readouts with functional rescue, single lab","pmids":["11464284"],"is_preprint":false},{"year":2002,"finding":"Cdx1 and Cdx2 double mutants show cooperative anterior homeotic transformations along an extensive vertebral column length and more extensive posterior shifts of Hox gene expression boundaries than single mutants, demonstrating that Cdx1 and Cdx2 cooperate in instructing vertebral progenitors through regulation of Hox gene rostral expression boundaries.","method":"Compound mouse mutant analysis, skeletal phenotyping, Hox gene expression analysis by in situ hybridization","journal":"Development (Cambridge, England)","confidence":"High","confidence_rationale":"Tier 2 — rigorous genetic epistasis with allelic series, strong evidence for cooperative function","pmids":["11959827"],"is_preprint":false},{"year":2002,"finding":"Oncogenic β-catenin/Tcf4 stimulates Cdx1 promoter activity and endogenous Cdx1 mRNA expression in colon cancer cells; conversely, CDX2 inhibits basal and β-catenin-stimulated Cdx1 promoter activity through its homeodomain, acting independently of canonical CDX-binding sites and TCF elements.","method":"Transient transfection of promoter reporters, expression of constitutively active β-catenin, CDX2 homeodomain mutant analysis","journal":"FEBS letters","confidence":"Medium","confidence_rationale":"Tier 3 — promoter reporter assays, single lab, single method","pmids":["11997022"],"is_preprint":false},{"year":2002,"finding":"CDX1 and Cdx2 expression reduces colon cancer cell proliferation, in part by inhibiting β-catenin/TCF transcriptional activity in a dose-dependent manner without altering β-catenin protein levels or intracellular distribution.","method":"Stable transfection of Cdx1/Cdx2 in multiple colon cancer cell lines, TCF reporter assays, β-catenin localization/Western blot, APC(Min/+) mouse polyp analysis","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 — multiple cell lines and in vivo verification, single lab","pmids":["15215241"],"is_preprint":false},{"year":2002,"finding":"Cdx1 regulates apolipoprotein B mRNA editing during intestinal development; Cdx1 overexpression in IEC-6 cells increases apoB mRNA editing more than 10-fold, associated with upregulation of the editing complex component ACF.","method":"Stable transfection of Cdx1 in IEC-6 cells, apoB mRNA editing quantification, ACF protein measurement","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 — clear mechanistic link to editing machinery component, single lab","pmids":["12493769"],"is_preprint":false},{"year":2002,"finding":"Cdx1 belongs to the p53-p21(WAF)-Bcl-2 network in intestinal epithelial cells: wild-type p53 inhibits the Cdx1 promoter; Cdx1 inhibits p21(WAF) promoter activity by binding its TATA-box and activates Bcl-2 promoter P2 through a CDX-binding site, increasing apoptotic resistance.","method":"Promoter reporter assays, EMSA for Cdx1 binding to p21 TATA-box, Bcl-2 Western blot, apoptosis resistance assays in IEC-6/SW480 cells","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 — promoter binding and reporter assays with functional apoptosis readout, single lab","pmids":["12270138"],"is_preprint":false},{"year":2003,"finding":"CDX1 directly binds the TATA-box region of the glucose-6-phosphatase (G6Pase) promoter and transactivates it, unlike CDX2 which binds but does not transactivate; CDX1-specific transactivation requires interaction with the TATA-binding protein (TBP).","method":"EMSA, mutagenesis of CDX-binding sites and TATA box, luciferase reporter assays in HepG2 and CaCo2 cells, stable transfection in IEC-6 cells","journal":"Nucleic acids research","confidence":"High","confidence_rationale":"Tier 1 — in vitro binding assays combined with mutagenesis and functional transactivation, demonstrating CDX1-TBP interaction specificity","pmids":["12954759"],"is_preprint":false},{"year":2003,"finding":"CDX1 is a key mediator of Barrett's metaplasia: conjugated bile salts, TNF-α and IL-1β increase CDX1 mRNA expression primarily through NF-κB signaling, but only when the CDX1 promoter is unmethylated or partially methylated.","method":"CDX1 mRNA quantification in esophageal cell lines after cytokine/bile salt treatment, NF-κB inhibition, promoter methylation analysis","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"Medium","confidence_rationale":"Tier 2 — multiple stimuli tested with pathway inhibition and promoter methylation correlation, single lab","pmids":["15894614"],"is_preprint":false},{"year":2003,"finding":"Retinoic acid regulates Cdx1 expression through an atypical RARE in the proximal promoter; RARE-null mutant mice show reduced Cdx1 expression, vertebral homeotic transformations and altered Hox gene expression, demonstrating that the RARE is required for a subset of Cdx1 function governing vertebral patterning in vivo.","method":"RARE mutagenesis knock-in mice, skeletal phenotyping, Hox gene expression analysis","journal":"Development (Cambridge, England)","confidence":"High","confidence_rationale":"Tier 1 — in vivo RARE mutagenesis with definitive phenotypic and molecular validation","pmids":["14660544"],"is_preprint":false},{"year":2004,"finding":"Cdx1 autoregulation is mediated by a novel complex between the Cdx1 homeodomain and the B box of LEF1; Cdx1 and LEF1 synergize to activate transcription from LEF/TCF response elements in the Cdx1 promoter, and compound Cdx1/Wnt3a(vt) mutants demonstrate convergence of these pathways on Cdx1 expression and vertebral patterning in vivo.","method":"Co-immunoprecipitation, GST pulldown mapping of homeodomain-B box interaction, luciferase reporter assays, Cdx1/Wnt3a compound mutant mouse analysis","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 1-2 — direct protein-protein interaction mapping with in vivo genetic epistasis validation","pmids":["15143193"],"is_preprint":false},{"year":2004,"finding":"CDX1 promoter silencing in colorectal carcinoma is primarily due to promoter CpG hypermethylation; treatment with the demethylating agent 5-aza-2'-deoxycytidine restores CDX1 expression in cell lines with partially methylated promoters.","method":"Promoter methylation analysis by bisulfite sequencing, methylation-specific PCR, 5-aza-2'-deoxycytidine treatment, RT-PCR expression analysis in 37 CRC cell lines","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 — systematic analysis across 37 lines with demethylation rescue, replicated in multiple independent studies","pmids":["14704280"],"is_preprint":false},{"year":2004,"finding":"Cdx1 or Cdx2 expression in COLO 205 colon cancer cells induces E-cadherin-dependent cell-cell adhesion and compaction without changing E-cadherin protein levels; adhesion was Ca2+-dependent and blocked by an anti-E-cadherin antibody, and was associated with acquisition of columnar morphology and differentiation markers.","method":"Stable transfection, E-cadherin blocking antibody, Ca2+ chelation, electron microscopy, immunofluorescence","journal":"American journal of physiology. Gastrointestinal and liver physiology","confidence":"Medium","confidence_rationale":"Tier 2 — functional antibody blocking and Ca2+ dependence establish E-cadherin mechanism, single lab","pmids":["14977637"],"is_preprint":false},{"year":2004,"finding":"CDX1 expression in transgenic mice induces gastric intestinal metaplasia comprising all four intestinal epithelial cell types (including Paneth cells absent from Cdx2-induced metaplasia), with diffuse proliferating cell nuclear antigen (PCNA)-positive cells, demonstrating distinct differentiation and proliferation programs compared to CDX2.","method":"Transgenic mouse model with gastric Cdx1 expression, histology, immunohistochemistry for PCNA and cell-type markers","journal":"Gut","confidence":"High","confidence_rationale":"Tier 2 — in vivo transgenic model with direct comparative analysis vs Cdx2 transgenic, strong functional readout","pmids":["15361487"],"is_preprint":false},{"year":2005,"finding":"COUP-TF transcription factors antagonize RA-induced Cdx1 expression by competing with RXR-RAR heterodimers for binding to the Cdx1 RARE, providing a repressor mechanism that restricts Cdx1 to the caudal embryo.","method":"Promoter reporter competition assays, EMSA, in situ hybridization of COUP-TF and Cdx1 expression domains","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 1-2 — direct competition binding demonstrated by EMSA plus in vivo expression correlation, single lab","pmids":["15677473"],"is_preprint":false},{"year":2006,"finding":"CDX1 physically interacts with the TATA-binding protein (TBP) via its homeodomain, and is connected to TFIID and Mediator complex members; the N-terminal domain is additionally required for transactivation; the C-terminal domain determines the functional specificity between CDX1 and CDX2 through intramolecular interactions.","method":"Co-immunoprecipitation, altered-specificity TBP mutant transcription assay, domain swapping between CDX1 and CDX2, luciferase reporters","journal":"Nucleic acids research","confidence":"High","confidence_rationale":"Tier 1-2 — direct protein interaction mapping with functional validation using altered-specificity mutant, mechanistically rigorous","pmids":["17158164"],"is_preprint":false},{"year":2007,"finding":"Wnt signaling is the primary pathway governing Cdx1 expression in vivo; LRE (LEF/TCF response element)-null mutant mice phenocopy Cdx1-null vertebral defects (affecting the entire cervical region), while RARE-null mutants have limited defects; LRE mutation also ablates RA-induced Cdx1 expression, demonstrating that Wnt signaling is required for RA responsiveness of Cdx1.","method":"Knock-in mice with LRE and/or RARE mutations, skeletal phenotyping, RA treatment, Cdx1 expression analysis","journal":"Development (Cambridge, England)","confidence":"High","confidence_rationale":"Tier 1 — in vivo cis-regulatory element mutagenesis with complete allelic series and definitive phenotypic readout","pmids":["17537796"],"is_preprint":false},{"year":2007,"finding":"CDX1 protein physically interacts with SMAD3 (independently of SMAD4) and inhibits SMAD3/SMAD4-dependent transcription approximately 10-fold, whereas CDX2 interacts with SMAD3 and stimulates its activity approximately 5-fold; this differential interaction explains distinct effects on intestinal inflammation outcome in Cdx1-/- vs Cdx2+/- mice.","method":"Co-immunoprecipitation, GST-pulldown, luciferase reporter assays, DSS-induced colitis model in Cdx1-/- and Cdx2+/- mice","journal":"Gut","confidence":"High","confidence_rationale":"Tier 1-2 — reciprocal co-IP and GST pulldown with functional reporter assays and in vivo genetic phenotype, mechanistically rigorous","pmids":["17595234"],"is_preprint":false},{"year":2007,"finding":"Cdx1 or Cdx2 expression in COLO 205 cells induces E-cadherin-dependent cell-cell adhesion by reducing tyrosine phosphorylation of β-catenin and p120-catenin; restoring β- and p120-catenin tyrosine phosphorylation (by knocking down PTP1B) reversed Cdx-induced cell-cell adhesion.","method":"Stable transfection, co-immunoprecipitation of E-cadherin/catenin complexes, phospho-tyrosine immunoprecipitation, PTP1B siRNA knockdown, migration/invasion assays","journal":"American journal of physiology. Gastrointestinal and liver physiology","confidence":"Medium","confidence_rationale":"Tier 2 — phosphorylation mechanism validated by rescue with siRNA, single lab","pmids":["17463179"],"is_preprint":false},{"year":2008,"finding":"CDX1 expression in cultured esophageal squamous epithelial cells induces Cdx2 protein production; in a Barrett's rat model (esophago-jejunal anastomosis), bile acids dose-dependently increase Cdx1 promoter activity and protein expression, suggesting a sequential Cdx1→Cdx2 cascade in Barrett's epithelium development.","method":"Cdx1 promoter luciferase assay, bile acid treatment, transfection of Cdx1 expression vector in esophageal cells, rat Barrett's model, immunohistochemistry","journal":"Gut","confidence":"Medium","confidence_rationale":"Tier 2 — promoter assay plus in vivo rat model with direct cellular induction experiment, single lab","pmids":["19136512"],"is_preprint":false},{"year":2008,"finding":"CDX1 transactivates the COX-2 gene in gastric cancer cells; bile acid induction of CDX1 is mediated by the orphan nuclear receptor SHP, establishing a SHP→CDX1→COX-2 sequential transcriptional cascade.","method":"Transfection/overexpression assays, COX-2 reporter, CDX1 promoter assay, SHP siRNA/overexpression","journal":"Carcinogenesis","confidence":"Medium","confidence_rationale":"Tier 2 — sequential pathway placement with reporter assays and RNAi, single lab","pmids":["18775915"],"is_preprint":false},{"year":2008,"finding":"Cdx1 and c-Myc cooperate to induce mucin production and changes in keratin expression characteristic of Barrett's esophagus in immortalized human esophageal keratinocytes grown in organotypic culture.","method":"Organotypic culture, microarray-guided candidate identification, retroviral expression of Cdx1 and c-Myc, immunostaining for mucins and keratins","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 — organotypic culture with cooperative functional readout, single lab","pmids":["18953412"],"is_preprint":false},{"year":2009,"finding":"CDX1 directly regulates Keratin 20 (KRT20) expression: CDX1 binds CDX elements within 246 bp upstream of the KRT20 transcription start site (confirmed by ChIP), and deletion/mutation of these elements abolishes CDX1-dependent KRT20 promoter activity.","method":"Microarray analysis, promoter deletion and mutation analysis, ChIP, immunohistochemistry, expression correlation across 38 CRC cell lines","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1-2 — ChIP plus promoter mutagenesis plus in vivo expression correlation, multiple orthogonal methods","pmids":["19188603"],"is_preprint":false},{"year":2008,"finding":"CDX1 promotes intestinal differentiation by activating PPARγ gene expression through functional interaction with C/EBPα; butyrate increases CDX1-C/EBPα protein interaction, leading to enhanced PPARγ expression.","method":"Co-immunoprecipitation, CDX1/C/EBPα co-transfection with PPARγ reporter, butyrate treatment, Western blot","journal":"FEBS letters","confidence":"Medium","confidence_rationale":"Tier 2 — direct protein interaction and functional reporter assay, single lab","pmids":["19059241"],"is_preprint":false},{"year":2009,"finding":"Cdx2 binds the Cdx1 promoter region in intestinal metaplasia (demonstrated by ChIP and EMSA) and upregulates Cdx1 transcription; siRNA-mediated Cdx2 knockdown reduces Cdx1 promoter activity; the Cdx1 promoter is unmethylated in Cdx2-transgenic mouse intestinal metaplasia.","method":"ChIP, EMSA, luciferase reporter assay, siRNA knockdown of Cdx2, bisulfite sequencing of Cdx1 promoter","journal":"The FEBS journal","confidence":"High","confidence_rationale":"Tier 1-2 — multiple orthogonal methods (ChIP, EMSA, reporter, siRNA) in one study","pmids":["19725873"],"is_preprint":false},{"year":2009,"finding":"Cdx2 substituted for Cdx1 in a knock-in model perfectly complements the Cdx1-null skeletal phenotype and Hox gene expression, demonstrating functional redundancy between Cdx1 and Cdx2 for vertebral anteroposterior patterning.","method":"Cdx2 knock-in at Cdx1 locus, skeletal phenotyping, Hox gene expression analysis","journal":"Developmental biology","confidence":"High","confidence_rationale":"Tier 1 — definitive genetic replacement experiment with complete phenotypic rescue","pmids":["19328777"],"is_preprint":false},{"year":2010,"finding":"Cdx1 directly represses Mafb expression in the neural tube posterior to the r6/r7 boundary, thereby refining hindbrain patterning; Cdx1 binds regulatory sequences of the Mafb gene as demonstrated by ChIP and in situ hybridization, establishing Mafb as a direct early target of Cdx1.","method":"ChIP, immunofluorescence, in situ hybridization, identification of Mafb regulatory sequences responsive to Cdx1","journal":"Development (Cambridge, England)","confidence":"High","confidence_rationale":"Tier 1-2 — ChIP demonstrating direct binding plus functional in vivo genetics","pmids":["21098558"],"is_preprint":false},{"year":2011,"finding":"CDX1 regulates the ASBT (apical sodium-dependent bile acid transporter) gene; CDX1 binds to six of nine predicted CDX binding sites in the ASBT promoter (verified by EMSA and ChIP in living cells), strongly induces ASBT promoter activity in reporter assays, and CDX1 siRNA knockdown reduces ASBT mRNA in intestinal cells.","method":"ChIP, EMSA, luciferase reporter assay, siRNA knockdown, correlation analysis in Barrett's esophagus biopsies","journal":"American journal of physiology. Gastrointestinal and liver physiology","confidence":"High","confidence_rationale":"Tier 1-2 — multiple orthogonal methods including in-cell ChIP and in vitro binding, single lab","pmids":["22016432"],"is_preprint":false},{"year":2012,"finding":"Oxidative stress (H2O2) silences CDX1 in colorectal cancer cells through epigenetic mechanisms: ROS upregulates DNMT1 and HDAC1 expression and activity, enhances DNMT1-HDAC1 association, and increases CDX1 promoter methylation; 5-aza-2'-deoxycytidine reverses these effects.","method":"H2O2 treatment, MSP, RT-PCR, Western blot, DNMT1/HDAC1 activity assays, N-acetylcysteine rescue, 5-aza-dC reversal","journal":"Gene","confidence":"Medium","confidence_rationale":"Tier 2 — multiple molecular mechanisms demonstrated with chemical rescue, single lab","pmids":["23618814"],"is_preprint":false},{"year":2012,"finding":"CDX1 directly activates SALL4 and KLF5 expression in gastric epithelial cells; CDX1-induced SALL4 and KLF5 convert gastric epithelial cells into intestinal stem-like progenitor cells, which then transdifferentiate into intestinal epithelial cells; inhibiting SALL4 or KLF5 suppresses CDX1-induced intestinal differentiation markers.","method":"Gene expression profiling (microarray), siRNA knockdown of SALL4 and KLF5, stable CDX1 expression in gastric epithelial cells, immunohistochemistry in human and mouse IM specimens","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 — genome-wide target identification with RNAi-based functional validation and in vivo tissue confirmation","pmids":["23112162"],"is_preprint":false},{"year":2012,"finding":"NF-κB binding to the CDX1 promoter is methylation-dependent; a methylated CDX1 promoter is associated with closed chromatin structure and reduced NF-κB binding; competitive EMSA and ChIP quantified this interaction, and along the gastritis-metaplasia-carcinoma sequence, CDX1 promoter methylation pattern inversely correlates with NF-κB signaling activity.","method":"Competitive EMSA, ChIP, bisulfite sequencing, TNF-α protein expression analysis across gastric tissue stages","journal":"The American journal of pathology","confidence":"Medium","confidence_rationale":"Tier 2 — ChIP and EMSA demonstrating methylation-sensitive transcription factor binding, single lab","pmids":["22749770"],"is_preprint":false},{"year":2012,"finding":"Cdx1 induces multiple microRNAs (miR-9, miR-16, miR-22) in colorectal tumor cells that directly bind the CDX2 mRNA 3'UTR and destabilize it; simultaneous mutation of miR-9 and miR-16 binding sites in CDX2 3'UTR was sufficient to block Cdx2 suppression by Cdx1.","method":"Microarray miRNA profiling, 3'UTR luciferase reporter with CDX2 binding-site mutations, stable Cdx1 transfection in SW480 cells","journal":"The Biochemical journal","confidence":"Medium","confidence_rationale":"Tier 2 — 3'UTR mutagenesis with functional validation, single lab","pmids":["22849325"],"is_preprint":false},{"year":2012,"finding":"Cdx1 directly binds to conserved CDX-binding sites within the HoxC8 early enhancer during Xenopus embryogenesis (demonstrated by ChIP), and Cdx1 overexpression or knockdown causes precocious or delayed HoxC8 expression respectively; differential binding affinity to multiple CDX sites may contribute to the temporal control of Hox activation.","method":"Xenopus Cdx1 overexpression and morpholino knockdown, mouse HoxC8 early enhancer reporter in Xenopus, ChIP, mutagenesis of Cdx binding sites","journal":"FASEB journal : official publication of the Federation of American Societies for Experimental Biology","confidence":"High","confidence_rationale":"Tier 1-2 — ChIP demonstrating direct in vivo binding plus loss/gain of function with enhancer mutagenesis","pmids":["22426122"],"is_preprint":false},{"year":2013,"finding":"CDX1 exhibits context-dependent transcriptional specificity: in intestinal cells, CDX2 is significantly less potent than CDX1 at activating the Cdx1 promoter autoregulatory response, and in vivo, CDX2 cannot substitute for CDX1 in the autoregulatory loop (unlike in paraxial mesoderm/vertebral patterning), demonstrated by a gene swap approach.","method":"Cell-based promoter reporter assay comparing Cdx1 vs Cdx2 potency, in vivo gene swap knock-in model","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 — in vivo genetic swap combined with cell-based assay, single lab","pmids":["23382958"],"is_preprint":false},{"year":2014,"finding":"Combined somatic loss of Cdx2 and the Cdx1 null allele in APC(Min/+) mice significantly increases the incidence of tumors in the distal colon relative to APC(Min/+)-Cdx2 mutants alone, demonstrating that Cdx1 functions as a tumor suppressor specifically in the distal colon.","method":"Conditional somatic Cdx2 deletion combined with Cdx1 null allele in APC(Min/+) background, tumor quantification by location","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 — compound genetic mouse model with site-specific tumor phenotype, clear epistatic relationship","pmids":["25320087"],"is_preprint":false},{"year":2014,"finding":"CDX1 restricts invasion of HTR-8/SVneo trophoblast cells by inhibiting MMP-9 expression and increasing TIMP-1 expression, independently of the PI3K/AKT signaling pathway; however, CDX1 itself is regulated by PI3K/AKT signaling.","method":"Stable CDX1 transfection, invasion assay (QCM ECMatrix kit), RT-PCR and Western blot for MMP-9/TIMP-1, PI3K inhibitor (perifosine) treatment","journal":"Placenta","confidence":"Medium","confidence_rationale":"Tier 2 — functional invasion assay with molecular target identification and pathway inhibition, single lab","pmids":["24836459"],"is_preprint":false},{"year":2014,"finding":"Transient CDX1 expression in embryonic epicardium promotes epithelial-to-mesenchymal transition (EMT) and migration/differentiation of epicardium-derived cells into α-SMA+ vascular smooth muscle; sustained high-level CDX1 or CDX1 deficiency both attenuate this process, and CDX1 induction alters transcript levels of genes involved in neuronal development, angiogenesis, and cell adhesion.","method":"Doxycycline-inducible CDX1 mouse model, primary epicardium culture, ex vivo heart culture, RNA-seq, α-SMA immunostaining, Cdx1 knockout comparison","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 — inducible in vivo model with loss/gain of function and transcriptomic analysis, single lab","pmids":["25068460"],"is_preprint":false},{"year":2015,"finding":"CDX1 directly activates miR-215 transcription (confirmed by ChIP-PCR and promoter luciferase assay); miR-215 mediates repression of cell cycle and stemness genes downstream of CDX1, including the stemness gene BMI1, linking CDX1 to colorectal cancer stem cell differentiation.","method":"Small RNA sequencing, ChIP-PCR, promoter luciferase assay, miR-215 overexpression/knockdown, FACS-enriched cancer stem cell comparison, clonogenicity assays","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1-2 — ChIP plus luciferase validation plus functional miRNA assays, multiple orthogonal methods","pmids":["25775580"],"is_preprint":false},{"year":2022,"finding":"EHF physically interacts with CDX1 via the EHF PNT domain; EHF and CDX1 co-operatively drive transcription of the colonic differentiation marker VIL1; compound genetic deletion of Ehf and Cdx1 in the mouse colon disrupts normal colonic differentiation and enhances colorectal tumour progression.","method":"Co-immunoprecipitation identifying EHF-CDX1 interaction, VIL1 promoter reporter co-transfection, compound Ehf/Cdx1 conditional knockout mouse, chromatin remodeling assays, transcriptional profiling","journal":"Cell death and differentiation","confidence":"High","confidence_rationale":"Tier 1-2 — direct protein interaction identified by Co-IP with in vivo genetic compound knockout validation and functional co-operative transcription assay","pmids":["35606410"],"is_preprint":false}],"current_model":"CDX1 is a homeodomain transcription factor that directly regulates Hox gene expression (establishing anterior-posterior vertebral patterning) and intestinal differentiation gene programs; it is transcriptionally activated by Wnt/β-catenin signaling (via LEF/TCF elements), retinoic acid (via a proximal RARE), and an autoregulatory loop requiring a CDX1-LEF1 protein complex; it physically interacts with TBP/TFIID/Mediator to transactivate specific targets (e.g., KRT20, G6Pase, miR-215, SALL4, KLF5), inhibits β-catenin/TCF transcriptional output to restrain proliferation (partly by reducing cyclin D1/D2), represses Mafb in the hindbrain, and is epigenetically silenced by promoter CpG hypermethylation in colorectal cancer; it also modulates SMAD3 transcriptional activity (opposing CDX2) and interacts with EHF to co-operatively drive colonic differentiation."},"narrative":{"teleology":[{"year":1995,"claim":"Establishing that CDX1 is a direct upstream regulator of Hox gene expression and vertebral identity resolved how caudal-type homeobox genes connect to the vertebral patterning code.","evidence":"Cdx1 knockout mice showing anterior homeotic transformations and posterior shifts in Hox expression, plus in vitro transactivation of Hoxa-7","pmids":["7585967"],"confidence":"High","gaps":["Mechanism by which Cdx1 selects specific Hox targets was unknown","Redundancy with other Cdx family members was untested","Whether Cdx1 regulates Hox genes directly via enhancer binding in vivo was not shown"]},{"year":2000,"claim":"Identification of Wnt/β-catenin and retinoic acid as the two major upstream signals directly activating Cdx1 transcription placed Cdx1 at a signaling node integrating morphogen inputs for axial patterning.","evidence":"Functional LEF/TCF elements and an atypical RARE in the Cdx1 promoter demonstrated by reporter assays, EMSA, and Tcf4-null mice losing Cdx1 expression","pmids":["10934025","10938132"],"confidence":"High","gaps":["Relative contribution of Wnt vs RA to Cdx1 expression in vivo was unclear","Whether the two inputs are independent or synergistic in vivo was unresolved"]},{"year":2000,"claim":"Demonstrating that Cdx1 inhibits intestinal cell proliferation by specifically reducing cyclin D1/D2 established a growth-suppressive function distinct from its patterning role.","evidence":"Inducible Cdx1 expression in IEC-6 cells causing G0/G1 arrest with specific cyclin D1/D2 reduction","pmids":["10660624"],"confidence":"High","gaps":["Whether cyclin D reduction is transcriptionally direct was unknown","Relationship to Cdx1's effect on β-catenin/TCF output was not connected"]},{"year":2001,"claim":"Genetic epistasis showing Wnt3a is required upstream of Cdx1 for vertebral patterning, combined with demonstration of Wnt/RA synergy and Cdx1 autoregulation, defined the signaling hierarchy and positive feedback loop maintaining Cdx1 expression.","evidence":"Wnt3a mutant mice with reduced Cdx1 and homeotic transformations; LEF/TCF mutagenesis and autoregulatory loop demonstration in reporters","pmids":["11335109","11784033"],"confidence":"High","gaps":["Molecular mechanism of autoregulation (direct or indirect) was unresolved","Whether autoregulation requires a Cdx1–LEF1 protein complex was unknown"]},{"year":2002,"claim":"Compound Cdx1/Cdx2 mutant analysis demonstrated cooperative, dose-dependent regulation of Hox boundaries along the entire vertebral column, establishing functional redundancy between the two paralogues.","evidence":"Cdx1/Cdx2 double-mutant mice with extensive homeotic transformations exceeding single mutants","pmids":["11959827"],"confidence":"High","gaps":["Whether functional equivalence is complete or context-dependent was untested","Cdx4 contribution was not assessed"]},{"year":2002,"claim":"Showing that CDX1 inhibits β-catenin/TCF transcriptional activity without affecting β-catenin levels identified a negative feedback mechanism whereby a Wnt target gene restrains the Wnt output.","evidence":"Stable CDX1 expression in multiple colon cancer lines reducing TCF reporter activity dose-dependently; APC(Min/+) polyp analysis","pmids":["15215241"],"confidence":"Medium","gaps":["Direct molecular mechanism of β-catenin/TCF inhibition by CDX1 was not identified","Whether this involves direct protein interaction with TCF was unknown"]},{"year":2003,"claim":"Mapping the CDX1 homeodomain–TBP interaction and its requirement for G6Pase transactivation revealed how CDX1 mechanistically engages the basal transcription machinery, distinguishing it from CDX2.","evidence":"EMSA, TATA-box mutagenesis, and luciferase reporters showing CDX1-specific TBP-dependent transactivation of G6Pase","pmids":["12954759"],"confidence":"High","gaps":["Structural basis of CDX1–TBP interaction was not determined","Whether Mediator engagement is direct was unresolved"]},{"year":2004,"claim":"Discovery that CDX1 autoregulation operates through a direct CDX1 homeodomain–LEF1 B-box protein complex explained how Wnt signaling and CDX1 converge on a single cis-regulatory element for self-sustaining expression.","evidence":"Co-IP and GST pulldown mapping the interaction domains; compound Cdx1/Wnt3a(vt) mutant genetic validation","pmids":["15143193"],"confidence":"High","gaps":["Whether the CDX1–LEF1 complex recruits distinct co-activators was unknown","Crystal structure of the complex was not obtained"]},{"year":2004,"claim":"Demonstrating frequent CDX1 promoter hypermethylation in colorectal cancer with demethylation-dependent rescue of expression established an epigenetic silencing mechanism contributing to loss of CDX1 tumor suppression.","evidence":"Bisulfite sequencing and MSP across 37 CRC cell lines; 5-aza-2′-deoxycytidine restoring CDX1 expression","pmids":["14704280"],"confidence":"High","gaps":["Causal relationship between methylation-driven CDX1 loss and tumor progression was not established in vivo","Which DNA methyltransferases are responsible was not identified"]},{"year":2004,"claim":"Transgenic CDX1 expression in stomach generating complete intestinal metaplasia including Paneth cells showed CDX1 is sufficient to specify all four intestinal cell lineages, revealing a broader differentiation capacity than CDX2.","evidence":"Gastric CDX1-transgenic mice producing goblet, absorptive, enteroendocrine, and Paneth cells","pmids":["15361487"],"confidence":"High","gaps":["Whether CDX1 directly activates lineage-specific transcription factors was unknown","Mechanism distinguishing CDX1 from CDX2 in Paneth cell specification was unresolved"]},{"year":2007,"claim":"In vivo cis-regulatory dissection showed that the LEF/TCF response element is the primary determinant of Cdx1 expression and vertebral patterning, subordinating the RARE input, and that RA responsiveness itself requires intact Wnt signaling through the LRE.","evidence":"LRE-null and RARE-null knock-in mice; LRE mutation phenocopies Cdx1-null while RARE mutation produces limited defects","pmids":["17537796"],"confidence":"High","gaps":["How Wnt signaling gates RA responsiveness mechanistically was not explained","Other cis-elements contributing to Cdx1 regulation in non-mesodermal tissues were not tested"]},{"year":2007,"claim":"Identifying CDX1 as a physical interactor and inhibitor of SMAD3-dependent transcription (opposing CDX2's stimulatory effect) revealed a mechanism for differential TGF-β/BMP pathway modulation by the two CDX paralogues.","evidence":"Reciprocal co-IP and GST pulldown; 10-fold inhibition of SMAD3/SMAD4 reporters by CDX1; DSS colitis in Cdx1-null mice","pmids":["17595234"],"confidence":"High","gaps":["Whether SMAD3 interaction competes with TBP binding was unknown","In vivo relevance to intestinal homeostasis beyond inflammation was not established"]},{"year":2009,"claim":"Cdx2 knock-in at the Cdx1 locus fully rescuing the skeletal phenotype demonstrated complete functional equivalence for vertebral patterning, proving that expression differences rather than protein divergence account for non-redundancy.","evidence":"Cdx2 knock-in replacing Cdx1 coding region; complete rescue of vertebral transformations and Hox expression","pmids":["19328777"],"confidence":"High","gaps":["Whether equivalence extends to intestinal functions was not tested","Endogenous Cdx2 was still present, complicating interpretation of dosage effects"]},{"year":2010,"claim":"Showing Cdx1 directly represses Mafb in the hindbrain expanded CDX1's known role from mesoderm to neural tube patterning and identified a direct transcriptional repression target.","evidence":"ChIP demonstrating Cdx1 binding to Mafb regulatory sequences; altered Mafb expression in Cdx1-null neural tube","pmids":["21098558"],"confidence":"High","gaps":["Mechanism of repression (co-repressor recruitment) was not identified","Other neural tube targets of Cdx1 were not catalogued"]},{"year":2012,"claim":"Identification of SALL4 and KLF5 as direct CDX1 target genes that convert gastric cells into intestinal stem-like progenitors provided a molecular mechanism for CDX1-driven intestinal metaplasia.","evidence":"Microarray, siRNA knockdown of SALL4/KLF5 suppressing CDX1-induced intestinal markers in gastric cells; confirmation in human/mouse IM specimens","pmids":["23112162"],"confidence":"High","gaps":["Whether CDX1 binds SALL4 and KLF5 promoters directly (ChIP) was not shown","Sufficiency of SALL4/KLF5 without CDX1 was not tested"]},{"year":2014,"claim":"Compound Cdx1/Cdx2 loss in APC(Min/+) mice increasing distal colon tumors provided definitive in vivo genetic evidence that CDX1 functions as a tumor suppressor cooperating with CDX2 specifically in the distal colon.","evidence":"Conditional somatic Cdx2 deletion combined with Cdx1-null in APC(Min/+) mice; site-specific tumor quantification","pmids":["25320087"],"confidence":"High","gaps":["Molecular targets mediating tumor suppression in distal colon were not identified","Whether CDX1 tumor suppression is cell-autonomous was not established"]},{"year":2015,"claim":"Demonstrating CDX1 directly activates miR-215 transcription, which in turn represses stemness genes including BMI1, connected CDX1's differentiation-promoting activity to a microRNA effector pathway in colorectal cancer stem cells.","evidence":"ChIP-PCR and promoter luciferase for CDX1 binding to miR-215 locus; miR-215 overexpression/knockdown in FACS-enriched cancer stem cells","pmids":["25775580"],"confidence":"High","gaps":["Full spectrum of miR-215 targets downstream of CDX1 was not determined","In vivo validation of CDX1–miR-215–BMI1 axis in tumors was lacking"]},{"year":2022,"claim":"Identification of EHF as a direct CDX1 interaction partner that cooperatively drives colonic differentiation gene expression (VIL1) and suppresses tumorigenesis revealed a new co-factor axis for CDX1 function in the colon.","evidence":"Co-IP of EHF–CDX1 via PNT domain; VIL1 promoter co-activation; compound Ehf/Cdx1 knockout mice with disrupted colonic differentiation and enhanced tumor progression","pmids":["35606410"],"confidence":"High","gaps":["Genome-wide co-occupancy of EHF and CDX1 was not mapped","Whether EHF modifies CDX1's interaction with TBP/Mediator is unknown"]},{"year":null,"claim":"A genome-wide map of direct CDX1 chromatin occupancy in normal intestinal epithelium is lacking, and the structural basis for CDX1's selective interactions with TBP, LEF1, SMAD3, and EHF — and how these are coordinated on different promoters — remains unresolved.","evidence":"","pmids":[],"confidence":"High","gaps":["No genome-wide ChIP-seq for CDX1 in normal intestine has been reported","No crystal or cryo-EM structure of CDX1 or its complexes exists","How CDX1 selectively activates versus represses targets (e.g., Hox activation vs Mafb repression) is mechanistically unexplained"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0003677","term_label":"DNA binding","supporting_discovery_ids":[0,13,28,32,33,38]},{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[0,13,21,28,35,43,44]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[13,16,21]}],"pathway":[{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[0,8,15,22,31,32]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[1,4,6,22,23]},{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[13,21,28,35,43,44]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[17,34,40]}],"complexes":[],"partners":["LEF1","TBP","SMAD3","EHF","CEBPA","CTNNB1"],"other_free_text":[]},"mechanistic_narrative":"CDX1 is a homeodomain transcription factor that governs anterior-posterior vertebral patterning and intestinal epithelial differentiation by directly regulating Hox gene expression boundaries and intestinal-specific gene programs. CDX1 is transcriptionally activated by Wnt/β-catenin signaling through LEF/TCF response elements (the dominant input in vivo) and by retinoic acid through a proximal RARE, and sustains its own expression via an autoregulatory loop requiring a CDX1–LEF1 protein complex [PMID:10934025, PMID:14660544, PMID:17537796, PMID:15143193]. It transactivates target genes (including KRT20, G6Pase, SALL4, KLF5, and miR-215) through its homeodomain-mediated interaction with TBP/TFIID and cooperation with partners such as C/EBPα and EHF, while restraining proliferation by inhibiting β-catenin/TCF transcriptional output, reducing cyclin D1/D2, and activating differentiation-promoting microRNAs [PMID:12954759, PMID:17158164, PMID:10660624, PMID:25775580, PMID:35606410]. CDX1 functions as a tumor suppressor in the distal colon, where its promoter is frequently silenced by CpG hypermethylation in colorectal carcinoma, and its loss cooperates with APC and Cdx2 mutations to promote tumorigenesis [PMID:14704280, PMID:25320087]."},"prefetch_data":{"uniprot":{"accession":"P47902","full_name":"Homeobox protein CDX-1","aliases":["Caudal-type homeobox protein 1"],"length_aa":265,"mass_kda":28.1,"function":"Plays a role in transcriptional regulation (PubMed:24623306). Involved in activated KRAS-mediated transcriptional activation of PRKD1 in colorectal cancer (CRC) cells (PubMed:24623306). Binds to the PRKD1 promoter in colorectal cancer (CRC) cells (PubMed:24623306). Could play a role in the terminal differentiation of the intestine. Binds preferentially to methylated DNA (PubMed:28473536)","subcellular_location":"Nucleus","url":"https://www.uniprot.org/uniprotkb/P47902/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/CDX1","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/CDX1","total_profiled":1310},"omim":[{"mim_id":"614266","title":"BARRETT ESOPHAGUS","url":"https://www.omim.org/entry/614266"},{"mim_id":"606847","title":"TREACLE RIBOSOME BIOGENESIS FACTOR 1; TCOF1","url":"https://www.omim.org/entry/606847"},{"mim_id":"600746","title":"CAUDAL-TYPE HOMEOBOX TRANSCRIPTION FACTOR 1; CDX1","url":"https://www.omim.org/entry/600746"},{"mim_id":"600297","title":"CAUDAL-TYPE HOMEOBOX TRANSCRIPTION FACTOR 2; CDX2","url":"https://www.omim.org/entry/600297"},{"mim_id":"300520","title":"CLAUDIN 2; CLDN2","url":"https://www.omim.org/entry/300520"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Tissue enriched","tissue_distribution":"Detected in some","driving_tissues":[{"tissue":"intestine","ntpm":93.3}],"url":"https://www.proteinatlas.org/search/CDX1"},"hgnc":{"alias_symbol":[],"prev_symbol":[]},"alphafold":{"accession":"P47902","domains":[{"cath_id":"1.10.10.60","chopping":"159-220","consensus_level":"medium","plddt":96.4918,"start":159,"end":220}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P47902","model_url":"https://alphafold.ebi.ac.uk/files/AF-P47902-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P47902-F1-predicted_aligned_error_v6.png","plddt_mean":66.69},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=CDX1","jax_strain_url":"https://www.jax.org/strain/search?query=CDX1"},"sequence":{"accession":"P47902","fasta_url":"https://rest.uniprot.org/uniprotkb/P47902.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P47902/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P47902"}},"corpus_meta":[{"pmid":"11040183","id":"PMC_11040183","title":"Cdx1 and cdx2 expression during intestinal development.","date":"2000","source":"Gastroenterology","url":"https://pubmed.ncbi.nlm.nih.gov/11040183","citation_count":506,"is_preprint":false},{"pmid":"7585967","id":"PMC_7585967","title":"Disruption of the murine homeobox gene Cdx1 affects axial skeletal identities by altering the mesodermal expression domains of Hox genes.","date":"1995","source":"Cell","url":"https://pubmed.ncbi.nlm.nih.gov/7585967","citation_count":291,"is_preprint":false},{"pmid":"11959827","id":"PMC_11959827","title":"Cdx1 and Cdx2 have overlapping functions in anteroposterior patterning and posterior axis elongation.","date":"2002","source":"Development (Cambridge, England)","url":"https://pubmed.ncbi.nlm.nih.gov/11959827","citation_count":238,"is_preprint":false},{"pmid":"12474224","id":"PMC_12474224","title":"Expression of intestine-specific transcription factors, CDX1 and CDX2, in intestinal metaplasia and gastric carcinomas.","date":"2003","source":"The Journal of pathology","url":"https://pubmed.ncbi.nlm.nih.gov/12474224","citation_count":236,"is_preprint":false},{"pmid":"9036867","id":"PMC_9036867","title":"Molecular cloning, sequencing and expression of the mRNA encoding human Cdx1 and Cdx2 homeobox. Down-regulation of Cdx1 and Cdx2 mRNA expression during colorectal carcinogenesis.","date":"1997","source":"International journal of cancer","url":"https://pubmed.ncbi.nlm.nih.gov/9036867","citation_count":188,"is_preprint":false},{"pmid":"10934025","id":"PMC_10934025","title":"Wnt/(beta)-catenin signaling regulates the expression of the homeobox gene Cdx1 in embryonic intestine.","date":"2000","source":"Development (Cambridge, England)","url":"https://pubmed.ncbi.nlm.nih.gov/10934025","citation_count":186,"is_preprint":false},{"pmid":"7900985","id":"PMC_7900985","title":"Mouse Cdx-1 expression during gastrulation.","date":"1993","source":"Development (Cambridge, England)","url":"https://pubmed.ncbi.nlm.nih.gov/7900985","citation_count":175,"is_preprint":false},{"pmid":"10392709","id":"PMC_10392709","title":"The Cdx-1 and Cdx-2 homeobox genes in the intestine.","date":"1998","source":"Biochemistry and cell biology = Biochimie et biologie cellulaire","url":"https://pubmed.ncbi.nlm.nih.gov/10392709","citation_count":170,"is_preprint":false},{"pmid":"9593754","id":"PMC_9593754","title":"Expression of the Cdx1 and Cdx2 homeotic genes leads to reduced malignancy in colon cancer-derived cells.","date":"1998","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/9593754","citation_count":151,"is_preprint":false},{"pmid":"11871772","id":"PMC_11871772","title":"Expression of homeobox gene CDX2 precedes that of CDX1 during the progression of intestinal metaplasia.","date":"2002","source":"Journal of gastroenterology","url":"https://pubmed.ncbi.nlm.nih.gov/11871772","citation_count":138,"is_preprint":false},{"pmid":"15361487","id":"PMC_15361487","title":"Cdx1 induced intestinal metaplasia in the transgenic mouse stomach: comparative study with Cdx2 transgenic mice.","date":"2004","source":"Gut","url":"https://pubmed.ncbi.nlm.nih.gov/15361487","citation_count":117,"is_preprint":false},{"pmid":"11335109","id":"PMC_11335109","title":"Wnt-3a is required for somite specification along the anteroposterior axis of the mouse embryo and for regulation of cdx-1 expression.","date":"2001","source":"Mechanisms of development","url":"https://pubmed.ncbi.nlm.nih.gov/11335109","citation_count":116,"is_preprint":false},{"pmid":"14655050","id":"PMC_14655050","title":"Down-regulation of a gastric transcription factor, Sox2, and ectopic expression of intestinal homeobox genes, Cdx1 and Cdx2: inverse correlation during progression from gastric/intestinal-mixed to complete intestinal metaplasia.","date":"2003","source":"Journal of cancer research and clinical oncology","url":"https://pubmed.ncbi.nlm.nih.gov/14655050","citation_count":116,"is_preprint":false},{"pmid":"14505364","id":"PMC_14505364","title":"The Cdx1 homeodomain protein: an integrator of posterior signaling in the mouse.","date":"2003","source":"BioEssays : news and reviews in molecular, cellular and developmental biology","url":"https://pubmed.ncbi.nlm.nih.gov/14505364","citation_count":109,"is_preprint":false},{"pmid":"23112162","id":"PMC_23112162","title":"CDX1 confers intestinal phenotype on gastric epithelial cells via induction of stemness-associated reprogramming factors SALL4 and KLF5.","date":"2012","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/23112162","citation_count":108,"is_preprint":false},{"pmid":"10579974","id":"PMC_10579974","title":"Cdx1 promotes differentiation in a rat intestinal epithelial cell line.","date":"1999","source":"Gastroenterology","url":"https://pubmed.ncbi.nlm.nih.gov/10579974","citation_count":100,"is_preprint":false},{"pmid":"29550489","id":"PMC_29550489","title":"Long non-coding RNA XIST inhibited breast cancer cell growth, migration, and invasion via miR-155/CDX1 axis.","date":"2018","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/29550489","citation_count":97,"is_preprint":false},{"pmid":"19188603","id":"PMC_19188603","title":"Gastrointestinal differentiation marker Cytokeratin 20 is regulated by homeobox gene CDX1.","date":"2009","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/19188603","citation_count":95,"is_preprint":false},{"pmid":"18953412","id":"PMC_18953412","title":"Cdx1 and c-Myc foster the initiation of transdifferentiation of the normal esophageal squamous epithelium toward Barrett's esophagus.","date":"2008","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/18953412","citation_count":95,"is_preprint":false},{"pmid":"25775580","id":"PMC_25775580","title":"The CDX1-microRNA-215 axis regulates colorectal cancer stem cell differentiation.","date":"2015","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/25775580","citation_count":90,"is_preprint":false},{"pmid":"15894614","id":"PMC_15894614","title":"CDX1 is an important molecular mediator of Barrett's metaplasia.","date":"2005","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/15894614","citation_count":88,"is_preprint":false},{"pmid":"11784033","id":"PMC_11784033","title":"Multiple pathways governing Cdx1 expression during murine development.","date":"2001","source":"Developmental biology","url":"https://pubmed.ncbi.nlm.nih.gov/11784033","citation_count":84,"is_preprint":false},{"pmid":"10938132","id":"PMC_10938132","title":"Retinoic acid regulation of Cdx1: an indirect mechanism for retinoids and vertebral specification.","date":"2000","source":"Molecular and cellular biology","url":"https://pubmed.ncbi.nlm.nih.gov/10938132","citation_count":82,"is_preprint":false},{"pmid":"11846061","id":"PMC_11846061","title":"Expression of Cdx1 and Cdx2 mRNAs and relevance of this expression to differentiation in human gastrointestinal mucosa--with special emphasis on participation in intestinal metaplasia of the human stomach.","date":"2001","source":"Gastric cancer : official journal of the International Gastric Cancer Association and the Japanese Gastric Cancer Association","url":"https://pubmed.ncbi.nlm.nih.gov/11846061","citation_count":80,"is_preprint":false},{"pmid":"9921649","id":"PMC_9921649","title":"The murine Cdx1 gene product localises to the proliferative compartment in the developing and regenerating intestinal epithelium.","date":"1998","source":"Differentiation; research in biological diversity","url":"https://pubmed.ncbi.nlm.nih.gov/9921649","citation_count":75,"is_preprint":false},{"pmid":"23185413","id":"PMC_23185413","title":"Whole-transcriptome sequencing identifies novel IRF2BP2-CDX1 fusion gene brought about by translocation t(1;5)(q42;q32) in mesenchymal chondrosarcoma.","date":"2012","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/23185413","citation_count":74,"is_preprint":false},{"pmid":"26537799","id":"PMC_26537799","title":"N-glycosylation Profiling of Colorectal Cancer Cell Lines Reveals Association of Fucosylation with Differentiation and Caudal Type Homebox 1 (CDX1)/Villin mRNA Expression.","date":"2015","source":"Molecular & cellular proteomics : MCP","url":"https://pubmed.ncbi.nlm.nih.gov/26537799","citation_count":70,"is_preprint":false},{"pmid":"23618814","id":"PMC_23618814","title":"Oxidative stress causes epigenetic alteration of CDX1 expression in colorectal cancer cells.","date":"2013","source":"Gene","url":"https://pubmed.ncbi.nlm.nih.gov/23618814","citation_count":68,"is_preprint":false},{"pmid":"25320087","id":"PMC_25320087","title":"Cdx1 and Cdx2 function as tumor suppressors.","date":"2014","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/25320087","citation_count":68,"is_preprint":false},{"pmid":"14660544","id":"PMC_14660544","title":"Retinoic acid regulates a subset of Cdx1 function in vivo.","date":"2003","source":"Development (Cambridge, England)","url":"https://pubmed.ncbi.nlm.nih.gov/14660544","citation_count":66,"is_preprint":false},{"pmid":"15143193","id":"PMC_15143193","title":"Cdx1 autoregulation is governed by a novel Cdx1-LEF1 transcription complex.","date":"2004","source":"Molecular and cellular biology","url":"https://pubmed.ncbi.nlm.nih.gov/15143193","citation_count":63,"is_preprint":false},{"pmid":"7903305","id":"PMC_7903305","title":"Isolation and characterization of the murine homeobox gene Cdx-1. Regulation of expression in intestinal epithelial cells.","date":"1993","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/7903305","citation_count":60,"is_preprint":false},{"pmid":"14704280","id":"PMC_14704280","title":"Loss of CDX1 expression in colorectal carcinoma: promoter methylation, mutation, and loss of heterozygosity analyses of 37 cell lines.","date":"2004","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/14704280","citation_count":60,"is_preprint":false},{"pmid":"15215241","id":"PMC_15215241","title":"Cdx1 inhibits human colon cancer cell proliferation by reducing beta-catenin/T-cell factor transcriptional activity.","date":"2004","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/15215241","citation_count":58,"is_preprint":false},{"pmid":"8530027","id":"PMC_8530027","title":"Isolation, characterization, and precise physical localization of human CDX1, a caudal-type homeobox gene.","date":"1995","source":"Genomics","url":"https://pubmed.ncbi.nlm.nih.gov/8530027","citation_count":58,"is_preprint":false},{"pmid":"10660624","id":"PMC_10660624","title":"The caudal-related homeodomain protein Cdx1 inhibits proliferation of intestinal epithelial cells by down-regulation of D-type cyclins.","date":"2000","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/10660624","citation_count":57,"is_preprint":false},{"pmid":"17537796","id":"PMC_17537796","title":"Wnt signaling is a key mediator of Cdx1 expression in vivo.","date":"2007","source":"Development (Cambridge, England)","url":"https://pubmed.ncbi.nlm.nih.gov/17537796","citation_count":56,"is_preprint":false},{"pmid":"14977637","id":"PMC_14977637","title":"Cdx1 or Cdx2 expression activates E-cadherin-mediated cell-cell adhesion and compaction in human COLO 205 cells.","date":"2004","source":"American journal of physiology. Gastrointestinal and liver physiology","url":"https://pubmed.ncbi.nlm.nih.gov/14977637","citation_count":54,"is_preprint":false},{"pmid":"36224588","id":"PMC_36224588","title":"Two circPPFIA1s negatively regulate liver metastasis of colon cancer via miR-155-5p/CDX1 and HuR/RAB36.","date":"2022","source":"Molecular cancer","url":"https://pubmed.ncbi.nlm.nih.gov/36224588","citation_count":53,"is_preprint":false},{"pmid":"19328777","id":"PMC_19328777","title":"Cdx1 and Cdx2 are functionally equivalent in vertebral patterning.","date":"2009","source":"Developmental biology","url":"https://pubmed.ncbi.nlm.nih.gov/19328777","citation_count":51,"is_preprint":false},{"pmid":"21532856","id":"PMC_21532856","title":"CDX1 and CDX2 expression in intestinal metaplasia, dysplasia and gastric cancer.","date":"2011","source":"Journal of Korean medical science","url":"https://pubmed.ncbi.nlm.nih.gov/21532856","citation_count":50,"is_preprint":false},{"pmid":"10833444","id":"PMC_10833444","title":"Deregulated expression of homeobox-containing genes, HOXB6, B8, C8, C9, and Cdx-1, in human colon cancer cell lines.","date":"2000","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/10833444","citation_count":48,"is_preprint":false},{"pmid":"11302520","id":"PMC_11302520","title":"Cdx1 promotes cellular growth of epithelial intestinal cells through induction of the secretory protein PAP I.","date":"2001","source":"European journal of cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/11302520","citation_count":45,"is_preprint":false},{"pmid":"14615935","id":"PMC_14615935","title":"Expression of the intestine-specific transcription factors, Cdx1 and Cdx2, correlates shift to an intestinal phenotype in gastric cancer cells.","date":"2003","source":"Journal of cancer research and clinical oncology","url":"https://pubmed.ncbi.nlm.nih.gov/14615935","citation_count":44,"is_preprint":false},{"pmid":"19136512","id":"PMC_19136512","title":"Roles of caudal-related homeobox gene Cdx1 in oesophageal epithelial cells in Barrett's epithelium development.","date":"2009","source":"Gut","url":"https://pubmed.ncbi.nlm.nih.gov/19136512","citation_count":43,"is_preprint":false},{"pmid":"19301404","id":"PMC_19301404","title":"Overlapping functions of Cdx1, Cdx2, and Cdx4 in the development of the amphibian Xenopus tropicalis.","date":"2009","source":"Developmental dynamics : an official publication of the American Association of Anatomists","url":"https://pubmed.ncbi.nlm.nih.gov/19301404","citation_count":40,"is_preprint":false},{"pmid":"11464284","id":"PMC_11464284","title":"Homeobox gene Cdx1 regulates Ras, Rho and PI3 kinase pathways leading to transformation and tumorigenesis of intestinal epithelial cells.","date":"2001","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/11464284","citation_count":40,"is_preprint":false},{"pmid":"11784046","id":"PMC_11784046","title":"RARgamma and Cdx1 interactions in vertebral patterning.","date":"2001","source":"Developmental biology","url":"https://pubmed.ncbi.nlm.nih.gov/11784046","citation_count":39,"is_preprint":false},{"pmid":"17595234","id":"PMC_17595234","title":"Different effects of the Cdx1 and Cdx2 homeobox genes in a murine model of intestinal inflammation.","date":"2007","source":"Gut","url":"https://pubmed.ncbi.nlm.nih.gov/17595234","citation_count":38,"is_preprint":false},{"pmid":"28962081","id":"PMC_28962081","title":"MiRNA-155 promotes proliferation by targeting caudal-type homeobox 1 (CDX1) in glioma cells.","date":"2017","source":"Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie","url":"https://pubmed.ncbi.nlm.nih.gov/28962081","citation_count":37,"is_preprint":false},{"pmid":"28138402","id":"PMC_28138402","title":"Construction and analysis of tissue microarrays in the era of digital pathology: a pilot study targeting CDX1 and CDX2 in a colon cancer cohort of 612 patients.","date":"2017","source":"The journal of pathology. Clinical research","url":"https://pubmed.ncbi.nlm.nih.gov/28138402","citation_count":35,"is_preprint":false},{"pmid":"30096452","id":"PMC_30096452","title":"Purified sulforaphane from broccoli (Brassica oleracea var. italica) leads to alterations of CDX1 and CDX2 expression and changes in miR-9 and miR-326 levels in human gastric cancer cells.","date":"2018","source":"Gene","url":"https://pubmed.ncbi.nlm.nih.gov/30096452","citation_count":34,"is_preprint":false},{"pmid":"21098558","id":"PMC_21098558","title":"Cdx1 refines positional identity of the vertebrate hindbrain by directly repressing Mafb expression.","date":"2010","source":"Development (Cambridge, England)","url":"https://pubmed.ncbi.nlm.nih.gov/21098558","citation_count":33,"is_preprint":false},{"pmid":"10666391","id":"PMC_10666391","title":"Expression of an intestine-specific transcription factor (CDX1) in intestinal metaplasia and in subsequently developed intestinal type of cholangiocarcinoma in rat liver.","date":"2000","source":"The American journal of pathology","url":"https://pubmed.ncbi.nlm.nih.gov/10666391","citation_count":33,"is_preprint":false},{"pmid":"15378566","id":"PMC_15378566","title":"CDX1 expression is reduced in colorectal carcinoma and is associated with promoter hypermethylation.","date":"2004","source":"The Journal of pathology","url":"https://pubmed.ncbi.nlm.nih.gov/15378566","citation_count":32,"is_preprint":false},{"pmid":"12954759","id":"PMC_12954759","title":"Differential regulation of the glucose-6-phosphatase TATA box by intestine-specific homeodomain proteins CDX1 and CDX2.","date":"2003","source":"Nucleic acids research","url":"https://pubmed.ncbi.nlm.nih.gov/12954759","citation_count":32,"is_preprint":false},{"pmid":"18372917","id":"PMC_18372917","title":"Cdx1, a dispensable homeobox gene for gut development with limited effect in intestinal cancer.","date":"2008","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/18372917","citation_count":31,"is_preprint":false},{"pmid":"31416838","id":"PMC_31416838","title":"RETRACTED: CDX1 Expression Induced by CagA-Expressing Helicobacter pylori Promotes Gastric Tumorigenesis.","date":"2019","source":"Molecular cancer research : MCR","url":"https://pubmed.ncbi.nlm.nih.gov/31416838","citation_count":30,"is_preprint":false},{"pmid":"17463179","id":"PMC_17463179","title":"The homeodomain transcription factors Cdx1 and Cdx2 induce E-cadherin adhesion activity by reducing beta- and p120-catenin tyrosine phosphorylation.","date":"2007","source":"American journal of physiology. Gastrointestinal and liver physiology","url":"https://pubmed.ncbi.nlm.nih.gov/17463179","citation_count":30,"is_preprint":false},{"pmid":"24836459","id":"PMC_24836459","title":"CDX1 restricts the invasion of HTR-8/SVneo trophoblast cells by inhibiting MMP-9 expression.","date":"2014","source":"Placenta","url":"https://pubmed.ncbi.nlm.nih.gov/24836459","citation_count":27,"is_preprint":false},{"pmid":"11997022","id":"PMC_11997022","title":"Stimulation of Cdx1 by oncogenic beta-catenin/Tcf4 in colon cancer cells; opposite effect of the CDX2 homeoprotein.","date":"2002","source":"FEBS letters","url":"https://pubmed.ncbi.nlm.nih.gov/11997022","citation_count":27,"is_preprint":false},{"pmid":"18775915","id":"PMC_18775915","title":"Bile acid induces expression of COX-2 through the homeodomain transcription factor CDX1 and orphan nuclear receptor SHP in human gastric cancer cells.","date":"2008","source":"Carcinogenesis","url":"https://pubmed.ncbi.nlm.nih.gov/18775915","citation_count":27,"is_preprint":false},{"pmid":"12970739","id":"PMC_12970739","title":"Cdx1 homeobox gene during human colon cancer progression.","date":"2003","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/12970739","citation_count":25,"is_preprint":false},{"pmid":"23382958","id":"PMC_23382958","title":"Cdx1 and Cdx2 exhibit transcriptional specificity in the intestine.","date":"2013","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/23382958","citation_count":24,"is_preprint":false},{"pmid":"21393996","id":"PMC_21393996","title":"Class I and III HDACs and loss of active chromatin features contribute to epigenetic silencing of CDX1 and EPHB tumor suppressor genes in colorectal cancer.","date":"2011","source":"Epigenetics","url":"https://pubmed.ncbi.nlm.nih.gov/21393996","citation_count":24,"is_preprint":false},{"pmid":"18231635","id":"PMC_18231635","title":"The homeodomain transcription factor Cdx1 does not behave as an oncogene in normal mouse intestine.","date":"2008","source":"Neoplasia (New York, N.Y.)","url":"https://pubmed.ncbi.nlm.nih.gov/18231635","citation_count":23,"is_preprint":false},{"pmid":"22215184","id":"PMC_22215184","title":"Association of CDX1 binding site of periostin gene with bone mineral density and vertebral fracture risk.","date":"2012","source":"Osteoporosis international : a journal established as result of cooperation between the European Foundation for Osteoporosis and the National Osteoporosis Foundation of the USA","url":"https://pubmed.ncbi.nlm.nih.gov/22215184","citation_count":23,"is_preprint":false},{"pmid":"22749770","id":"PMC_22749770","title":"Methylation-dependent activation of CDX1 through NF-κB: a link from inflammation to intestinal metaplasia in the human stomach.","date":"2012","source":"The American journal of pathology","url":"https://pubmed.ncbi.nlm.nih.gov/22749770","citation_count":23,"is_preprint":false},{"pmid":"12270138","id":"PMC_12270138","title":"The homeobox gene Cdx1 belongs to the p53-p21(WAF)-Bcl-2 network in intestinal epithelial cells.","date":"2002","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/12270138","citation_count":23,"is_preprint":false},{"pmid":"22405696","id":"PMC_22405696","title":"Perinatal undernutrition alters intestinal alkaline phosphatase and its main transcription factors KLF4 and Cdx1 in adult offspring fed a high-fat diet.","date":"2012","source":"The Journal of nutritional biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/22405696","citation_count":22,"is_preprint":false},{"pmid":"30909444","id":"PMC_30909444","title":"N-Glycomic and Transcriptomic Changes Associated with CDX1 mRNA Expression in Colorectal Cancer Cell Lines.","date":"2019","source":"Cells","url":"https://pubmed.ncbi.nlm.nih.gov/30909444","citation_count":22,"is_preprint":false},{"pmid":"11566252","id":"PMC_11566252","title":"CDX-1 and CDX-2 are expressed in human colonic mucosa and are down-regulated in patients with Hirschsprung's disease associated enterocolitis.","date":"2001","source":"Biochimica et biophysica acta","url":"https://pubmed.ncbi.nlm.nih.gov/11566252","citation_count":22,"is_preprint":false},{"pmid":"22016432","id":"PMC_22016432","title":"Regulation of the gene encoding the intestinal bile acid transporter ASBT by the caudal-type homeobox proteins CDX1 and CDX2.","date":"2011","source":"American journal of physiology. Gastrointestinal and liver physiology","url":"https://pubmed.ncbi.nlm.nih.gov/22016432","citation_count":21,"is_preprint":false},{"pmid":"12493769","id":"PMC_12493769","title":"Developmental regulation of apolipoprotein B mRNA editing is an autonomous function of small intestine involving homeobox gene Cdx1.","date":"2002","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/12493769","citation_count":20,"is_preprint":false},{"pmid":"30685841","id":"PMC_30685841","title":"CDX1/2 and KLF5 Expression and Epigenetic Modulation of Sonic Hedgehog Signaling in Gastric Adenocarcinoma.","date":"2019","source":"Pathology oncology research : POR","url":"https://pubmed.ncbi.nlm.nih.gov/30685841","citation_count":20,"is_preprint":false},{"pmid":"26841784","id":"PMC_26841784","title":"Follow-Up Study on CDX1 and CDX2 mRNA Expression in Noncancerous Gastric Mucosae After Helicobacter pylori Eradication.","date":"2016","source":"Digestive diseases and sciences","url":"https://pubmed.ncbi.nlm.nih.gov/26841784","citation_count":19,"is_preprint":false},{"pmid":"19725873","id":"PMC_19725873","title":"Transgenic Cdx2 induces endogenous Cdx1 in intestinal metaplasia of Cdx2-transgenic mouse stomach.","date":"2009","source":"The FEBS journal","url":"https://pubmed.ncbi.nlm.nih.gov/19725873","citation_count":19,"is_preprint":false},{"pmid":"30289576","id":"PMC_30289576","title":"Transduced caudal-type homeobox (CDX) 2/CDX1 can induce growth inhibition on CDX-deficient gastric cancer by rapid intestinal differentiation.","date":"2018","source":"Cancer science","url":"https://pubmed.ncbi.nlm.nih.gov/30289576","citation_count":19,"is_preprint":false},{"pmid":"35606410","id":"PMC_35606410","title":"Epithelial de-differentiation triggered by co-ordinate epigenetic inactivation of the EHF and CDX1 transcription factors drives colorectal cancer progression.","date":"2022","source":"Cell death and differentiation","url":"https://pubmed.ncbi.nlm.nih.gov/35606410","citation_count":18,"is_preprint":false},{"pmid":"23613102","id":"PMC_23613102","title":"Dysregulation of CDX1, CDX2 and SOX2 in patients with gastric cancer also affects the non-malignant mucosa.","date":"2013","source":"Journal of clinical pathology","url":"https://pubmed.ncbi.nlm.nih.gov/23613102","citation_count":17,"is_preprint":false},{"pmid":"11743638","id":"PMC_11743638","title":"The caudal-related homeodomain protein CDX1 activates proliferating cell nuclear antigen expression in hepatocellular and colorectal carcinoma cells.","date":"2002","source":"International journal of oncology","url":"https://pubmed.ncbi.nlm.nih.gov/11743638","citation_count":17,"is_preprint":false},{"pmid":"15677473","id":"PMC_15677473","title":"Chicken ovalbumin upstream promoter-transcription factor members repress retinoic acid-induced Cdx1 expression.","date":"2005","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/15677473","citation_count":16,"is_preprint":false},{"pmid":"28305738","id":"PMC_28305738","title":"Expression of carp-cdx1, a caudal homolog, in embryos of the carp, Cyprinus carpio.","date":"1995","source":"Roux's archives of developmental biology : the official organ of the EDBO","url":"https://pubmed.ncbi.nlm.nih.gov/28305738","citation_count":13,"is_preprint":false},{"pmid":"32876500","id":"PMC_32876500","title":"MiR-24 Promotes Cell Growth in Human Glioma by CDX1/PI3K/Akt Signaling Pathway.","date":"2020","source":"Cancer biotherapy & radiopharmaceuticals","url":"https://pubmed.ncbi.nlm.nih.gov/32876500","citation_count":11,"is_preprint":false},{"pmid":"25068460","id":"PMC_25068460","title":"A novel role of CDX1 in embryonic epicardial development.","date":"2014","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/25068460","citation_count":10,"is_preprint":false},{"pmid":"17158164","id":"PMC_17158164","title":"Functional interaction between the homeoprotein CDX1 and the transcriptional machinery containing the TATA-binding protein.","date":"2006","source":"Nucleic acids research","url":"https://pubmed.ncbi.nlm.nih.gov/17158164","citation_count":10,"is_preprint":false},{"pmid":"31897203","id":"PMC_31897203","title":"Primary mesenchymal chondrosarcoma of the kidney without HEY1-NCOA2 and IRF2BP2-CDX1 fusion: A case report and review.","date":"2019","source":"Oncology letters","url":"https://pubmed.ncbi.nlm.nih.gov/31897203","citation_count":10,"is_preprint":false},{"pmid":"22849325","id":"PMC_22849325","title":"Multiple microRNAs induced by Cdx1 suppress Cdx2 in human colorectal tumour cells.","date":"2012","source":"The Biochemical journal","url":"https://pubmed.ncbi.nlm.nih.gov/22849325","citation_count":10,"is_preprint":false},{"pmid":"19059241","id":"PMC_19059241","title":"Homeodomain transcription factor CDX1 is required for the transcriptional induction of PPARgamma in intestinal cell differentiation.","date":"2008","source":"FEBS letters","url":"https://pubmed.ncbi.nlm.nih.gov/19059241","citation_count":10,"is_preprint":false},{"pmid":"22426122","id":"PMC_22426122","title":"Cdx1 is essential for the initiation of HoxC8 expression during early embryogenesis.","date":"2012","source":"FASEB journal : official publication of the Federation of American Societies for Experimental Biology","url":"https://pubmed.ncbi.nlm.nih.gov/22426122","citation_count":9,"is_preprint":false},{"pmid":"19241391","id":"PMC_19241391","title":"Cdx1::Cre allele for gene analysis in the extraembryonic ectoderm and the three germ layers of mice at mid-gastrulation.","date":"2009","source":"Genesis (New York, N.Y. : 2000)","url":"https://pubmed.ncbi.nlm.nih.gov/19241391","citation_count":9,"is_preprint":false},{"pmid":"31841177","id":"PMC_31841177","title":"LncRNA FOXD2-AS1 accelerates the progression of cervical cancer via downregulating CDX1.","date":"2019","source":"European review for medical and pharmacological sciences","url":"https://pubmed.ncbi.nlm.nih.gov/31841177","citation_count":9,"is_preprint":false},{"pmid":"21613300","id":"PMC_21613300","title":"Hypoxia induces expression of COX-2 through the homeodomain transcription factor CDX1 and orphan nuclear receptor SHP in human endometrial cells.","date":"2011","source":"Molecular human reproduction","url":"https://pubmed.ncbi.nlm.nih.gov/21613300","citation_count":9,"is_preprint":false},{"pmid":"14715525","id":"PMC_14715525","title":"Putative intestine-specific enhancers located in 5' sequence of the CDX1 gene regulate CDX1 expression in the intestine.","date":"2004","source":"American journal of physiology. Gastrointestinal and liver physiology","url":"https://pubmed.ncbi.nlm.nih.gov/14715525","citation_count":9,"is_preprint":false},{"pmid":"23329892","id":"PMC_23329892","title":"Mutations and down-regulation of CDX1 in children with anorectal malformations.","date":"2013","source":"International journal of medical sciences","url":"https://pubmed.ncbi.nlm.nih.gov/23329892","citation_count":8,"is_preprint":false},{"pmid":"21360791","id":"PMC_21360791","title":"Negative autoregulation of Oct3/4 through Cdx1 promotes the onset of gastrulation.","date":"2011","source":"Developmental dynamics : an official publication of the American Association of Anatomists","url":"https://pubmed.ncbi.nlm.nih.gov/21360791","citation_count":8,"is_preprint":false},{"pmid":"16491830","id":"PMC_16491830","title":"Relationships between the expressions of CDX1 and CDX2 mRNA and clinicopathologic features in colorectal cancers.","date":"2005","source":"The Korean journal of internal medicine","url":"https://pubmed.ncbi.nlm.nih.gov/16491830","citation_count":6,"is_preprint":false},{"pmid":"32831364","id":"PMC_32831364","title":"Vitamin D Receptor Gene Polymorphisms Taq-1 and Cdx-1 in Female Pattern Hair Loss.","date":"2020","source":"Indian journal of dermatology","url":"https://pubmed.ncbi.nlm.nih.gov/32831364","citation_count":6,"is_preprint":false},{"pmid":"10964750","id":"PMC_10964750","title":"Overexpression of Cdx1 and Cdx2 homeogenes enhances expression of the HLA-I in HT-29 cells.","date":"2000","source":"Molecular cell biology research communications : MCBRC","url":"https://pubmed.ncbi.nlm.nih.gov/10964750","citation_count":5,"is_preprint":false},{"pmid":"32820872","id":"PMC_32820872","title":"MicroRNA-24 inhibits CDX1 expression in decidual tissues of recurrent spontaneous abortion mice to reduce the abortion risk.","date":"2020","source":"Advances in clinical and experimental medicine : official organ Wroclaw Medical University","url":"https://pubmed.ncbi.nlm.nih.gov/32820872","citation_count":5,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":50734,"output_tokens":10466,"usd":0.154596},"stage2":{"model":"claude-opus-4-6","input_tokens":14529,"output_tokens":4307,"usd":0.27048},"total_usd":0.425076,"stage1_batch_id":"msgbatch_011kfMfE81o6CTcyhVUqumuW","stage2_batch_id":"msgbatch_01DTputS6WNkH745x1nVSoBo","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1995,\n      \"finding\": \"Cdx1 loss-of-function (homologous recombination knockout) causes anterior homeotic transformations of vertebrae, accompanied by posterior shifts of Hox gene expression domains in somitic mesoderm; putative Cdx1-binding sites were identified in Hox gene control regions, and in vitro transactivation of Hoxa-7 was demonstrated, indicating direct regulation of Hox genes by Cdx1.\",\n      \"method\": \"Homologous recombination knockout, in vitro transactivation assay, in situ hybridization of Hox expression domains\",\n      \"journal\": \"Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — reconstitution of Hox transactivation in vitro plus definitive loss-of-function with clear skeletal phenotype, foundational paper with 291 citations\",\n      \"pmids\": [\"7585967\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"Cdx1 is a direct transcriptional target of the Wnt/β-catenin signaling pathway; the Cdx1 promoter contains functional TCF/LEF-binding motifs that bind TCF/LEF1/β-catenin complexes and mediate β-catenin-dependent transactivation; Tcf4-deficient mice lose Cdx1 protein in small intestinal epithelium.\",\n      \"method\": \"Promoter reporter assays, gel shift (EMSA), in vivo Wnt stimulation of ES cells and embryonic endoderm, Tcf4 knockout mice analysis\",\n      \"journal\": \"Development (Cambridge, England)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — multiple orthogonal methods (reporter assay, EMSA, in vivo genetic model), Strong evidence replicated in subsequent studies\",\n      \"pmids\": [\"10934025\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"Cdx1 is a direct retinoic acid (RA) target gene; an atypical RA response element (RARE) in the proximal Cdx1 promoter mediates retinoid-dependent activation, providing an indirect pathway for RA to regulate Hox gene expression and vertebral patterning.\",\n      \"method\": \"Promoter reporter assay, RARE mutagenesis, retinoid receptor loss-of-function genetics\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — promoter mutagenesis and in vivo genetic validation, independently confirmed by RARE-null mouse line in 2003\",\n      \"pmids\": [\"10938132\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"Cdx1 inhibits intestinal epithelial cell proliferation by arresting cells in G0/G1, specifically by reducing cyclin D1 and D2 protein levels (without affecting other cyclins or CDK inhibitors), leading to increased hypophosphorylated Rb and p130.\",\n      \"method\": \"Stable transfection and adenoviral induction of Cdx1 in rat IEC-6 cells, flow cytometry, Western blot for cyclins and Rb\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — clean inducible system with multiple molecular readouts, specific mechanistic dissection of cyclin targets\",\n      \"pmids\": [\"10660624\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"Cdx1 expression is regulated by both Wnt3a signaling (through functional LEF/TCF response elements) and by an autoregulatory loop; Wnt3a and retinoic acid synergize strongly to activate Cdx1, and Cdx1 positively regulates its own expression.\",\n      \"method\": \"LEF/TCF motif mutagenesis in promoter reporters, Wnt3a hypomorph (vestigial tail) mouse analysis, EMSA, compound mutant analysis\",\n      \"journal\": \"Developmental biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — promoter mutagenesis, in vivo genetic model, multiple orthogonal methods\",\n      \"pmids\": [\"11784033\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"CDX1 regulates PAP I (Pancreatitis Associated Protein I) gene expression in intestinal cells by directly binding the PAP I promoter; PAP I acts downstream of Cdx1 to promote intestinal cell proliferation via an autocrine/paracrine mechanism.\",\n      \"method\": \"Stable transfection of Cdx1 in IEC-6 cells, promoter binding/deletion assay, adenoviral PAP I expression, antisense inhibition of PAP I\",\n      \"journal\": \"European journal of cell biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct promoter binding demonstrated with deletion analysis, functional rescue/antisense experiments, single lab\",\n      \"pmids\": [\"11302520\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"Wnt-3a is required for Cdx1 expression in the primitive streak and tail bud; Wnt-3a mutant mice show reduced Cdx1 expression concomitant with vertebral homeotic transformations, placing Wnt-3a upstream of Cdx1 in the axial patterning pathway.\",\n      \"method\": \"Wnt-3a mutant mouse analysis, in situ hybridization, skeletal phenotyping\",\n      \"journal\": \"Mechanisms of development\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic epistasis in vivo with clear pathway placement, consistent with complementary studies\",\n      \"pmids\": [\"11335109\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"Cdx1 expression in intestinal epithelial IEC-6 cells activates Ras (increased GTP-bound Ras), modulates Cdc42 and RhoA activities, and accumulates PI3-kinase products; combined inhibition of Ras/Rho and PI3K signaling blocked Cdx1-induced anchorage-independent growth and tumorigenesis.\",\n      \"method\": \"Stable transfection, Ras GTP-loading assay, Rho activity assay, PI3K lipid product measurement, pharmacological inhibition, soft agar and xenograft assays\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple signaling pathway readouts with functional rescue, single lab\",\n      \"pmids\": [\"11464284\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"Cdx1 and Cdx2 double mutants show cooperative anterior homeotic transformations along an extensive vertebral column length and more extensive posterior shifts of Hox gene expression boundaries than single mutants, demonstrating that Cdx1 and Cdx2 cooperate in instructing vertebral progenitors through regulation of Hox gene rostral expression boundaries.\",\n      \"method\": \"Compound mouse mutant analysis, skeletal phenotyping, Hox gene expression analysis by in situ hybridization\",\n      \"journal\": \"Development (Cambridge, England)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — rigorous genetic epistasis with allelic series, strong evidence for cooperative function\",\n      \"pmids\": [\"11959827\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"Oncogenic β-catenin/Tcf4 stimulates Cdx1 promoter activity and endogenous Cdx1 mRNA expression in colon cancer cells; conversely, CDX2 inhibits basal and β-catenin-stimulated Cdx1 promoter activity through its homeodomain, acting independently of canonical CDX-binding sites and TCF elements.\",\n      \"method\": \"Transient transfection of promoter reporters, expression of constitutively active β-catenin, CDX2 homeodomain mutant analysis\",\n      \"journal\": \"FEBS letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — promoter reporter assays, single lab, single method\",\n      \"pmids\": [\"11997022\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"CDX1 and Cdx2 expression reduces colon cancer cell proliferation, in part by inhibiting β-catenin/TCF transcriptional activity in a dose-dependent manner without altering β-catenin protein levels or intracellular distribution.\",\n      \"method\": \"Stable transfection of Cdx1/Cdx2 in multiple colon cancer cell lines, TCF reporter assays, β-catenin localization/Western blot, APC(Min/+) mouse polyp analysis\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple cell lines and in vivo verification, single lab\",\n      \"pmids\": [\"15215241\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"Cdx1 regulates apolipoprotein B mRNA editing during intestinal development; Cdx1 overexpression in IEC-6 cells increases apoB mRNA editing more than 10-fold, associated with upregulation of the editing complex component ACF.\",\n      \"method\": \"Stable transfection of Cdx1 in IEC-6 cells, apoB mRNA editing quantification, ACF protein measurement\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — clear mechanistic link to editing machinery component, single lab\",\n      \"pmids\": [\"12493769\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"Cdx1 belongs to the p53-p21(WAF)-Bcl-2 network in intestinal epithelial cells: wild-type p53 inhibits the Cdx1 promoter; Cdx1 inhibits p21(WAF) promoter activity by binding its TATA-box and activates Bcl-2 promoter P2 through a CDX-binding site, increasing apoptotic resistance.\",\n      \"method\": \"Promoter reporter assays, EMSA for Cdx1 binding to p21 TATA-box, Bcl-2 Western blot, apoptosis resistance assays in IEC-6/SW480 cells\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — promoter binding and reporter assays with functional apoptosis readout, single lab\",\n      \"pmids\": [\"12270138\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"CDX1 directly binds the TATA-box region of the glucose-6-phosphatase (G6Pase) promoter and transactivates it, unlike CDX2 which binds but does not transactivate; CDX1-specific transactivation requires interaction with the TATA-binding protein (TBP).\",\n      \"method\": \"EMSA, mutagenesis of CDX-binding sites and TATA box, luciferase reporter assays in HepG2 and CaCo2 cells, stable transfection in IEC-6 cells\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — in vitro binding assays combined with mutagenesis and functional transactivation, demonstrating CDX1-TBP interaction specificity\",\n      \"pmids\": [\"12954759\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"CDX1 is a key mediator of Barrett's metaplasia: conjugated bile salts, TNF-α and IL-1β increase CDX1 mRNA expression primarily through NF-κB signaling, but only when the CDX1 promoter is unmethylated or partially methylated.\",\n      \"method\": \"CDX1 mRNA quantification in esophageal cell lines after cytokine/bile salt treatment, NF-κB inhibition, promoter methylation analysis\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple stimuli tested with pathway inhibition and promoter methylation correlation, single lab\",\n      \"pmids\": [\"15894614\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"Retinoic acid regulates Cdx1 expression through an atypical RARE in the proximal promoter; RARE-null mutant mice show reduced Cdx1 expression, vertebral homeotic transformations and altered Hox gene expression, demonstrating that the RARE is required for a subset of Cdx1 function governing vertebral patterning in vivo.\",\n      \"method\": \"RARE mutagenesis knock-in mice, skeletal phenotyping, Hox gene expression analysis\",\n      \"journal\": \"Development (Cambridge, England)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — in vivo RARE mutagenesis with definitive phenotypic and molecular validation\",\n      \"pmids\": [\"14660544\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"Cdx1 autoregulation is mediated by a novel complex between the Cdx1 homeodomain and the B box of LEF1; Cdx1 and LEF1 synergize to activate transcription from LEF/TCF response elements in the Cdx1 promoter, and compound Cdx1/Wnt3a(vt) mutants demonstrate convergence of these pathways on Cdx1 expression and vertebral patterning in vivo.\",\n      \"method\": \"Co-immunoprecipitation, GST pulldown mapping of homeodomain-B box interaction, luciferase reporter assays, Cdx1/Wnt3a compound mutant mouse analysis\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — direct protein-protein interaction mapping with in vivo genetic epistasis validation\",\n      \"pmids\": [\"15143193\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"CDX1 promoter silencing in colorectal carcinoma is primarily due to promoter CpG hypermethylation; treatment with the demethylating agent 5-aza-2'-deoxycytidine restores CDX1 expression in cell lines with partially methylated promoters.\",\n      \"method\": \"Promoter methylation analysis by bisulfite sequencing, methylation-specific PCR, 5-aza-2'-deoxycytidine treatment, RT-PCR expression analysis in 37 CRC cell lines\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — systematic analysis across 37 lines with demethylation rescue, replicated in multiple independent studies\",\n      \"pmids\": [\"14704280\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"Cdx1 or Cdx2 expression in COLO 205 colon cancer cells induces E-cadherin-dependent cell-cell adhesion and compaction without changing E-cadherin protein levels; adhesion was Ca2+-dependent and blocked by an anti-E-cadherin antibody, and was associated with acquisition of columnar morphology and differentiation markers.\",\n      \"method\": \"Stable transfection, E-cadherin blocking antibody, Ca2+ chelation, electron microscopy, immunofluorescence\",\n      \"journal\": \"American journal of physiology. Gastrointestinal and liver physiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — functional antibody blocking and Ca2+ dependence establish E-cadherin mechanism, single lab\",\n      \"pmids\": [\"14977637\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"CDX1 expression in transgenic mice induces gastric intestinal metaplasia comprising all four intestinal epithelial cell types (including Paneth cells absent from Cdx2-induced metaplasia), with diffuse proliferating cell nuclear antigen (PCNA)-positive cells, demonstrating distinct differentiation and proliferation programs compared to CDX2.\",\n      \"method\": \"Transgenic mouse model with gastric Cdx1 expression, histology, immunohistochemistry for PCNA and cell-type markers\",\n      \"journal\": \"Gut\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — in vivo transgenic model with direct comparative analysis vs Cdx2 transgenic, strong functional readout\",\n      \"pmids\": [\"15361487\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"COUP-TF transcription factors antagonize RA-induced Cdx1 expression by competing with RXR-RAR heterodimers for binding to the Cdx1 RARE, providing a repressor mechanism that restricts Cdx1 to the caudal embryo.\",\n      \"method\": \"Promoter reporter competition assays, EMSA, in situ hybridization of COUP-TF and Cdx1 expression domains\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1-2 — direct competition binding demonstrated by EMSA plus in vivo expression correlation, single lab\",\n      \"pmids\": [\"15677473\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"CDX1 physically interacts with the TATA-binding protein (TBP) via its homeodomain, and is connected to TFIID and Mediator complex members; the N-terminal domain is additionally required for transactivation; the C-terminal domain determines the functional specificity between CDX1 and CDX2 through intramolecular interactions.\",\n      \"method\": \"Co-immunoprecipitation, altered-specificity TBP mutant transcription assay, domain swapping between CDX1 and CDX2, luciferase reporters\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — direct protein interaction mapping with functional validation using altered-specificity mutant, mechanistically rigorous\",\n      \"pmids\": [\"17158164\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"Wnt signaling is the primary pathway governing Cdx1 expression in vivo; LRE (LEF/TCF response element)-null mutant mice phenocopy Cdx1-null vertebral defects (affecting the entire cervical region), while RARE-null mutants have limited defects; LRE mutation also ablates RA-induced Cdx1 expression, demonstrating that Wnt signaling is required for RA responsiveness of Cdx1.\",\n      \"method\": \"Knock-in mice with LRE and/or RARE mutations, skeletal phenotyping, RA treatment, Cdx1 expression analysis\",\n      \"journal\": \"Development (Cambridge, England)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — in vivo cis-regulatory element mutagenesis with complete allelic series and definitive phenotypic readout\",\n      \"pmids\": [\"17537796\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"CDX1 protein physically interacts with SMAD3 (independently of SMAD4) and inhibits SMAD3/SMAD4-dependent transcription approximately 10-fold, whereas CDX2 interacts with SMAD3 and stimulates its activity approximately 5-fold; this differential interaction explains distinct effects on intestinal inflammation outcome in Cdx1-/- vs Cdx2+/- mice.\",\n      \"method\": \"Co-immunoprecipitation, GST-pulldown, luciferase reporter assays, DSS-induced colitis model in Cdx1-/- and Cdx2+/- mice\",\n      \"journal\": \"Gut\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — reciprocal co-IP and GST pulldown with functional reporter assays and in vivo genetic phenotype, mechanistically rigorous\",\n      \"pmids\": [\"17595234\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"Cdx1 or Cdx2 expression in COLO 205 cells induces E-cadherin-dependent cell-cell adhesion by reducing tyrosine phosphorylation of β-catenin and p120-catenin; restoring β- and p120-catenin tyrosine phosphorylation (by knocking down PTP1B) reversed Cdx-induced cell-cell adhesion.\",\n      \"method\": \"Stable transfection, co-immunoprecipitation of E-cadherin/catenin complexes, phospho-tyrosine immunoprecipitation, PTP1B siRNA knockdown, migration/invasion assays\",\n      \"journal\": \"American journal of physiology. Gastrointestinal and liver physiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — phosphorylation mechanism validated by rescue with siRNA, single lab\",\n      \"pmids\": [\"17463179\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"CDX1 expression in cultured esophageal squamous epithelial cells induces Cdx2 protein production; in a Barrett's rat model (esophago-jejunal anastomosis), bile acids dose-dependently increase Cdx1 promoter activity and protein expression, suggesting a sequential Cdx1→Cdx2 cascade in Barrett's epithelium development.\",\n      \"method\": \"Cdx1 promoter luciferase assay, bile acid treatment, transfection of Cdx1 expression vector in esophageal cells, rat Barrett's model, immunohistochemistry\",\n      \"journal\": \"Gut\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — promoter assay plus in vivo rat model with direct cellular induction experiment, single lab\",\n      \"pmids\": [\"19136512\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"CDX1 transactivates the COX-2 gene in gastric cancer cells; bile acid induction of CDX1 is mediated by the orphan nuclear receptor SHP, establishing a SHP→CDX1→COX-2 sequential transcriptional cascade.\",\n      \"method\": \"Transfection/overexpression assays, COX-2 reporter, CDX1 promoter assay, SHP siRNA/overexpression\",\n      \"journal\": \"Carcinogenesis\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — sequential pathway placement with reporter assays and RNAi, single lab\",\n      \"pmids\": [\"18775915\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Cdx1 and c-Myc cooperate to induce mucin production and changes in keratin expression characteristic of Barrett's esophagus in immortalized human esophageal keratinocytes grown in organotypic culture.\",\n      \"method\": \"Organotypic culture, microarray-guided candidate identification, retroviral expression of Cdx1 and c-Myc, immunostaining for mucins and keratins\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — organotypic culture with cooperative functional readout, single lab\",\n      \"pmids\": [\"18953412\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"CDX1 directly regulates Keratin 20 (KRT20) expression: CDX1 binds CDX elements within 246 bp upstream of the KRT20 transcription start site (confirmed by ChIP), and deletion/mutation of these elements abolishes CDX1-dependent KRT20 promoter activity.\",\n      \"method\": \"Microarray analysis, promoter deletion and mutation analysis, ChIP, immunohistochemistry, expression correlation across 38 CRC cell lines\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — ChIP plus promoter mutagenesis plus in vivo expression correlation, multiple orthogonal methods\",\n      \"pmids\": [\"19188603\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"CDX1 promotes intestinal differentiation by activating PPARγ gene expression through functional interaction with C/EBPα; butyrate increases CDX1-C/EBPα protein interaction, leading to enhanced PPARγ expression.\",\n      \"method\": \"Co-immunoprecipitation, CDX1/C/EBPα co-transfection with PPARγ reporter, butyrate treatment, Western blot\",\n      \"journal\": \"FEBS letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct protein interaction and functional reporter assay, single lab\",\n      \"pmids\": [\"19059241\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"Cdx2 binds the Cdx1 promoter region in intestinal metaplasia (demonstrated by ChIP and EMSA) and upregulates Cdx1 transcription; siRNA-mediated Cdx2 knockdown reduces Cdx1 promoter activity; the Cdx1 promoter is unmethylated in Cdx2-transgenic mouse intestinal metaplasia.\",\n      \"method\": \"ChIP, EMSA, luciferase reporter assay, siRNA knockdown of Cdx2, bisulfite sequencing of Cdx1 promoter\",\n      \"journal\": \"The FEBS journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — multiple orthogonal methods (ChIP, EMSA, reporter, siRNA) in one study\",\n      \"pmids\": [\"19725873\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"Cdx2 substituted for Cdx1 in a knock-in model perfectly complements the Cdx1-null skeletal phenotype and Hox gene expression, demonstrating functional redundancy between Cdx1 and Cdx2 for vertebral anteroposterior patterning.\",\n      \"method\": \"Cdx2 knock-in at Cdx1 locus, skeletal phenotyping, Hox gene expression analysis\",\n      \"journal\": \"Developmental biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — definitive genetic replacement experiment with complete phenotypic rescue\",\n      \"pmids\": [\"19328777\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Cdx1 directly represses Mafb expression in the neural tube posterior to the r6/r7 boundary, thereby refining hindbrain patterning; Cdx1 binds regulatory sequences of the Mafb gene as demonstrated by ChIP and in situ hybridization, establishing Mafb as a direct early target of Cdx1.\",\n      \"method\": \"ChIP, immunofluorescence, in situ hybridization, identification of Mafb regulatory sequences responsive to Cdx1\",\n      \"journal\": \"Development (Cambridge, England)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — ChIP demonstrating direct binding plus functional in vivo genetics\",\n      \"pmids\": [\"21098558\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"CDX1 regulates the ASBT (apical sodium-dependent bile acid transporter) gene; CDX1 binds to six of nine predicted CDX binding sites in the ASBT promoter (verified by EMSA and ChIP in living cells), strongly induces ASBT promoter activity in reporter assays, and CDX1 siRNA knockdown reduces ASBT mRNA in intestinal cells.\",\n      \"method\": \"ChIP, EMSA, luciferase reporter assay, siRNA knockdown, correlation analysis in Barrett's esophagus biopsies\",\n      \"journal\": \"American journal of physiology. Gastrointestinal and liver physiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — multiple orthogonal methods including in-cell ChIP and in vitro binding, single lab\",\n      \"pmids\": [\"22016432\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Oxidative stress (H2O2) silences CDX1 in colorectal cancer cells through epigenetic mechanisms: ROS upregulates DNMT1 and HDAC1 expression and activity, enhances DNMT1-HDAC1 association, and increases CDX1 promoter methylation; 5-aza-2'-deoxycytidine reverses these effects.\",\n      \"method\": \"H2O2 treatment, MSP, RT-PCR, Western blot, DNMT1/HDAC1 activity assays, N-acetylcysteine rescue, 5-aza-dC reversal\",\n      \"journal\": \"Gene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple molecular mechanisms demonstrated with chemical rescue, single lab\",\n      \"pmids\": [\"23618814\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"CDX1 directly activates SALL4 and KLF5 expression in gastric epithelial cells; CDX1-induced SALL4 and KLF5 convert gastric epithelial cells into intestinal stem-like progenitor cells, which then transdifferentiate into intestinal epithelial cells; inhibiting SALL4 or KLF5 suppresses CDX1-induced intestinal differentiation markers.\",\n      \"method\": \"Gene expression profiling (microarray), siRNA knockdown of SALL4 and KLF5, stable CDX1 expression in gastric epithelial cells, immunohistochemistry in human and mouse IM specimens\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genome-wide target identification with RNAi-based functional validation and in vivo tissue confirmation\",\n      \"pmids\": [\"23112162\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"NF-κB binding to the CDX1 promoter is methylation-dependent; a methylated CDX1 promoter is associated with closed chromatin structure and reduced NF-κB binding; competitive EMSA and ChIP quantified this interaction, and along the gastritis-metaplasia-carcinoma sequence, CDX1 promoter methylation pattern inversely correlates with NF-κB signaling activity.\",\n      \"method\": \"Competitive EMSA, ChIP, bisulfite sequencing, TNF-α protein expression analysis across gastric tissue stages\",\n      \"journal\": \"The American journal of pathology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — ChIP and EMSA demonstrating methylation-sensitive transcription factor binding, single lab\",\n      \"pmids\": [\"22749770\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Cdx1 induces multiple microRNAs (miR-9, miR-16, miR-22) in colorectal tumor cells that directly bind the CDX2 mRNA 3'UTR and destabilize it; simultaneous mutation of miR-9 and miR-16 binding sites in CDX2 3'UTR was sufficient to block Cdx2 suppression by Cdx1.\",\n      \"method\": \"Microarray miRNA profiling, 3'UTR luciferase reporter with CDX2 binding-site mutations, stable Cdx1 transfection in SW480 cells\",\n      \"journal\": \"The Biochemical journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — 3'UTR mutagenesis with functional validation, single lab\",\n      \"pmids\": [\"22849325\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Cdx1 directly binds to conserved CDX-binding sites within the HoxC8 early enhancer during Xenopus embryogenesis (demonstrated by ChIP), and Cdx1 overexpression or knockdown causes precocious or delayed HoxC8 expression respectively; differential binding affinity to multiple CDX sites may contribute to the temporal control of Hox activation.\",\n      \"method\": \"Xenopus Cdx1 overexpression and morpholino knockdown, mouse HoxC8 early enhancer reporter in Xenopus, ChIP, mutagenesis of Cdx binding sites\",\n      \"journal\": \"FASEB journal : official publication of the Federation of American Societies for Experimental Biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — ChIP demonstrating direct in vivo binding plus loss/gain of function with enhancer mutagenesis\",\n      \"pmids\": [\"22426122\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"CDX1 exhibits context-dependent transcriptional specificity: in intestinal cells, CDX2 is significantly less potent than CDX1 at activating the Cdx1 promoter autoregulatory response, and in vivo, CDX2 cannot substitute for CDX1 in the autoregulatory loop (unlike in paraxial mesoderm/vertebral patterning), demonstrated by a gene swap approach.\",\n      \"method\": \"Cell-based promoter reporter assay comparing Cdx1 vs Cdx2 potency, in vivo gene swap knock-in model\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — in vivo genetic swap combined with cell-based assay, single lab\",\n      \"pmids\": [\"23382958\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Combined somatic loss of Cdx2 and the Cdx1 null allele in APC(Min/+) mice significantly increases the incidence of tumors in the distal colon relative to APC(Min/+)-Cdx2 mutants alone, demonstrating that Cdx1 functions as a tumor suppressor specifically in the distal colon.\",\n      \"method\": \"Conditional somatic Cdx2 deletion combined with Cdx1 null allele in APC(Min/+) background, tumor quantification by location\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — compound genetic mouse model with site-specific tumor phenotype, clear epistatic relationship\",\n      \"pmids\": [\"25320087\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"CDX1 restricts invasion of HTR-8/SVneo trophoblast cells by inhibiting MMP-9 expression and increasing TIMP-1 expression, independently of the PI3K/AKT signaling pathway; however, CDX1 itself is regulated by PI3K/AKT signaling.\",\n      \"method\": \"Stable CDX1 transfection, invasion assay (QCM ECMatrix kit), RT-PCR and Western blot for MMP-9/TIMP-1, PI3K inhibitor (perifosine) treatment\",\n      \"journal\": \"Placenta\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — functional invasion assay with molecular target identification and pathway inhibition, single lab\",\n      \"pmids\": [\"24836459\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Transient CDX1 expression in embryonic epicardium promotes epithelial-to-mesenchymal transition (EMT) and migration/differentiation of epicardium-derived cells into α-SMA+ vascular smooth muscle; sustained high-level CDX1 or CDX1 deficiency both attenuate this process, and CDX1 induction alters transcript levels of genes involved in neuronal development, angiogenesis, and cell adhesion.\",\n      \"method\": \"Doxycycline-inducible CDX1 mouse model, primary epicardium culture, ex vivo heart culture, RNA-seq, α-SMA immunostaining, Cdx1 knockout comparison\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — inducible in vivo model with loss/gain of function and transcriptomic analysis, single lab\",\n      \"pmids\": [\"25068460\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"CDX1 directly activates miR-215 transcription (confirmed by ChIP-PCR and promoter luciferase assay); miR-215 mediates repression of cell cycle and stemness genes downstream of CDX1, including the stemness gene BMI1, linking CDX1 to colorectal cancer stem cell differentiation.\",\n      \"method\": \"Small RNA sequencing, ChIP-PCR, promoter luciferase assay, miR-215 overexpression/knockdown, FACS-enriched cancer stem cell comparison, clonogenicity assays\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — ChIP plus luciferase validation plus functional miRNA assays, multiple orthogonal methods\",\n      \"pmids\": [\"25775580\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"EHF physically interacts with CDX1 via the EHF PNT domain; EHF and CDX1 co-operatively drive transcription of the colonic differentiation marker VIL1; compound genetic deletion of Ehf and Cdx1 in the mouse colon disrupts normal colonic differentiation and enhances colorectal tumour progression.\",\n      \"method\": \"Co-immunoprecipitation identifying EHF-CDX1 interaction, VIL1 promoter reporter co-transfection, compound Ehf/Cdx1 conditional knockout mouse, chromatin remodeling assays, transcriptional profiling\",\n      \"journal\": \"Cell death and differentiation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — direct protein interaction identified by Co-IP with in vivo genetic compound knockout validation and functional co-operative transcription assay\",\n      \"pmids\": [\"35606410\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"CDX1 is a homeodomain transcription factor that directly regulates Hox gene expression (establishing anterior-posterior vertebral patterning) and intestinal differentiation gene programs; it is transcriptionally activated by Wnt/β-catenin signaling (via LEF/TCF elements), retinoic acid (via a proximal RARE), and an autoregulatory loop requiring a CDX1-LEF1 protein complex; it physically interacts with TBP/TFIID/Mediator to transactivate specific targets (e.g., KRT20, G6Pase, miR-215, SALL4, KLF5), inhibits β-catenin/TCF transcriptional output to restrain proliferation (partly by reducing cyclin D1/D2), represses Mafb in the hindbrain, and is epigenetically silenced by promoter CpG hypermethylation in colorectal cancer; it also modulates SMAD3 transcriptional activity (opposing CDX2) and interacts with EHF to co-operatively drive colonic differentiation.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"CDX1 is a homeodomain transcription factor that governs anterior-posterior vertebral patterning and intestinal epithelial differentiation by directly regulating Hox gene expression boundaries and intestinal-specific gene programs. CDX1 is transcriptionally activated by Wnt/β-catenin signaling through LEF/TCF response elements (the dominant input in vivo) and by retinoic acid through a proximal RARE, and sustains its own expression via an autoregulatory loop requiring a CDX1–LEF1 protein complex [PMID:10934025, PMID:14660544, PMID:17537796, PMID:15143193]. It transactivates target genes (including KRT20, G6Pase, SALL4, KLF5, and miR-215) through its homeodomain-mediated interaction with TBP/TFIID and cooperation with partners such as C/EBPα and EHF, while restraining proliferation by inhibiting β-catenin/TCF transcriptional output, reducing cyclin D1/D2, and activating differentiation-promoting microRNAs [PMID:12954759, PMID:17158164, PMID:10660624, PMID:25775580, PMID:35606410]. CDX1 functions as a tumor suppressor in the distal colon, where its promoter is frequently silenced by CpG hypermethylation in colorectal carcinoma, and its loss cooperates with APC and Cdx2 mutations to promote tumorigenesis [PMID:14704280, PMID:25320087].\",\n  \"teleology\": [\n    {\n      \"year\": 1995,\n      \"claim\": \"Establishing that CDX1 is a direct upstream regulator of Hox gene expression and vertebral identity resolved how caudal-type homeobox genes connect to the vertebral patterning code.\",\n      \"evidence\": \"Cdx1 knockout mice showing anterior homeotic transformations and posterior shifts in Hox expression, plus in vitro transactivation of Hoxa-7\",\n      \"pmids\": [\"7585967\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism by which Cdx1 selects specific Hox targets was unknown\", \"Redundancy with other Cdx family members was untested\", \"Whether Cdx1 regulates Hox genes directly via enhancer binding in vivo was not shown\"]\n    },\n    {\n      \"year\": 2000,\n      \"claim\": \"Identification of Wnt/β-catenin and retinoic acid as the two major upstream signals directly activating Cdx1 transcription placed Cdx1 at a signaling node integrating morphogen inputs for axial patterning.\",\n      \"evidence\": \"Functional LEF/TCF elements and an atypical RARE in the Cdx1 promoter demonstrated by reporter assays, EMSA, and Tcf4-null mice losing Cdx1 expression\",\n      \"pmids\": [\"10934025\", \"10938132\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Relative contribution of Wnt vs RA to Cdx1 expression in vivo was unclear\", \"Whether the two inputs are independent or synergistic in vivo was unresolved\"]\n    },\n    {\n      \"year\": 2000,\n      \"claim\": \"Demonstrating that Cdx1 inhibits intestinal cell proliferation by specifically reducing cyclin D1/D2 established a growth-suppressive function distinct from its patterning role.\",\n      \"evidence\": \"Inducible Cdx1 expression in IEC-6 cells causing G0/G1 arrest with specific cyclin D1/D2 reduction\",\n      \"pmids\": [\"10660624\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether cyclin D reduction is transcriptionally direct was unknown\", \"Relationship to Cdx1's effect on β-catenin/TCF output was not connected\"]\n    },\n    {\n      \"year\": 2001,\n      \"claim\": \"Genetic epistasis showing Wnt3a is required upstream of Cdx1 for vertebral patterning, combined with demonstration of Wnt/RA synergy and Cdx1 autoregulation, defined the signaling hierarchy and positive feedback loop maintaining Cdx1 expression.\",\n      \"evidence\": \"Wnt3a mutant mice with reduced Cdx1 and homeotic transformations; LEF/TCF mutagenesis and autoregulatory loop demonstration in reporters\",\n      \"pmids\": [\"11335109\", \"11784033\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular mechanism of autoregulation (direct or indirect) was unresolved\", \"Whether autoregulation requires a Cdx1–LEF1 protein complex was unknown\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Compound Cdx1/Cdx2 mutant analysis demonstrated cooperative, dose-dependent regulation of Hox boundaries along the entire vertebral column, establishing functional redundancy between the two paralogues.\",\n      \"evidence\": \"Cdx1/Cdx2 double-mutant mice with extensive homeotic transformations exceeding single mutants\",\n      \"pmids\": [\"11959827\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether functional equivalence is complete or context-dependent was untested\", \"Cdx4 contribution was not assessed\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Showing that CDX1 inhibits β-catenin/TCF transcriptional activity without affecting β-catenin levels identified a negative feedback mechanism whereby a Wnt target gene restrains the Wnt output.\",\n      \"evidence\": \"Stable CDX1 expression in multiple colon cancer lines reducing TCF reporter activity dose-dependently; APC(Min/+) polyp analysis\",\n      \"pmids\": [\"15215241\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct molecular mechanism of β-catenin/TCF inhibition by CDX1 was not identified\", \"Whether this involves direct protein interaction with TCF was unknown\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Mapping the CDX1 homeodomain–TBP interaction and its requirement for G6Pase transactivation revealed how CDX1 mechanistically engages the basal transcription machinery, distinguishing it from CDX2.\",\n      \"evidence\": \"EMSA, TATA-box mutagenesis, and luciferase reporters showing CDX1-specific TBP-dependent transactivation of G6Pase\",\n      \"pmids\": [\"12954759\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of CDX1–TBP interaction was not determined\", \"Whether Mediator engagement is direct was unresolved\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Discovery that CDX1 autoregulation operates through a direct CDX1 homeodomain–LEF1 B-box protein complex explained how Wnt signaling and CDX1 converge on a single cis-regulatory element for self-sustaining expression.\",\n      \"evidence\": \"Co-IP and GST pulldown mapping the interaction domains; compound Cdx1/Wnt3a(vt) mutant genetic validation\",\n      \"pmids\": [\"15143193\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether the CDX1–LEF1 complex recruits distinct co-activators was unknown\", \"Crystal structure of the complex was not obtained\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Demonstrating frequent CDX1 promoter hypermethylation in colorectal cancer with demethylation-dependent rescue of expression established an epigenetic silencing mechanism contributing to loss of CDX1 tumor suppression.\",\n      \"evidence\": \"Bisulfite sequencing and MSP across 37 CRC cell lines; 5-aza-2′-deoxycytidine restoring CDX1 expression\",\n      \"pmids\": [\"14704280\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Causal relationship between methylation-driven CDX1 loss and tumor progression was not established in vivo\", \"Which DNA methyltransferases are responsible was not identified\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Transgenic CDX1 expression in stomach generating complete intestinal metaplasia including Paneth cells showed CDX1 is sufficient to specify all four intestinal cell lineages, revealing a broader differentiation capacity than CDX2.\",\n      \"evidence\": \"Gastric CDX1-transgenic mice producing goblet, absorptive, enteroendocrine, and Paneth cells\",\n      \"pmids\": [\"15361487\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether CDX1 directly activates lineage-specific transcription factors was unknown\", \"Mechanism distinguishing CDX1 from CDX2 in Paneth cell specification was unresolved\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"In vivo cis-regulatory dissection showed that the LEF/TCF response element is the primary determinant of Cdx1 expression and vertebral patterning, subordinating the RARE input, and that RA responsiveness itself requires intact Wnt signaling through the LRE.\",\n      \"evidence\": \"LRE-null and RARE-null knock-in mice; LRE mutation phenocopies Cdx1-null while RARE mutation produces limited defects\",\n      \"pmids\": [\"17537796\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How Wnt signaling gates RA responsiveness mechanistically was not explained\", \"Other cis-elements contributing to Cdx1 regulation in non-mesodermal tissues were not tested\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Identifying CDX1 as a physical interactor and inhibitor of SMAD3-dependent transcription (opposing CDX2's stimulatory effect) revealed a mechanism for differential TGF-β/BMP pathway modulation by the two CDX paralogues.\",\n      \"evidence\": \"Reciprocal co-IP and GST pulldown; 10-fold inhibition of SMAD3/SMAD4 reporters by CDX1; DSS colitis in Cdx1-null mice\",\n      \"pmids\": [\"17595234\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether SMAD3 interaction competes with TBP binding was unknown\", \"In vivo relevance to intestinal homeostasis beyond inflammation was not established\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Cdx2 knock-in at the Cdx1 locus fully rescuing the skeletal phenotype demonstrated complete functional equivalence for vertebral patterning, proving that expression differences rather than protein divergence account for non-redundancy.\",\n      \"evidence\": \"Cdx2 knock-in replacing Cdx1 coding region; complete rescue of vertebral transformations and Hox expression\",\n      \"pmids\": [\"19328777\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether equivalence extends to intestinal functions was not tested\", \"Endogenous Cdx2 was still present, complicating interpretation of dosage effects\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Showing Cdx1 directly represses Mafb in the hindbrain expanded CDX1's known role from mesoderm to neural tube patterning and identified a direct transcriptional repression target.\",\n      \"evidence\": \"ChIP demonstrating Cdx1 binding to Mafb regulatory sequences; altered Mafb expression in Cdx1-null neural tube\",\n      \"pmids\": [\"21098558\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism of repression (co-repressor recruitment) was not identified\", \"Other neural tube targets of Cdx1 were not catalogued\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Identification of SALL4 and KLF5 as direct CDX1 target genes that convert gastric cells into intestinal stem-like progenitors provided a molecular mechanism for CDX1-driven intestinal metaplasia.\",\n      \"evidence\": \"Microarray, siRNA knockdown of SALL4/KLF5 suppressing CDX1-induced intestinal markers in gastric cells; confirmation in human/mouse IM specimens\",\n      \"pmids\": [\"23112162\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether CDX1 binds SALL4 and KLF5 promoters directly (ChIP) was not shown\", \"Sufficiency of SALL4/KLF5 without CDX1 was not tested\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Compound Cdx1/Cdx2 loss in APC(Min/+) mice increasing distal colon tumors provided definitive in vivo genetic evidence that CDX1 functions as a tumor suppressor cooperating with CDX2 specifically in the distal colon.\",\n      \"evidence\": \"Conditional somatic Cdx2 deletion combined with Cdx1-null in APC(Min/+) mice; site-specific tumor quantification\",\n      \"pmids\": [\"25320087\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular targets mediating tumor suppression in distal colon were not identified\", \"Whether CDX1 tumor suppression is cell-autonomous was not established\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Demonstrating CDX1 directly activates miR-215 transcription, which in turn represses stemness genes including BMI1, connected CDX1's differentiation-promoting activity to a microRNA effector pathway in colorectal cancer stem cells.\",\n      \"evidence\": \"ChIP-PCR and promoter luciferase for CDX1 binding to miR-215 locus; miR-215 overexpression/knockdown in FACS-enriched cancer stem cells\",\n      \"pmids\": [\"25775580\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Full spectrum of miR-215 targets downstream of CDX1 was not determined\", \"In vivo validation of CDX1–miR-215–BMI1 axis in tumors was lacking\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Identification of EHF as a direct CDX1 interaction partner that cooperatively drives colonic differentiation gene expression (VIL1) and suppresses tumorigenesis revealed a new co-factor axis for CDX1 function in the colon.\",\n      \"evidence\": \"Co-IP of EHF–CDX1 via PNT domain; VIL1 promoter co-activation; compound Ehf/Cdx1 knockout mice with disrupted colonic differentiation and enhanced tumor progression\",\n      \"pmids\": [\"35606410\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Genome-wide co-occupancy of EHF and CDX1 was not mapped\", \"Whether EHF modifies CDX1's interaction with TBP/Mediator is unknown\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"A genome-wide map of direct CDX1 chromatin occupancy in normal intestinal epithelium is lacking, and the structural basis for CDX1's selective interactions with TBP, LEF1, SMAD3, and EHF — and how these are coordinated on different promoters — remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No genome-wide ChIP-seq for CDX1 in normal intestine has been reported\", \"No crystal or cryo-EM structure of CDX1 or its complexes exists\", \"How CDX1 selectively activates versus represses targets (e.g., Hox activation vs Mafb repression) is mechanistically unexplained\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0003677\", \"supporting_discovery_ids\": [0, 13, 28, 32, 33, 38]},\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [0, 13, 21, 28, 35, 43, 44]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [13, 16, 21]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [0, 8, 15, 22, 31, 32]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [1, 4, 6, 22, 23]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [13, 21, 28, 35, 43, 44]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [17, 34, 40]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\n      \"LEF1\",\n      \"TBP\",\n      \"SMAD3\",\n      \"EHF\",\n      \"CEBPA\",\n      \"CTNNB1\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}