{"gene":"CDX1","run_date":"2026-06-09T22:57:18","timeline":{"discoveries":[{"year":1995,"finding":"Cdx1 knockout mice exhibit anterior homeotic transformations of vertebrae, concomitant with 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 by Cdx1 was demonstrated, indicating direct regulation of Hox genes by Cdx1.","method":"Homologous recombination (gene knockout), skeletal phenotype analysis, in vitro transactivation assay","journal":"Cell","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — loss-of-function genetic model combined with in vitro transactivation and identification of binding sites, replicated in subsequent studies","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-binding motifs that bind Tcf/Lef1/β-catenin complexes and mediate β-catenin-dependent transactivation. Tcf4-deficient mouse embryos show abrogation of Cdx1 protein in the small intestinal epithelium.","method":"Promoter-reporter assays, gel shift assays, Tcf4-knockout mouse analysis, Wnt stimulation of ES cells and embryonic endoderm","journal":"Development (Cambridge, England)","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — multiple orthogonal methods (promoter reporter, EMSA, in vivo knockout), replicated by subsequent studies","pmids":["10934025"],"is_preprint":false},{"year":2000,"finding":"Cdx1 is a direct retinoic acid (RA) target gene. RA regulation of Cdx1 occurs through an atypical RA response element (RARE) in the proximal Cdx1 promoter, providing an indirect mechanism by which retinoid signaling impacts Hox expression and vertebral patterning.","method":"Promoter-reporter assays, retinoid receptor binding studies, in vitro RA treatment","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — direct promoter analysis with RARE identification, confirmed in vivo by RARE-null mutant mice in follow-up study (PMID:14660544)","pmids":["10938132"],"is_preprint":false},{"year":2001,"finding":"Cdx1 expression is regulated by multiple pathways: (1) direct retinoid signaling through an atypical RARE at early stages; (2) Wnt3a signaling through functional LEF/TCF response elements at later stages; and (3) an autoregulatory loop in which Cdx1 positively regulates its own expression. Wnt3a and RA synergize strongly to activate Cdx1.","method":"Promoter-reporter assays, LEF/TCF motif mutagenesis, Wnt3a hypomorph (vestigial tail) mouse analysis, RA treatment experiments","journal":"Developmental biology","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — multiple orthogonal methods including in vivo mutant analysis and promoter mutagenesis, consistent with independent studies","pmids":["11784033"],"is_preprint":false},{"year":2001,"finding":"Wnt-3a is required for normal cdx-1 expression in the primitive streak and tail bud region. Loss of Wnt-3a signaling leads to reduced Cdx1 expression and anterior homeotic vertebral transformations, placing Wnt-3a upstream of cdx-1 in anteroposterior patterning.","method":"Wnt3a mutant mouse analysis, in situ hybridization for Cdx1 expression","journal":"Mechanisms of development","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic epistasis in vivo, single lab, single primary method","pmids":["11335109"],"is_preprint":false},{"year":2000,"finding":"Cdx1 inhibits intestinal epithelial cell (IEC-6) proliferation by causing G0/G1 arrest through marked reduction of cyclin D1 and D2 protein levels, leading to increased hypophosphorylated Rb and p130. Cyclin-dependent kinase inhibitors (p16, p18, p21, p27, p57) were not affected.","method":"Stable transfection of inducible Cdx1 constructs and adenoviral expression in IEC-6 cells, flow cytometry, Western blot for cell cycle proteins","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — clean loss/gain-of-function with defined molecular readouts, two delivery methods (stable transfection + adenovirus), consistent findings","pmids":["10660624"],"is_preprint":false},{"year":1999,"finding":"Cdx1 expression in IEC-6 intestinal epithelial cells promotes differentiation toward a columnar enterocyte phenotype, including induction of aminopeptidase N and villin expression, redistribution of actin filaments to the cortex, and formation of multilayers with apical microvilli. Cdx1 also increased proliferation rate, resistance to apoptosis, and migration speed.","method":"Stable transfection of Cdx1 in IEC-6 cells, morphological analysis, immunofluorescence, in vitro wound assay","journal":"Gastroenterology","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — stable overexpression with multiple phenotypic readouts, single lab","pmids":["10579974"],"is_preprint":false},{"year":2001,"finding":"Cdx1 expression in IEC-6 intestinal epithelial cells induces anchorage-independent growth and adenocarcinoma formation in vivo. These oncogenic effects correlate with increased GTP-bound Ras, modulation of Cdc42 and RhoA activities, and accumulation of PI3 kinase products. Combined inhibition of Ras/Rho and PI3 kinase signaling blocked colony formation.","method":"Stable transfection, soft agar assay, in vivo tumor formation, GTP-pulldown assays, PI3K inhibitor treatment","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal assays (in vitro and in vivo), single lab","pmids":["11464284"],"is_preprint":false},{"year":2001,"finding":"Cdx1 directly activates the PAP I (Pancreatitis Associated Protein I) promoter through a Cdx1-binding element, as demonstrated by promoter binding and deletion analysis. PAP I in turn acts as a proliferative factor for intestinal cells via an autocrine/paracrine mechanism, mediating part of the Cdx1-induced growth effect.","method":"Stable transfection, gel shift assay, promoter deletion analysis, antisense knockdown of PAP I, adenoviral PAP I overexpression","journal":"European journal of cell biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct promoter binding demonstrated with functional deletion and antisense validation, single lab","pmids":["11302520"],"is_preprint":false},{"year":2002,"finding":"Cdx1 and Cdx2 cooperate in anteroposterior vertebral patterning and posterior axis elongation. Compound Cdx1 null/Cdx2 heterozygous mutants show extensive homeotic transformations along the entire vertebral column and posterior truncation, associated with early alterations in Hox gene expression boundaries in the somitic mesoderm.","method":"Generation of compound Cdx1/Cdx2 mutant mice, skeletal analysis, Hox gene expression by in situ hybridization","journal":"Development (Cambridge, England)","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic epistasis in vivo with compound mutants, replicated by independent lab","pmids":["11959827"],"is_preprint":false},{"year":2003,"finding":"RARE-null (retinoic acid response element-null) Cdx1 mutant mice exhibit reduced Cdx1 expression, vertebral homeotic transformations, and altered Hox gene expression similar to a subset of Cdx1-null defects, demonstrating that the RARE in the Cdx1 proximal promoter is functionally required in vivo for a specific subset of Cdx1 expression and function.","method":"Targeted mutation of the RARE in the Cdx1 promoter in mice, skeletal analysis, Hox expression analysis","journal":"Development (Cambridge, England)","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — in vivo promoter element mutagenesis confirming functional relevance of RARE, consistent with in vitro data","pmids":["14660544"],"is_preprint":false},{"year":2004,"finding":"Cdx1 autoregulation occurs through a novel physical interaction between the homeodomain of Cdx1 and the B box of LEF1. Cdx1 and LEF1 synergize to induce Cdx1 expression from its own promoter through LEF/TCF response elements. This was confirmed in vivo by Cdx1/Wnt3a(vt) compound mutants showing convergent effects on Cdx1 expression and vertebral patterning.","method":"Co-immunoprecipitation, promoter-reporter assays, domain-swap experiments, Cdx1/Wnt3a compound mutant mouse analysis","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — direct protein–protein interaction demonstrated by Co-IP plus in vivo genetic validation in compound mutants","pmids":["15143193"],"is_preprint":false},{"year":2004,"finding":"Cdx1 or Cdx2 expression inhibits β-catenin/TCF transcriptional activity in colon cancer cells in a dose-dependent manner, reducing colon cancer cell proliferation. This inhibitory effect does not alter β-catenin protein levels or intracellular distribution, and does not induce an inhibitory TCF isoform.","method":"Transfection of Cdx1/Cdx2 expression constructs, TCF/β-catenin reporter assays, Western blot, proliferation assays","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — reporter assays and multiple cell lines, single lab","pmids":["15215241"],"is_preprint":false},{"year":2004,"finding":"Loss of CDX1 expression in colorectal carcinoma is primarily regulated by promoter methylation. All CRC cell lines lacking CDX1 mRNA had a methylated CDX1 promoter, and demethylation with 5-aza-2'-deoxycytidine restored CDX1 expression. No coding mutations or LOH explained the loss of expression.","method":"Methylation-specific PCR, RT-PCR, demethylation treatment, LOH analysis, mutation 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 / Strong — comprehensive analysis of 37 cell lines with multiple molecular methods, confirmed by pharmacological demethylation","pmids":["14704280"],"is_preprint":false},{"year":2004,"finding":"CDX1 directly regulates the KRT20 (Cytokeratin 20) promoter. ChIP analysis confirmed CDX1 binding to predicted CDX elements within 246 bp upstream of the KRT20 transcription start site in vivo. CDX1 and KRT20 expression are significantly correlated in colorectal cancer cell lines.","method":"Chromatin immunoprecipitation (ChIP), promoter deletion and mutation analysis, microarray, expression correlation in 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 / Strong — ChIP confirming in vivo binding plus promoter mutagenesis defining minimal regulatory region","pmids":["19188603"],"is_preprint":false},{"year":2003,"finding":"CDX1 specifically transactivates the glucose-6-phosphatase (Glc6Pase) promoter through its TATA box, while CDX2 cannot, because CDX1 (but not CDX2) can physically interact with the TATA-binding protein (TBP). This functional difference is mediated by the carboxy domains defining the specificity of CDX1 versus CDX2.","method":"Gel shift assay, mutagenesis, transient transfection reporter assays, stable transfection of CDX1 in IEC6 cells with Glc6Pase protein induction","journal":"Nucleic acids research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vitro binding + reporter assays + cell-based protein induction, single lab","pmids":["12954759"],"is_preprint":false},{"year":2006,"finding":"CDX1 interacts physically with the TATA-binding protein (TBP) via its homeodomain, and this interaction connects CDX1 to members of the TFIID and Mediator complexes. The transcriptional activation requires both the homeodomain (for TBP interaction) and the N-terminal domain upstream of the homeodomain. The carboxy domains of CDX1 and CDX2 determine their specificity, as CDX2 does not interact with TBP despite having intrinsic activation capacity.","method":"Co-immunoprecipitation, domain-swap experiments, altered-specificity TBP mutant transfection assays, luciferase reporter assays","journal":"Nucleic acids research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal domain analysis and TBP altered-specificity mutant, single lab","pmids":["17158164"],"is_preprint":false},{"year":2004,"finding":"Cdx1 expression in COLO 205 colon cancer cells induces E-cadherin-dependent cell-cell adhesion and compaction. This is a specific transcriptional response; a Cdx1 mutant failed to elicit the effect. The adhesion phenotype is Ca2+-dependent and blockable by an E-cadherin-blocking antibody, but E-cadherin protein levels and intracellular distribution were unchanged by Cdx1.","method":"Stable transfection of Cdx1 in COLO 205 cells, blocking antibody experiments, electron microscopy, proliferation and gene expression assays","journal":"American journal of physiology. Gastrointestinal and liver physiology","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — specific Cdx1 mutant control included, multiple assays, single lab","pmids":["14977637"],"is_preprint":false},{"year":2007,"finding":"Cdx1 and Cdx2 expression in COLO 205 cells induces E-cadherin-mediated cell adhesion by reducing tyrosine phosphorylation of β-catenin and p120-catenin. Restoring tyrosine phosphorylation (by knocking down protein tyrosine phosphatase 1B) in Cdx2-expressing cells significantly reduced cell-cell adhesion, demonstrating the functional relevance of this mechanism.","method":"Stable transfection, co-immunoprecipitation, tyrosine phosphorylation-specific Western blot, siRNA knockdown of PTP1B, migration/invasion assays","journal":"American journal of physiology. Gastrointestinal and liver physiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — mechanistic rescue experiment with siRNA, multiple biochemical methods, single lab","pmids":["17463179"],"is_preprint":false},{"year":2007,"finding":"LRE (LEF/TCF response element) mutation in the Cdx1 proximal promoter is sufficient to phenocopy Cdx1-null vertebral defects in mice, demonstrating that Wnt signaling is the key mediator of Cdx1 expression in vivo. Mutation of LRE also greatly reduced RA-induced Cdx1 expression, demonstrating that Wnt signaling is required for retinoid regulation of Cdx1.","method":"Generation of LRE-null and LRE+RARE-null knock-in mice, skeletal analysis, Cdx1 expression analysis","journal":"Development (Cambridge, England)","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — in vivo promoter element mutagenesis with complete phenotypic analysis, demonstrates functional hierarchy of Wnt over RA at this locus","pmids":["17537796"],"is_preprint":false},{"year":2009,"finding":"Cdx1 directly represses Mafb expression in the neural tube posterior to the r6/r7 boundary, thereby refining hindbrain positional identity. ChIP analysis confirmed Cdx1 binding to regulatory sequences responsible for posterior Mafb repression. This repression is transient; after the 10-somite stage another mechanism restricts Mafb to r5/r6.","method":"In situ hybridization, immunofluorescence, chromatin immunoprecipitation (ChIP), regulatory sequence analysis in Cdx1 mutant mice","journal":"Development (Cambridge, England)","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — ChIP demonstrating direct in vivo binding plus in vivo loss-of-function showing derepression of Mafb","pmids":["21098558"],"is_preprint":false},{"year":2002,"finding":"Wild-type p53 inhibits the transcriptional activity of the Cdx1 promoter, while the inactive p53 mutant has no effect. Cdx1 in turn inhibits p21(WAF) transcription by binding to the p21(WAF) TATA-box and activates the Bcl-2 promoter P2 through a consensus Cdx-binding site, making Cdx1-overexpressing cells more resistant to adriamycin-induced apoptosis.","method":"Promoter-reporter assays, transient transfection in IEC-6 and SW480 cells, apoptosis assays","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — promoter binding and functional reporter assays with defined binding sites, single lab","pmids":["12270138"],"is_preprint":false},{"year":2007,"finding":"CDX1 protein interacts with SMAD3 independently of SMAD4, and this interaction inhibits SMAD3/SMAD4-dependent transcription by 10-fold. CDX2, by contrast, stimulates SMAD3 transcriptional activity 5-fold. These distinct interactions with SMAD3 underlie the differential effects of CDX1 and CDX2 on intestinal inflammation responses.","method":"Co-immunoprecipitation, GST-pulldown, luciferase reporter assays","journal":"Gut","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP and GST-pulldown with functional reporter assays, single lab","pmids":["17595234"],"is_preprint":false},{"year":2005,"finding":"COUP-TF (chicken ovalbumin upstream promoter-transcription factor) members antagonize RA-induced Cdx1 expression by competing with RXR-RAR heterodimers for binding to the Cdx1 RA response element, providing a repressor mechanism that restricts Cdx1 expression to the caudal embryo at E8.5.","method":"Promoter-reporter assays, binding competition experiments, in situ hybridization showing COUP-TF expression in anterior domains lacking Cdx1","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — in vitro binding competition with correlative in vivo expression data, single lab","pmids":["15677473"],"is_preprint":false},{"year":2009,"finding":"Cdx2 substituted into the Cdx1 locus (knock-in) perfectly complements the Cdx1-null skeletal phenotype, demonstrating that Cdx1 and Cdx2 are functionally equivalent for vertebral patterning in paraxial mesoderm. This functional redundancy is context-dependent, as shown by later work on intestinal transcriptional specificity.","method":"Cdx2 knock-in replacing Cdx1 locus in mice, skeletal analysis, Hox gene expression analysis, BAC transgenic overexpression","journal":"Developmental biology","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — definitive in vivo complementation experiment with full skeletal and molecular phenotyping","pmids":["19328777"],"is_preprint":false},{"year":2012,"finding":"CDX1 directly activates expression of stemness-associated reprogramming factors SALL4 and KLF5 in gastric epithelial cells. CDX1-induced SALL4 and KLF5 convert gastric epithelial cells into tissue stem-like progenitor cells that then transdifferentiate into intestinal epithelial cells. Inhibition of SALL4 or KLF5 suppresses CDX1-induced intestinal marker expression.","method":"ChIP-seq/microarray for CDX1 targets, siRNA knockdown of SALL4/KLF5, immunohistochemistry in human and mouse CDX1+ intestinal metaplasia","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — genome-wide CDX1 target identification combined with functional siRNA rescue experiments and in vivo validation","pmids":["23112162"],"is_preprint":false},{"year":2014,"finding":"Concomitant somatic loss of Cdx2 with a Cdx1 null allele in APC(Min/+) mice significantly increases the incidence of tumors in the distal colon, demonstrating that Cdx1 functions as a tumor suppressor specifically in the distal colon in the context of APC loss.","method":"Conditional somatic deletion of Cdx2 combined with Cdx1 null allele in APC(Min/+) mice, intestinal tumor analysis","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — compound genetic mouse model with defined phenotypic readout, in vivo loss-of-function epistasis","pmids":["25320087"],"is_preprint":false},{"year":2015,"finding":"CDX1 directly activates microRNA-215 (miR-215) transcription, as confirmed by ChIP-PCR and promoter luciferase assays. miR-215 in turn represses BMI1 and other stemness/cell-cycle genes, thereby mediating CDX1-induced differentiation and reduction of clonogenicity in colorectal cancer stem cells.","method":"Small RNA sequencing, quantitative ChIP-PCR, promoter luciferase assays, miR-215 overexpression/knockdown, genome-wide miR-215 target identification","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — ChIP confirming direct binding, promoter reporter validation, and functional miRNA overexpression/knockdown with defined targets","pmids":["25775580"],"is_preprint":false},{"year":2002,"finding":"Cdx1 expression in IEC-6 cells increases apolipoprotein B mRNA editing over 10-fold, associated with a significant increase in the editing factor ACF. This links Cdx1 to developmental regulation of apoB mRNA editing during intestinal differentiation.","method":"Stable transfection of Cdx1 in IEC-6 cells, apoB mRNA editing quantification, ACF protein analysis, small intestine isograft developmental analysis","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — gain-of-function in vitro with molecular readout (editing levels + ACF), supported by in vivo developmental correlation, single lab","pmids":["12493769"],"is_preprint":false},{"year":2002,"finding":"Oncogenic activation of the β-catenin/Tcf4 pathway in human colon cancer cells stimulates endogenous Cdx1 mRNA expression and Cdx1 promoter activity. Cdx2 exerts an inhibitory effect on both basal and β-catenin-stimulated Cdx1 promoter activity through its homeodomain, independently of canonical CDX binding sites.","method":"Transfection of activated β-catenin/TCF4 constructs, Cdx1 promoter-reporter assays, homeodomain mutant analysis in human colon cancer cell lines","journal":"FEBS letters","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — promoter-reporter with mutant homeodomain control, single lab","pmids":["11997022"],"is_preprint":false},{"year":2009,"finding":"Transgenic Cdx2 induces endogenous Cdx1 expression in the intestinal metaplastic mucosa of Cdx2-transgenic mouse stomach by directly binding to the unmethylated Cdx1 promoter region, as demonstrated by ChIP, EMSA, and luciferase reporter assays. siRNA-Cdx2 downregulates Cdx1 transcriptional activity, confirming Cdx2 as a direct positive regulator of Cdx1.","method":"Chromatin immunoprecipitation (ChIP), EMSA, luciferase reporter assays, siRNA knockdown of Cdx2, bisulfite sequencing of Cdx1 promoter","journal":"The FEBS journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP and EMSA confirming direct binding with functional reporter and siRNA confirmation, single lab","pmids":["19725873"],"is_preprint":false},{"year":2013,"finding":"Cdx1 and Cdx2 exhibit context-dependent transcriptional specificity in the intestine. Cdx2 is significantly less potent than Cdx1 at driving transcription from the Cdx1 promoter, and knock-in of Cdx2 in the Cdx1 locus cannot substitute for Cdx1 in the autoregulatory loop in intestinal cells—in contrast to its ability to complement Cdx1 in paraxial mesoderm.","method":"Cell-based reporter assays, in vivo Cdx2 gene-swap (knock-in) analysis in intestinal context","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo knock-in combined with in vitro reporter assays demonstrating context-dependent specificity, single lab","pmids":["23382958"],"is_preprint":false},{"year":2012,"finding":"Cdx1 directly binds conserved CDX binding sites within the HoxC8 early enhancer during Xenopus embryogenesis, as demonstrated by ChIP. Cdx1 overexpression leads to precocious HoxC8 expression and knockdown to slower HoxC8 expression. The mouse HoxC8 early enhancer in Xenopus recapitulates the same Cdx1-responsive temporal expression pattern.","method":"Chromatin immunoprecipitation (ChIP) in Xenopus embryos, Cdx1 overexpression and morpholino knockdown, cross-species enhancer assay","journal":"FASEB journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP in vivo with gain- and loss-of-function in Xenopus, single lab","pmids":["22426122"],"is_preprint":false},{"year":2011,"finding":"Cdx1 expression induces endogenous Cdx2 expression in transfected oesophageal squamous epithelial cells, suggesting a sequential CDX1→CDX2 pathway. Bile acids dose-dependently increase Cdx1 promoter activity and Cdx1 protein in oesophageal epithelial cells, upstream of CDX2 induction.","method":"Cdx1 expression vector transfection in oesophageal cells, Cdx1 promoter luciferase assay, immunohistochemistry in Barrett's rat model","journal":"Gut","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — promoter reporter and transfection experiments with in vivo rat model correlation, single lab","pmids":["19136512"],"is_preprint":false},{"year":2008,"finding":"CDX1 directly activates PPARγ gene expression at the transcriptional level through functional interaction with C/EBPα. Butyrate treatment increases the physical protein-protein interaction between CDX1 and C/EBPα, leading to enhanced PPARγ expression and intestinal cell differentiation.","method":"Promoter-reporter assays, co-immunoprecipitation of CDX1 and C/EBPα, butyrate treatment","journal":"FEBS letters","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — Co-IP demonstrating interaction plus reporter assays with butyrate modulation, single lab","pmids":["19059241"],"is_preprint":false},{"year":2011,"finding":"CDX1 and CDX2 directly bind to multiple sites in the ASBT (apical sodium-dependent bile acid transporter) gene promoter. Six CDX binding sites were verified by EMSA and ChIP assays in living cells, and CDX siRNA knockdown reduced ASBT mRNA. CDX1 and CDX2 strongly induced ASBT promoter activity in reporter assays.","method":"EMSA, chromatin immunoprecipitation (ChIP), siRNA knockdown, promoter-reporter assays, real-time PCR in Barrett's esophagus biopsies","journal":"American journal of physiology. Gastrointestinal and liver physiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo ChIP plus EMSA plus siRNA with functional reporter validation, single lab","pmids":["22016432"],"is_preprint":false},{"year":2013,"finding":"Oxidative stress (H2O2) silences CDX1 in colorectal cancer cells through epigenetic mechanisms: H2O2 increases CDX1 promoter methylation, upregulates DNMT1 and HDAC1 expression and activity, and enhances the physical association between DNMT1 and HDAC1. Pretreatment with the demethylation agent 5-Aza-dC reverses the H2O2-induced CDX1 silencing.","method":"Methylation-specific PCR, Western blot, DNMT1/HDAC1 activity assays, co-immunoprecipitation of DNMT1 and HDAC1, pharmacological inhibitor treatment","journal":"Gene","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — multiple biochemical methods in a single cell line, single lab","pmids":["23618814"],"is_preprint":false},{"year":2012,"finding":"Methylation of the CDX1 promoter is associated with closed chromatin structure and reduced NF-κB binding. NF-κB binding to the CDX1 promoter is methylation-dependent, demonstrated by competitive EMSA and ChIP. Along the gastritis-metaplasia-carcinoma sequence, an inverse biphasic pattern of CDX1 promoter methylation correlates inversely with NF-κB signaling activity and CDX1 expression.","method":"Competitive EMSA, chromatin immunoprecipitation (ChIP), bisulfite sequencing, clinical tissue series analysis","journal":"The American journal of pathology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — EMSA and ChIP establishing methylation-dependent NF-κB binding, single lab","pmids":["22749770"],"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 when expressed in immortalized human esophageal keratinocytes cultured in organotypic models, initiating the earliest stages of transdifferentiation.","method":"Microarray of esophageal/Barrett's/small intestinal biopsies, organotypic culture of esophageal keratinocytes with Cdx1 and c-myc expression, morphological and marker analysis","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — organotypic gain-of-function assay with molecular marker readouts, single lab","pmids":["18953412"],"is_preprint":false},{"year":2012,"finding":"Multiple miRNAs (miR-9, miR-16, miR-22) induced by Cdx1 expression directly bind to the CDX2 mRNA 3'UTR to destabilize and degrade CDX2 transcripts. Simultaneous mutation of both the miR-9- and miR-16-binding sites in the CDX2 3'UTR was sufficient to block Cdx2 suppression by Cdx1.","method":"MiRNA microarray, luciferase 3'UTR reporter assays, 3'UTR mutant analysis in SW480 cells","journal":"The Biochemical journal","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — 3'UTR reporter with site-specific mutations, single lab","pmids":["22849325"],"is_preprint":false},{"year":2014,"finding":"CDX1 restricts trophoblast cell invasiveness in HTR-8/SVneo cells by inhibiting MMP-9 expression and increasing TIMP-1 expression, independently of the PI3K/AKT signaling pathway. CDX1 itself is regulated by PI3K/AKT signaling.","method":"Stable transfection of CDX1, invasion assay (QCM ECMatrix), Western blot, qRT-PCR, PI3K inhibitor (perifosine) treatment","journal":"Placenta","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — gain-of-function with invasion assay and pharmacological dissection, single lab","pmids":["24836459"],"is_preprint":false},{"year":2022,"finding":"EHF physically interacts with CDX1 via its 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 significantly enhances colorectal tumor progression.","method":"Co-immunoprecipitation (EHF-CDX1 interaction), chromatin remodeling assays, transcriptional assays for VIL1, Ehf/Cdx1 compound conditional knockout mice, tumor progression analysis","journal":"Cell death and differentiation","confidence":"High","confidence_rationale":"Tier 2 / Strong — direct protein–protein interaction by Co-IP with defined domain, cooperative transcriptional assay, and compound in vivo genetic validation","pmids":["35606410"],"is_preprint":false},{"year":2011,"finding":"Class I and III HDACs contribute to epigenetic silencing of CDX1 in colorectal cancer. Unlike EPHB2-4 genes, the inactive CDX1 locus shows strong reduction of active histone modifications. Treatment with HDAC inhibitors combined with DNA methyltransferase inhibitors restores CDX1 expression depending upon the epigenetic features of its promoter.","method":"Quantitative expression profiling of matched normal/adenoma/carcinoma, histone modification ChIP, pharmacological treatment with DNMT and HDAC inhibitors in CRC cell lines","journal":"Epigenetics","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — ChIP for histone modifications plus pharmacological dissection, single lab","pmids":["21393996"],"is_preprint":false},{"year":2014,"finding":"Transient expression of CDX1 at E11.5 dpc in mouse embryonic hearts promotes epicardial epithelial-to-mesenchymal transition (EMT). Low-dose CDX1 induction enhances migration and differentiation of epicardium-derived cells into α-SMA+ vascular smooth muscle, while high-level or absence of CDX1 attenuates these abilities. RNA-seq showed CDX1 alters transcripts involved in neuronal development, angiogenesis, and cell adhesion.","method":"Doxycycline-inducible CDX1 mouse model, primary epicardium culture, ex vivo heart culture, RNA-seq","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — inducible in vivo model with primary cell culture validation and transcriptomic characterization, single lab","pmids":["25068460"],"is_preprint":false},{"year":2011,"finding":"Cdx1 negatively regulates the Pou5f1 (Oct3/4) gene network during gastrulation: Oct3/4 factors (Oct60, Oct25, Oct91) initially activate Cdx1 expression through FGF signaling before gastrulation, then become repressors during gastrulation. Cdx1 subsequently represses Pou5f1 genes, contributing to repression of pluripotency and promotion of gastrulation.","method":"Xenopus gain-of-function and morpholino knockdown, promoter analysis, FGF signaling pathway analysis","journal":"Developmental dynamics","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — Xenopus gain/loss-of-function with identified regulatory interaction, single lab","pmids":["21360791"],"is_preprint":false},{"year":2004,"finding":"Intestine-specific enhancers of CDX1 are located between -15601 and -5667 bp upstream of the CDX1 transcription start site. Transgenic mouse analysis showed that sequences between -5667 and +68 drive ectopic expression, while -15601 to +68 restricts expression to the intestinal epithelium. Two DNase I hypersensitive sites at ~-5.8 and -6.8 kb mark putative intestine-specific enhancers.","method":"Transgenic mouse analysis with CDX1 5' flanking sequences, DNase I hypersensitivity assay","journal":"American journal of physiology. Gastrointestinal and liver physiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo transgenic mouse promoter analysis with DNase I chromatin accessibility, single lab","pmids":["14715525"],"is_preprint":false},{"year":2002,"finding":"CDX1 transactivates the human PCNA gene promoter through Caudal-related homeodomain binding sequences in the PCNA 5'-flanking region in hepatocellular and colorectal carcinoma cell lines, while CDX2 does not. CDX1-induced PCNA expression was confirmed at the protein level, and CDX1 enhanced BrdU incorporation.","method":"Co-transfection of PCNA reporter with CDX1/CDX2 expression plasmids, Western blot, immunocytochemistry, BrdU incorporation assay","journal":"International journal of oncology","confidence":"Low","confidence_rationale":"Tier 3 / Weak — reporter assays and protein detection, single lab, no direct binding confirmation in this study","pmids":["11743638"],"is_preprint":false},{"year":2008,"finding":"Bile acid induces COX-2 expression in gastric cancer cells through a sequential pathway: bile acid induces the orphan nuclear receptor SHP, which then induces CDX1 expression; CDX1 in turn enhances COX-2 gene expression. This transcriptional cascade was verified by ectopic expression experiments.","method":"Promoter-reporter assays, ectopic expression of CDX1 and SHP, RT-PCR in human IM lesions","journal":"Carcinogenesis","confidence":"Low","confidence_rationale":"Tier 3 / Weak — overexpression reporter assays without direct binding confirmation for CDX1 on COX-2 promoter, single lab","pmids":["18775915"],"is_preprint":false}],"current_model":"CDX1 is a caudal-type homeodomain transcription factor that directly regulates Hox gene expression (including transactivation of HoxA7 and repression of Mafb, and timing of HoxC8 activation) to establish anteroposterior vertebral patterning; it is transcriptionally activated by Wnt/β-catenin signaling (through LEF/TCF response elements in its promoter, which are required in vivo), retinoic acid (through an atypical RARE), and FGF pathways, and it maintains its own expression via an autoregulatory loop dependent on a physical CDX1–LEF1 interaction; in the intestinal epithelium CDX1 promotes enterocyte differentiation (inducing KRT20, villin, aminopeptidase N) and E-cadherin-mediated cell adhesion (by reducing β- and p120-catenin tyrosine phosphorylation), suppresses proliferation by downregulating cyclin D1/D2, activates a CDX1→miR-215→BMI1 axis to suppress stemness, directly interacts with TBP and the TFIID/Mediator complexes for promoter-specific activation, interacts with SMAD3 to inhibit TGF-β transcriptional responses, and physically cooperates with EHF to drive colonic differentiation; its silencing in colorectal cancer is primarily mediated by promoter hypermethylation driven by oxidative stress, HDACs, and DNMT1."},"narrative":{"mechanistic_narrative":"CDX1 is a caudal-type homeodomain transcription factor that establishes anteroposterior axial identity by directly regulating Hox gene expression, with loss of function producing anterior homeotic vertebral transformations and posterior shifts in somitic Hox domains [PMID:7585967, PMID:11959827]. It acts at Hox loci both as an activator (transactivation of Hoxa-7; control of HoxC8 enhancer timing) and as a repressor (direct binding and posterior repression of Mafb in the hindbrain) [PMID:7585967, PMID:22426122, PMID:21098558]. CDX1 transcription integrates the major axial patterning signals: it is a direct Wnt/β-catenin target through promoter LEF/TCF response elements that are functionally required in vivo, a direct retinoic acid target through an atypical promoter RARE, and is maintained by an autoregulatory loop driven by a physical interaction between the CDX1 homeodomain and the B box of LEF1, with Wnt acting as the dominant input that is also required for retinoid responsiveness [PMID:10934025, PMID:10938132, PMID:11784033, PMID:15143193, PMID:17537796]. CDX1 and CDX2 are functionally interchangeable for vertebral patterning, as Cdx2 knocked into the Cdx1 locus fully complements the skeletal phenotype [PMID:19328777]. In the intestinal epithelium CDX1 drives enterocyte differentiation—inducing KRT20, villin and aminopeptidase N and reinforcing E-cadherin-mediated adhesion by lowering β-catenin and p120-catenin tyrosine phosphorylation—while restraining proliferation via downregulation of cyclin D1/D2 and inhibition of β-catenin/TCF activity [PMID:10660624, PMID:10579974, PMID:19188603, PMID:14977637, PMID:17463179, PMID:15215241]. It promotes a differentiated, less stem-like state through a CDX1→miR-215→BMI1 axis and cooperates physically with EHF to activate VIL1 and drive colonic differentiation, with compound Ehf/Cdx1 loss accelerating colorectal tumor progression and Cdx1 acting as a distal-colon tumor suppressor in the APC-mutant background [PMID:25775580, PMID:35606410, PMID:25320087]. Mechanistically, CDX1 achieves promoter-specific activation by interacting through its homeodomain with TBP and the TFIID/Mediator machinery—a property not shared by CDX2—and modulates other transcriptional programs by binding SMAD3 to suppress TGF-β responses [PMID:17158164, PMID:12954759, PMID:17595234]. In epithelial neoplasia, CDX1 is epigenetically silenced through promoter hypermethylation enforced by oxidative stress, DNMT1 and HDAC activity [PMID:14704280, PMID:23618814, PMID:21393996].","teleology":[{"year":1995,"claim":"Established CDX1 as a developmental regulator of axial identity by linking its loss to homeotic vertebral defects and identifying Hox genes as direct targets.","evidence":"Cdx1 knockout mice with skeletal phenotyping and in vitro Hoxa-7 transactivation","pmids":["7585967"],"confidence":"High","gaps":["Direct in vivo occupancy at Hox enhancers not yet shown","Activator vs repressor logic at individual Hox loci undefined"]},{"year":2000,"claim":"Resolved how CDX1 expression is positioned along the embryonic axis by showing it is a direct transcriptional readout of both Wnt/β-catenin and retinoic acid signaling.","evidence":"Promoter-reporter/EMSA with Tcf binding motifs plus Tcf4-knockout embryos, and an atypical RARE defined by promoter analysis","pmids":["10934025","10938132"],"confidence":"High","gaps":["Relative weighting of Wnt vs RA inputs not yet resolved","How signal inputs are spatially integrated unclear at this stage"]},{"year":2001,"claim":"Defined a multi-input regulatory architecture with RA early, Wnt later, and CDX1 autoregulation, and demonstrated Wnt3a is genetically required upstream of Cdx1.","evidence":"Promoter motif mutagenesis, Wnt3a hypomorph and Wnt3a-mutant mouse analysis with in situ hybridization","pmids":["11784033","11335109"],"confidence":"High","gaps":["Molecular basis of autoregulation not yet identified","Hierarchy among the three inputs not established"]},{"year":2003,"claim":"Validated the RARE as functionally required in vivo, confirming retinoid input directly controls a subset of CDX1 expression and patterning.","evidence":"Targeted RARE mutation knock-in mice with skeletal and Hox analysis","pmids":["14660544"],"confidence":"High","gaps":["RARE controls only a subset of Cdx1 function; remaining inputs unaccounted","Receptor occupancy in vivo not directly demonstrated"]},{"year":2004,"claim":"Explained CDX1 autoregulation mechanistically through a direct CDX1 homeodomain–LEF1 B-box interaction that synergistically drives the Cdx1 promoter.","evidence":"Co-IP, domain-swap reporter assays, and Cdx1/Wnt3a compound mutant mice","pmids":["15143193"],"confidence":"High","gaps":["Structural basis of the homeodomain–B box interface unknown","Whether this loop operates identically in intestine vs mesoderm not addressed here"]},{"year":2007,"claim":"Demonstrated the functional hierarchy of inputs by showing LEF/TCF element mutation alone phenocopies Cdx1-null defects and is required for RA-induced expression.","evidence":"LRE-null and LRE+RARE-null knock-in mice with skeletal and expression analysis","pmids":["17537796"],"confidence":"High","gaps":["Mechanism by which Wnt input gates RA responsiveness at the locus unclear"]},{"year":2009,"claim":"Tested CDX1/CDX2 equivalence by showing Cdx2 knocked into the Cdx1 locus fully complements vertebral patterning, defining context-dependent redundancy.","evidence":"Cdx2-into-Cdx1 knock-in mice with full skeletal and Hox phenotyping","pmids":["19328777"],"confidence":"High","gaps":["Why redundancy fails in intestine not explained by this study","Target-level differences underlying context dependence not mapped"]},{"year":2009,"claim":"Showed CDX1 acts as a direct repressor in addition to an activator by binding Mafb regulatory sequences to refine posterior hindbrain identity.","evidence":"ChIP and in situ analysis in Cdx1 mutant mouse neural tube","pmids":["21098558"],"confidence":"High","gaps":["Co-repressor partners at the Mafb locus unidentified","Mechanism switching CDX1 between activation and repression unknown"]},{"year":2006,"claim":"Provided a biochemical basis for CDX1 promoter-specific activation by demonstrating its homeodomain binds TBP and connects to TFIID/Mediator, a property distinguishing it from CDX2.","evidence":"Co-IP, domain swaps, and altered-specificity TBP mutant reporter assays","pmids":["12954759","17158164"],"confidence":"Medium","gaps":["Single lab; structural details of CDX1-TBP contact unresolved","Genome-wide consequence of TBP recruitment not assessed"]},{"year":2000,"claim":"Defined a core intestinal function for CDX1: enforcing differentiation while restraining cell cycle progression via cyclin D1/D2 downregulation.","evidence":"Inducible/stable and adenoviral CDX1 in IEC-6 cells with cell-cycle and differentiation marker readouts","pmids":["10660624","10579974"],"confidence":"High","gaps":["Direct CDX1 targets among cell-cycle genes not all defined","Some studies report opposing proliferation effects across cell contexts"]},{"year":2004,"claim":"Connected CDX1 to epithelial adhesion and to antagonism of oncogenic Wnt signaling, showing it induces E-cadherin-dependent adhesion and inhibits β-catenin/TCF activity.","evidence":"Stable transfection in COLO 205 colon cancer cells, blocking-antibody/EM assays, and TCF/β-catenin reporter assays","pmids":["14977637","15215241"],"confidence":"Medium","gaps":["Direct transcriptional target mediating adhesion not identified in 2004","Mechanism of β-catenin/TCF inhibition without altering β-catenin levels unclear"]},{"year":2007,"claim":"Provided a molecular mechanism for CDX1-driven adhesion via reduced tyrosine phosphorylation of β- and p120-catenin, and identified SMAD3 as a direct partner repressing TGF-β transcription.","evidence":"Co-IP, phospho-specific Western, PTP1B knockdown rescue, and SMAD3 GST-pulldown/reporter assays","pmids":["17463179","17595234"],"confidence":"Medium","gaps":["The phosphatase/kinase CDX1 acts through to alter catenin phosphorylation not defined","Single lab for SMAD3 interaction"]},{"year":2013,"claim":"Identified the regulatory basis of CDX1 loss in cancer as promoter hypermethylation coupled to HDAC-dependent chromatin silencing, reversible by demethylation.","evidence":"Methylation-specific PCR and demethylation rescue across 37 CRC cell lines, plus histone-modification ChIP and HDAC/DNMT inhibitor treatment","pmids":["14704280","21393996"],"confidence":"High","gaps":["Trigger initiating de novo methylation in vivo not defined here","Whether silencing is cause or consequence of dedifferentiation unresolved"]},{"year":2014,"claim":"Established CDX1 as a tumor suppressor in the distal colon in the APC-mutant context and identified a CDX1→miR-215→BMI1 axis suppressing stemness and clonogenicity.","evidence":"Compound Cdx1/Cdx2-loss APC(Min/+) tumor model, and ChIP-PCR/promoter reporter with miR-215 gain/loss-of-function","pmids":["25320087","25775580"],"confidence":"High","gaps":["Full set of CDX1/miR-215 effector targets incomplete","Region-specificity of tumor suppression mechanistically unexplained"]},{"year":2022,"claim":"Defined a physical CDX1–EHF partnership that cooperatively drives colonic differentiation genes and protects against tumor progression.","evidence":"Co-IP mapping the EHF PNT domain, VIL1 transcriptional assays, and Ehf/Cdx1 compound conditional knockout mice","pmids":["35606410"],"confidence":"High","gaps":["Genome-wide CDX1–EHF co-occupancy not fully mapped","Whether EHF cooperation extends beyond colon unknown"]},{"year":null,"claim":"How CDX1 switches between activator and repressor modes and selects target promoters across developmental versus intestinal contexts remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structural model of CDX1 on DNA or with TBP/LEF1/SMAD3/EHF","Genome-wide CDX1 binding atlas across tissues lacking","Mechanistic basis of CDX1 vs CDX2 target specificity incompletely defined"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[0,1,2,14,20,27]},{"term_id":"GO:0003677","term_label":"DNA binding","supporting_discovery_ids":[0,14,20,32,35]},{"term_id":"GO:0140097","term_label":"catalytic activity, acting on DNA","supporting_discovery_ids":[16]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[1,20]}],"pathway":[{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[0,9,19,24]},{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[14,16,20,27]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[1,12,22]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[13,26,36]}],"complexes":[],"partners":["LEF1","TBP","SMAD3","EHF","CTNNB1","CEBPA"],"other_free_text":[]}},"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":238,"is_preprint":false},{"pmid":"9036867","id":"PMC_9036867","title":"Molecular cloning, sequencing and expression of the mRNA encoding human Cdx1 and Cdx2 homeobox. 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Putative Cdx1-binding sites were identified in Hox gene control regions, and in vitro transactivation of Hoxa-7 by Cdx1 was demonstrated, indicating direct regulation of Hox genes by Cdx1.\",\n      \"method\": \"Homologous recombination (gene knockout), skeletal phenotype analysis, in vitro transactivation assay\",\n      \"journal\": \"Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — loss-of-function genetic model combined with in vitro transactivation and identification of binding sites, replicated in subsequent studies\",\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-binding motifs that bind Tcf/Lef1/β-catenin complexes and mediate β-catenin-dependent transactivation. Tcf4-deficient mouse embryos show abrogation of Cdx1 protein in the small intestinal epithelium.\",\n      \"method\": \"Promoter-reporter assays, gel shift assays, Tcf4-knockout mouse analysis, Wnt stimulation of ES cells and embryonic endoderm\",\n      \"journal\": \"Development (Cambridge, England)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — multiple orthogonal methods (promoter reporter, EMSA, in vivo knockout), replicated by 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. RA regulation of Cdx1 occurs through an atypical RA response element (RARE) in the proximal Cdx1 promoter, providing an indirect mechanism by which retinoid signaling impacts Hox expression and vertebral patterning.\",\n      \"method\": \"Promoter-reporter assays, retinoid receptor binding studies, in vitro RA treatment\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — direct promoter analysis with RARE identification, confirmed in vivo by RARE-null mutant mice in follow-up study (PMID:14660544)\",\n      \"pmids\": [\"10938132\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"Cdx1 expression is regulated by multiple pathways: (1) direct retinoid signaling through an atypical RARE at early stages; (2) Wnt3a signaling through functional LEF/TCF response elements at later stages; and (3) an autoregulatory loop in which Cdx1 positively regulates its own expression. Wnt3a and RA synergize strongly to activate Cdx1.\",\n      \"method\": \"Promoter-reporter assays, LEF/TCF motif mutagenesis, Wnt3a hypomorph (vestigial tail) mouse analysis, RA treatment experiments\",\n      \"journal\": \"Developmental biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — multiple orthogonal methods including in vivo mutant analysis and promoter mutagenesis, consistent with independent studies\",\n      \"pmids\": [\"11784033\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"Wnt-3a is required for normal cdx-1 expression in the primitive streak and tail bud region. Loss of Wnt-3a signaling leads to reduced Cdx1 expression and anterior homeotic vertebral transformations, placing Wnt-3a upstream of cdx-1 in anteroposterior patterning.\",\n      \"method\": \"Wnt3a mutant mouse analysis, in situ hybridization for Cdx1 expression\",\n      \"journal\": \"Mechanisms of development\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic epistasis in vivo, single lab, single primary method\",\n      \"pmids\": [\"11335109\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"Cdx1 inhibits intestinal epithelial cell (IEC-6) proliferation by causing G0/G1 arrest through marked reduction of cyclin D1 and D2 protein levels, leading to increased hypophosphorylated Rb and p130. Cyclin-dependent kinase inhibitors (p16, p18, p21, p27, p57) were not affected.\",\n      \"method\": \"Stable transfection of inducible Cdx1 constructs and adenoviral expression in IEC-6 cells, flow cytometry, Western blot for cell cycle proteins\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — clean loss/gain-of-function with defined molecular readouts, two delivery methods (stable transfection + adenovirus), consistent findings\",\n      \"pmids\": [\"10660624\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"Cdx1 expression in IEC-6 intestinal epithelial cells promotes differentiation toward a columnar enterocyte phenotype, including induction of aminopeptidase N and villin expression, redistribution of actin filaments to the cortex, and formation of multilayers with apical microvilli. Cdx1 also increased proliferation rate, resistance to apoptosis, and migration speed.\",\n      \"method\": \"Stable transfection of Cdx1 in IEC-6 cells, morphological analysis, immunofluorescence, in vitro wound assay\",\n      \"journal\": \"Gastroenterology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — stable overexpression with multiple phenotypic readouts, single lab\",\n      \"pmids\": [\"10579974\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"Cdx1 expression in IEC-6 intestinal epithelial cells induces anchorage-independent growth and adenocarcinoma formation in vivo. These oncogenic effects correlate with increased GTP-bound Ras, modulation of Cdc42 and RhoA activities, and accumulation of PI3 kinase products. Combined inhibition of Ras/Rho and PI3 kinase signaling blocked colony formation.\",\n      \"method\": \"Stable transfection, soft agar assay, in vivo tumor formation, GTP-pulldown assays, PI3K inhibitor treatment\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal assays (in vitro and in vivo), single lab\",\n      \"pmids\": [\"11464284\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"Cdx1 directly activates the PAP I (Pancreatitis Associated Protein I) promoter through a Cdx1-binding element, as demonstrated by promoter binding and deletion analysis. PAP I in turn acts as a proliferative factor for intestinal cells via an autocrine/paracrine mechanism, mediating part of the Cdx1-induced growth effect.\",\n      \"method\": \"Stable transfection, gel shift assay, promoter deletion analysis, antisense knockdown of PAP I, adenoviral PAP I overexpression\",\n      \"journal\": \"European journal of cell biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct promoter binding demonstrated with functional deletion and antisense validation, single lab\",\n      \"pmids\": [\"11302520\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"Cdx1 and Cdx2 cooperate in anteroposterior vertebral patterning and posterior axis elongation. Compound Cdx1 null/Cdx2 heterozygous mutants show extensive homeotic transformations along the entire vertebral column and posterior truncation, associated with early alterations in Hox gene expression boundaries in the somitic mesoderm.\",\n      \"method\": \"Generation of compound Cdx1/Cdx2 mutant mice, skeletal analysis, Hox gene expression by in situ hybridization\",\n      \"journal\": \"Development (Cambridge, England)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic epistasis in vivo with compound mutants, replicated by independent lab\",\n      \"pmids\": [\"11959827\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"RARE-null (retinoic acid response element-null) Cdx1 mutant mice exhibit reduced Cdx1 expression, vertebral homeotic transformations, and altered Hox gene expression similar to a subset of Cdx1-null defects, demonstrating that the RARE in the Cdx1 proximal promoter is functionally required in vivo for a specific subset of Cdx1 expression and function.\",\n      \"method\": \"Targeted mutation of the RARE in the Cdx1 promoter in mice, skeletal analysis, Hox expression analysis\",\n      \"journal\": \"Development (Cambridge, England)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — in vivo promoter element mutagenesis confirming functional relevance of RARE, consistent with in vitro data\",\n      \"pmids\": [\"14660544\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"Cdx1 autoregulation occurs through a novel physical interaction between the homeodomain of Cdx1 and the B box of LEF1. Cdx1 and LEF1 synergize to induce Cdx1 expression from its own promoter through LEF/TCF response elements. This was confirmed in vivo by Cdx1/Wnt3a(vt) compound mutants showing convergent effects on Cdx1 expression and vertebral patterning.\",\n      \"method\": \"Co-immunoprecipitation, promoter-reporter assays, domain-swap experiments, Cdx1/Wnt3a compound mutant mouse analysis\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — direct protein–protein interaction demonstrated by Co-IP plus in vivo genetic validation in compound mutants\",\n      \"pmids\": [\"15143193\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"Cdx1 or Cdx2 expression inhibits β-catenin/TCF transcriptional activity in colon cancer cells in a dose-dependent manner, reducing colon cancer cell proliferation. This inhibitory effect does not alter β-catenin protein levels or intracellular distribution, and does not induce an inhibitory TCF isoform.\",\n      \"method\": \"Transfection of Cdx1/Cdx2 expression constructs, TCF/β-catenin reporter assays, Western blot, proliferation assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — reporter assays and multiple cell lines, single lab\",\n      \"pmids\": [\"15215241\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"Loss of CDX1 expression in colorectal carcinoma is primarily regulated by promoter methylation. All CRC cell lines lacking CDX1 mRNA had a methylated CDX1 promoter, and demethylation with 5-aza-2'-deoxycytidine restored CDX1 expression. No coding mutations or LOH explained the loss of expression.\",\n      \"method\": \"Methylation-specific PCR, RT-PCR, demethylation treatment, LOH analysis, mutation 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 / Strong — comprehensive analysis of 37 cell lines with multiple molecular methods, confirmed by pharmacological demethylation\",\n      \"pmids\": [\"14704280\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"CDX1 directly regulates the KRT20 (Cytokeratin 20) promoter. ChIP analysis confirmed CDX1 binding to predicted CDX elements within 246 bp upstream of the KRT20 transcription start site in vivo. CDX1 and KRT20 expression are significantly correlated in colorectal cancer cell lines.\",\n      \"method\": \"Chromatin immunoprecipitation (ChIP), promoter deletion and mutation analysis, microarray, expression correlation in 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 / Strong — ChIP confirming in vivo binding plus promoter mutagenesis defining minimal regulatory region\",\n      \"pmids\": [\"19188603\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"CDX1 specifically transactivates the glucose-6-phosphatase (Glc6Pase) promoter through its TATA box, while CDX2 cannot, because CDX1 (but not CDX2) can physically interact with the TATA-binding protein (TBP). This functional difference is mediated by the carboxy domains defining the specificity of CDX1 versus CDX2.\",\n      \"method\": \"Gel shift assay, mutagenesis, transient transfection reporter assays, stable transfection of CDX1 in IEC6 cells with Glc6Pase protein induction\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vitro binding + reporter assays + cell-based protein induction, single lab\",\n      \"pmids\": [\"12954759\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"CDX1 interacts physically with the TATA-binding protein (TBP) via its homeodomain, and this interaction connects CDX1 to members of the TFIID and Mediator complexes. The transcriptional activation requires both the homeodomain (for TBP interaction) and the N-terminal domain upstream of the homeodomain. The carboxy domains of CDX1 and CDX2 determine their specificity, as CDX2 does not interact with TBP despite having intrinsic activation capacity.\",\n      \"method\": \"Co-immunoprecipitation, domain-swap experiments, altered-specificity TBP mutant transfection assays, luciferase reporter assays\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal domain analysis and TBP altered-specificity mutant, single lab\",\n      \"pmids\": [\"17158164\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"Cdx1 expression in COLO 205 colon cancer cells induces E-cadherin-dependent cell-cell adhesion and compaction. This is a specific transcriptional response; a Cdx1 mutant failed to elicit the effect. The adhesion phenotype is Ca2+-dependent and blockable by an E-cadherin-blocking antibody, but E-cadherin protein levels and intracellular distribution were unchanged by Cdx1.\",\n      \"method\": \"Stable transfection of Cdx1 in COLO 205 cells, blocking antibody experiments, electron microscopy, proliferation and gene expression assays\",\n      \"journal\": \"American journal of physiology. Gastrointestinal and liver physiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — specific Cdx1 mutant control included, multiple assays, single lab\",\n      \"pmids\": [\"14977637\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"Cdx1 and Cdx2 expression in COLO 205 cells induces E-cadherin-mediated cell adhesion by reducing tyrosine phosphorylation of β-catenin and p120-catenin. Restoring tyrosine phosphorylation (by knocking down protein tyrosine phosphatase 1B) in Cdx2-expressing cells significantly reduced cell-cell adhesion, demonstrating the functional relevance of this mechanism.\",\n      \"method\": \"Stable transfection, co-immunoprecipitation, tyrosine phosphorylation-specific Western blot, siRNA knockdown of PTP1B, migration/invasion assays\",\n      \"journal\": \"American journal of physiology. Gastrointestinal and liver physiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — mechanistic rescue experiment with siRNA, multiple biochemical methods, single lab\",\n      \"pmids\": [\"17463179\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"LRE (LEF/TCF response element) mutation in the Cdx1 proximal promoter is sufficient to phenocopy Cdx1-null vertebral defects in mice, demonstrating that Wnt signaling is the key mediator of Cdx1 expression in vivo. Mutation of LRE also greatly reduced RA-induced Cdx1 expression, demonstrating that Wnt signaling is required for retinoid regulation of Cdx1.\",\n      \"method\": \"Generation of LRE-null and LRE+RARE-null knock-in mice, skeletal analysis, Cdx1 expression analysis\",\n      \"journal\": \"Development (Cambridge, England)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — in vivo promoter element mutagenesis with complete phenotypic analysis, demonstrates functional hierarchy of Wnt over RA at this locus\",\n      \"pmids\": [\"17537796\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"Cdx1 directly represses Mafb expression in the neural tube posterior to the r6/r7 boundary, thereby refining hindbrain positional identity. ChIP analysis confirmed Cdx1 binding to regulatory sequences responsible for posterior Mafb repression. This repression is transient; after the 10-somite stage another mechanism restricts Mafb to r5/r6.\",\n      \"method\": \"In situ hybridization, immunofluorescence, chromatin immunoprecipitation (ChIP), regulatory sequence analysis in Cdx1 mutant mice\",\n      \"journal\": \"Development (Cambridge, England)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — ChIP demonstrating direct in vivo binding plus in vivo loss-of-function showing derepression of Mafb\",\n      \"pmids\": [\"21098558\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"Wild-type p53 inhibits the transcriptional activity of the Cdx1 promoter, while the inactive p53 mutant has no effect. Cdx1 in turn inhibits p21(WAF) transcription by binding to the p21(WAF) TATA-box and activates the Bcl-2 promoter P2 through a consensus Cdx-binding site, making Cdx1-overexpressing cells more resistant to adriamycin-induced apoptosis.\",\n      \"method\": \"Promoter-reporter assays, transient transfection in IEC-6 and SW480 cells, apoptosis assays\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — promoter binding and functional reporter assays with defined binding sites, single lab\",\n      \"pmids\": [\"12270138\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"CDX1 protein interacts with SMAD3 independently of SMAD4, and this interaction inhibits SMAD3/SMAD4-dependent transcription by 10-fold. CDX2, by contrast, stimulates SMAD3 transcriptional activity 5-fold. These distinct interactions with SMAD3 underlie the differential effects of CDX1 and CDX2 on intestinal inflammation responses.\",\n      \"method\": \"Co-immunoprecipitation, GST-pulldown, luciferase reporter assays\",\n      \"journal\": \"Gut\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP and GST-pulldown with functional reporter assays, single lab\",\n      \"pmids\": [\"17595234\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"COUP-TF (chicken ovalbumin upstream promoter-transcription factor) members antagonize RA-induced Cdx1 expression by competing with RXR-RAR heterodimers for binding to the Cdx1 RA response element, providing a repressor mechanism that restricts Cdx1 expression to the caudal embryo at E8.5.\",\n      \"method\": \"Promoter-reporter assays, binding competition experiments, in situ hybridization showing COUP-TF expression in anterior domains lacking Cdx1\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — in vitro binding competition with correlative in vivo expression data, single lab\",\n      \"pmids\": [\"15677473\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"Cdx2 substituted into the Cdx1 locus (knock-in) perfectly complements the Cdx1-null skeletal phenotype, demonstrating that Cdx1 and Cdx2 are functionally equivalent for vertebral patterning in paraxial mesoderm. This functional redundancy is context-dependent, as shown by later work on intestinal transcriptional specificity.\",\n      \"method\": \"Cdx2 knock-in replacing Cdx1 locus in mice, skeletal analysis, Hox gene expression analysis, BAC transgenic overexpression\",\n      \"journal\": \"Developmental biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — definitive in vivo complementation experiment with full skeletal and molecular phenotyping\",\n      \"pmids\": [\"19328777\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"CDX1 directly activates expression of stemness-associated reprogramming factors SALL4 and KLF5 in gastric epithelial cells. CDX1-induced SALL4 and KLF5 convert gastric epithelial cells into tissue stem-like progenitor cells that then transdifferentiate into intestinal epithelial cells. Inhibition of SALL4 or KLF5 suppresses CDX1-induced intestinal marker expression.\",\n      \"method\": \"ChIP-seq/microarray for CDX1 targets, siRNA knockdown of SALL4/KLF5, immunohistochemistry in human and mouse CDX1+ intestinal metaplasia\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — genome-wide CDX1 target identification combined with functional siRNA rescue experiments and in vivo validation\",\n      \"pmids\": [\"23112162\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Concomitant somatic loss of Cdx2 with a Cdx1 null allele in APC(Min/+) mice significantly increases the incidence of tumors in the distal colon, demonstrating that Cdx1 functions as a tumor suppressor specifically in the distal colon in the context of APC loss.\",\n      \"method\": \"Conditional somatic deletion of Cdx2 combined with Cdx1 null allele in APC(Min/+) mice, intestinal tumor analysis\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — compound genetic mouse model with defined phenotypic readout, in vivo loss-of-function epistasis\",\n      \"pmids\": [\"25320087\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"CDX1 directly activates microRNA-215 (miR-215) transcription, as confirmed by ChIP-PCR and promoter luciferase assays. miR-215 in turn represses BMI1 and other stemness/cell-cycle genes, thereby mediating CDX1-induced differentiation and reduction of clonogenicity in colorectal cancer stem cells.\",\n      \"method\": \"Small RNA sequencing, quantitative ChIP-PCR, promoter luciferase assays, miR-215 overexpression/knockdown, genome-wide miR-215 target identification\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — ChIP confirming direct binding, promoter reporter validation, and functional miRNA overexpression/knockdown with defined targets\",\n      \"pmids\": [\"25775580\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"Cdx1 expression in IEC-6 cells increases apolipoprotein B mRNA editing over 10-fold, associated with a significant increase in the editing factor ACF. This links Cdx1 to developmental regulation of apoB mRNA editing during intestinal differentiation.\",\n      \"method\": \"Stable transfection of Cdx1 in IEC-6 cells, apoB mRNA editing quantification, ACF protein analysis, small intestine isograft developmental analysis\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — gain-of-function in vitro with molecular readout (editing levels + ACF), supported by in vivo developmental correlation, single lab\",\n      \"pmids\": [\"12493769\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"Oncogenic activation of the β-catenin/Tcf4 pathway in human colon cancer cells stimulates endogenous Cdx1 mRNA expression and Cdx1 promoter activity. Cdx2 exerts an inhibitory effect on both basal and β-catenin-stimulated Cdx1 promoter activity through its homeodomain, independently of canonical CDX binding sites.\",\n      \"method\": \"Transfection of activated β-catenin/TCF4 constructs, Cdx1 promoter-reporter assays, homeodomain mutant analysis in human colon cancer cell lines\",\n      \"journal\": \"FEBS letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — promoter-reporter with mutant homeodomain control, single lab\",\n      \"pmids\": [\"11997022\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"Transgenic Cdx2 induces endogenous Cdx1 expression in the intestinal metaplastic mucosa of Cdx2-transgenic mouse stomach by directly binding to the unmethylated Cdx1 promoter region, as demonstrated by ChIP, EMSA, and luciferase reporter assays. siRNA-Cdx2 downregulates Cdx1 transcriptional activity, confirming Cdx2 as a direct positive regulator of Cdx1.\",\n      \"method\": \"Chromatin immunoprecipitation (ChIP), EMSA, luciferase reporter assays, siRNA knockdown of Cdx2, bisulfite sequencing of Cdx1 promoter\",\n      \"journal\": \"The FEBS journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP and EMSA confirming direct binding with functional reporter and siRNA confirmation, single lab\",\n      \"pmids\": [\"19725873\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Cdx1 and Cdx2 exhibit context-dependent transcriptional specificity in the intestine. Cdx2 is significantly less potent than Cdx1 at driving transcription from the Cdx1 promoter, and knock-in of Cdx2 in the Cdx1 locus cannot substitute for Cdx1 in the autoregulatory loop in intestinal cells—in contrast to its ability to complement Cdx1 in paraxial mesoderm.\",\n      \"method\": \"Cell-based reporter assays, in vivo Cdx2 gene-swap (knock-in) analysis in intestinal context\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo knock-in combined with in vitro reporter assays demonstrating context-dependent specificity, single lab\",\n      \"pmids\": [\"23382958\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Cdx1 directly binds conserved CDX binding sites within the HoxC8 early enhancer during Xenopus embryogenesis, as demonstrated by ChIP. Cdx1 overexpression leads to precocious HoxC8 expression and knockdown to slower HoxC8 expression. The mouse HoxC8 early enhancer in Xenopus recapitulates the same Cdx1-responsive temporal expression pattern.\",\n      \"method\": \"Chromatin immunoprecipitation (ChIP) in Xenopus embryos, Cdx1 overexpression and morpholino knockdown, cross-species enhancer assay\",\n      \"journal\": \"FASEB journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP in vivo with gain- and loss-of-function in Xenopus, single lab\",\n      \"pmids\": [\"22426122\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Cdx1 expression induces endogenous Cdx2 expression in transfected oesophageal squamous epithelial cells, suggesting a sequential CDX1→CDX2 pathway. Bile acids dose-dependently increase Cdx1 promoter activity and Cdx1 protein in oesophageal epithelial cells, upstream of CDX2 induction.\",\n      \"method\": \"Cdx1 expression vector transfection in oesophageal cells, Cdx1 promoter luciferase assay, immunohistochemistry in Barrett's rat model\",\n      \"journal\": \"Gut\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — promoter reporter and transfection experiments with in vivo rat model correlation, single lab\",\n      \"pmids\": [\"19136512\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"CDX1 directly activates PPARγ gene expression at the transcriptional level through functional interaction with C/EBPα. Butyrate treatment increases the physical protein-protein interaction between CDX1 and C/EBPα, leading to enhanced PPARγ expression and intestinal cell differentiation.\",\n      \"method\": \"Promoter-reporter assays, co-immunoprecipitation of CDX1 and C/EBPα, butyrate treatment\",\n      \"journal\": \"FEBS letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — Co-IP demonstrating interaction plus reporter assays with butyrate modulation, single lab\",\n      \"pmids\": [\"19059241\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"CDX1 and CDX2 directly bind to multiple sites in the ASBT (apical sodium-dependent bile acid transporter) gene promoter. Six CDX binding sites were verified by EMSA and ChIP assays in living cells, and CDX siRNA knockdown reduced ASBT mRNA. CDX1 and CDX2 strongly induced ASBT promoter activity in reporter assays.\",\n      \"method\": \"EMSA, chromatin immunoprecipitation (ChIP), siRNA knockdown, promoter-reporter assays, real-time PCR in Barrett's esophagus biopsies\",\n      \"journal\": \"American journal of physiology. Gastrointestinal and liver physiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo ChIP plus EMSA plus siRNA with functional reporter validation, single lab\",\n      \"pmids\": [\"22016432\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Oxidative stress (H2O2) silences CDX1 in colorectal cancer cells through epigenetic mechanisms: H2O2 increases CDX1 promoter methylation, upregulates DNMT1 and HDAC1 expression and activity, and enhances the physical association between DNMT1 and HDAC1. Pretreatment with the demethylation agent 5-Aza-dC reverses the H2O2-induced CDX1 silencing.\",\n      \"method\": \"Methylation-specific PCR, Western blot, DNMT1/HDAC1 activity assays, co-immunoprecipitation of DNMT1 and HDAC1, pharmacological inhibitor treatment\",\n      \"journal\": \"Gene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — multiple biochemical methods in a single cell line, single lab\",\n      \"pmids\": [\"23618814\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Methylation of the CDX1 promoter is associated with closed chromatin structure and reduced NF-κB binding. NF-κB binding to the CDX1 promoter is methylation-dependent, demonstrated by competitive EMSA and ChIP. Along the gastritis-metaplasia-carcinoma sequence, an inverse biphasic pattern of CDX1 promoter methylation correlates inversely with NF-κB signaling activity and CDX1 expression.\",\n      \"method\": \"Competitive EMSA, chromatin immunoprecipitation (ChIP), bisulfite sequencing, clinical tissue series analysis\",\n      \"journal\": \"The American journal of pathology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — EMSA and ChIP establishing methylation-dependent NF-κB binding, single lab\",\n      \"pmids\": [\"22749770\"],\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 when expressed in immortalized human esophageal keratinocytes cultured in organotypic models, initiating the earliest stages of transdifferentiation.\",\n      \"method\": \"Microarray of esophageal/Barrett's/small intestinal biopsies, organotypic culture of esophageal keratinocytes with Cdx1 and c-myc expression, morphological and marker analysis\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — organotypic gain-of-function assay with molecular marker readouts, single lab\",\n      \"pmids\": [\"18953412\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Multiple miRNAs (miR-9, miR-16, miR-22) induced by Cdx1 expression directly bind to the CDX2 mRNA 3'UTR to destabilize and degrade CDX2 transcripts. Simultaneous mutation of both the miR-9- and miR-16-binding sites in the CDX2 3'UTR was sufficient to block Cdx2 suppression by Cdx1.\",\n      \"method\": \"MiRNA microarray, luciferase 3'UTR reporter assays, 3'UTR mutant analysis in SW480 cells\",\n      \"journal\": \"The Biochemical journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — 3'UTR reporter with site-specific mutations, single lab\",\n      \"pmids\": [\"22849325\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"CDX1 restricts trophoblast cell invasiveness in HTR-8/SVneo cells by inhibiting MMP-9 expression and increasing TIMP-1 expression, independently of the PI3K/AKT signaling pathway. CDX1 itself is regulated by PI3K/AKT signaling.\",\n      \"method\": \"Stable transfection of CDX1, invasion assay (QCM ECMatrix), Western blot, qRT-PCR, PI3K inhibitor (perifosine) treatment\",\n      \"journal\": \"Placenta\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — gain-of-function with invasion assay and pharmacological dissection, single lab\",\n      \"pmids\": [\"24836459\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"EHF physically interacts with CDX1 via its 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 significantly enhances colorectal tumor progression.\",\n      \"method\": \"Co-immunoprecipitation (EHF-CDX1 interaction), chromatin remodeling assays, transcriptional assays for VIL1, Ehf/Cdx1 compound conditional knockout mice, tumor progression analysis\",\n      \"journal\": \"Cell death and differentiation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — direct protein–protein interaction by Co-IP with defined domain, cooperative transcriptional assay, and compound in vivo genetic validation\",\n      \"pmids\": [\"35606410\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Class I and III HDACs contribute to epigenetic silencing of CDX1 in colorectal cancer. Unlike EPHB2-4 genes, the inactive CDX1 locus shows strong reduction of active histone modifications. Treatment with HDAC inhibitors combined with DNA methyltransferase inhibitors restores CDX1 expression depending upon the epigenetic features of its promoter.\",\n      \"method\": \"Quantitative expression profiling of matched normal/adenoma/carcinoma, histone modification ChIP, pharmacological treatment with DNMT and HDAC inhibitors in CRC cell lines\",\n      \"journal\": \"Epigenetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — ChIP for histone modifications plus pharmacological dissection, single lab\",\n      \"pmids\": [\"21393996\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Transient expression of CDX1 at E11.5 dpc in mouse embryonic hearts promotes epicardial epithelial-to-mesenchymal transition (EMT). Low-dose CDX1 induction enhances migration and differentiation of epicardium-derived cells into α-SMA+ vascular smooth muscle, while high-level or absence of CDX1 attenuates these abilities. RNA-seq showed CDX1 alters transcripts involved in neuronal development, angiogenesis, and cell adhesion.\",\n      \"method\": \"Doxycycline-inducible CDX1 mouse model, primary epicardium culture, ex vivo heart culture, RNA-seq\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — inducible in vivo model with primary cell culture validation and transcriptomic characterization, single lab\",\n      \"pmids\": [\"25068460\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Cdx1 negatively regulates the Pou5f1 (Oct3/4) gene network during gastrulation: Oct3/4 factors (Oct60, Oct25, Oct91) initially activate Cdx1 expression through FGF signaling before gastrulation, then become repressors during gastrulation. Cdx1 subsequently represses Pou5f1 genes, contributing to repression of pluripotency and promotion of gastrulation.\",\n      \"method\": \"Xenopus gain-of-function and morpholino knockdown, promoter analysis, FGF signaling pathway analysis\",\n      \"journal\": \"Developmental dynamics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — Xenopus gain/loss-of-function with identified regulatory interaction, single lab\",\n      \"pmids\": [\"21360791\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"Intestine-specific enhancers of CDX1 are located between -15601 and -5667 bp upstream of the CDX1 transcription start site. Transgenic mouse analysis showed that sequences between -5667 and +68 drive ectopic expression, while -15601 to +68 restricts expression to the intestinal epithelium. Two DNase I hypersensitive sites at ~-5.8 and -6.8 kb mark putative intestine-specific enhancers.\",\n      \"method\": \"Transgenic mouse analysis with CDX1 5' flanking sequences, DNase I hypersensitivity assay\",\n      \"journal\": \"American journal of physiology. Gastrointestinal and liver physiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo transgenic mouse promoter analysis with DNase I chromatin accessibility, single lab\",\n      \"pmids\": [\"14715525\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"CDX1 transactivates the human PCNA gene promoter through Caudal-related homeodomain binding sequences in the PCNA 5'-flanking region in hepatocellular and colorectal carcinoma cell lines, while CDX2 does not. CDX1-induced PCNA expression was confirmed at the protein level, and CDX1 enhanced BrdU incorporation.\",\n      \"method\": \"Co-transfection of PCNA reporter with CDX1/CDX2 expression plasmids, Western blot, immunocytochemistry, BrdU incorporation assay\",\n      \"journal\": \"International journal of oncology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — reporter assays and protein detection, single lab, no direct binding confirmation in this study\",\n      \"pmids\": [\"11743638\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Bile acid induces COX-2 expression in gastric cancer cells through a sequential pathway: bile acid induces the orphan nuclear receptor SHP, which then induces CDX1 expression; CDX1 in turn enhances COX-2 gene expression. This transcriptional cascade was verified by ectopic expression experiments.\",\n      \"method\": \"Promoter-reporter assays, ectopic expression of CDX1 and SHP, RT-PCR in human IM lesions\",\n      \"journal\": \"Carcinogenesis\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — overexpression reporter assays without direct binding confirmation for CDX1 on COX-2 promoter, single lab\",\n      \"pmids\": [\"18775915\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"CDX1 is a caudal-type homeodomain transcription factor that directly regulates Hox gene expression (including transactivation of HoxA7 and repression of Mafb, and timing of HoxC8 activation) to establish anteroposterior vertebral patterning; it is transcriptionally activated by Wnt/β-catenin signaling (through LEF/TCF response elements in its promoter, which are required in vivo), retinoic acid (through an atypical RARE), and FGF pathways, and it maintains its own expression via an autoregulatory loop dependent on a physical CDX1–LEF1 interaction; in the intestinal epithelium CDX1 promotes enterocyte differentiation (inducing KRT20, villin, aminopeptidase N) and E-cadherin-mediated cell adhesion (by reducing β- and p120-catenin tyrosine phosphorylation), suppresses proliferation by downregulating cyclin D1/D2, activates a CDX1→miR-215→BMI1 axis to suppress stemness, directly interacts with TBP and the TFIID/Mediator complexes for promoter-specific activation, interacts with SMAD3 to inhibit TGF-β transcriptional responses, and physically cooperates with EHF to drive colonic differentiation; its silencing in colorectal cancer is primarily mediated by promoter hypermethylation driven by oxidative stress, HDACs, and DNMT1.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"CDX1 is a caudal-type homeodomain transcription factor that establishes anteroposterior axial identity by directly regulating Hox gene expression, with loss of function producing anterior homeotic vertebral transformations and posterior shifts in somitic Hox domains [#0, #9]. It acts at Hox loci both as an activator (transactivation of Hoxa-7; control of HoxC8 enhancer timing) and as a repressor (direct binding and posterior repression of Mafb in the hindbrain) [#0, #32, #20]. CDX1 transcription integrates the major axial patterning signals: it is a direct Wnt/\\u03b2-catenin target through promoter LEF/TCF response elements that are functionally required in vivo, a direct retinoic acid target through an atypical promoter RARE, and is maintained by an autoregulatory loop driven by a physical interaction between the CDX1 homeodomain and the B box of LEF1, with Wnt acting as the dominant input that is also required for retinoid responsiveness [#1, #2, #3, #11, #19]. CDX1 and CDX2 are functionally interchangeable for vertebral patterning, as Cdx2 knocked into the Cdx1 locus fully complements the skeletal phenotype [#24]. In the intestinal epithelium CDX1 drives enterocyte differentiation\\u2014inducing KRT20, villin and aminopeptidase N and reinforcing E-cadherin-mediated adhesion by lowering \\u03b2-catenin and p120-catenin tyrosine phosphorylation\\u2014while restraining proliferation via downregulation of cyclin D1/D2 and inhibition of \\u03b2-catenin/TCF activity [#5, #6, #14, #17, #18, #12]. It promotes a differentiated, less stem-like state through a CDX1\\u2192miR-215\\u2192BMI1 axis and cooperates physically with EHF to activate VIL1 and drive colonic differentiation, with compound Ehf/Cdx1 loss accelerating colorectal tumor progression and Cdx1 acting as a distal-colon tumor suppressor in the APC-mutant background [#27, #41, #26]. Mechanistically, CDX1 achieves promoter-specific activation by interacting through its homeodomain with TBP and the TFIID/Mediator machinery\\u2014a property not shared by CDX2\\u2014and modulates other transcriptional programs by binding SMAD3 to suppress TGF-\\u03b2 responses [#16, #15, #22]. In epithelial neoplasia, CDX1 is epigenetically silenced through promoter hypermethylation enforced by oxidative stress, DNMT1 and HDAC activity [#13, #36, #42].\",\n  \"teleology\": [\n    {\n      \"year\": 1995,\n      \"claim\": \"Established CDX1 as a developmental regulator of axial identity by linking its loss to homeotic vertebral defects and identifying Hox genes as direct targets.\",\n      \"evidence\": \"Cdx1 knockout mice with skeletal phenotyping and in vitro Hoxa-7 transactivation\",\n      \"pmids\": [\"7585967\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct in vivo occupancy at Hox enhancers not yet shown\", \"Activator vs repressor logic at individual Hox loci undefined\"]\n    },\n    {\n      \"year\": 2000,\n      \"claim\": \"Resolved how CDX1 expression is positioned along the embryonic axis by showing it is a direct transcriptional readout of both Wnt/\\u03b2-catenin and retinoic acid signaling.\",\n      \"evidence\": \"Promoter-reporter/EMSA with Tcf binding motifs plus Tcf4-knockout embryos, and an atypical RARE defined by promoter analysis\",\n      \"pmids\": [\"10934025\", \"10938132\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Relative weighting of Wnt vs RA inputs not yet resolved\", \"How signal inputs are spatially integrated unclear at this stage\"]\n    },\n    {\n      \"year\": 2001,\n      \"claim\": \"Defined a multi-input regulatory architecture with RA early, Wnt later, and CDX1 autoregulation, and demonstrated Wnt3a is genetically required upstream of Cdx1.\",\n      \"evidence\": \"Promoter motif mutagenesis, Wnt3a hypomorph and Wnt3a-mutant mouse analysis with in situ hybridization\",\n      \"pmids\": [\"11784033\", \"11335109\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular basis of autoregulation not yet identified\", \"Hierarchy among the three inputs not established\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Validated the RARE as functionally required in vivo, confirming retinoid input directly controls a subset of CDX1 expression and patterning.\",\n      \"evidence\": \"Targeted RARE mutation knock-in mice with skeletal and Hox analysis\",\n      \"pmids\": [\"14660544\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"RARE controls only a subset of Cdx1 function; remaining inputs unaccounted\", \"Receptor occupancy in vivo not directly demonstrated\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Explained CDX1 autoregulation mechanistically through a direct CDX1 homeodomain\\u2013LEF1 B-box interaction that synergistically drives the Cdx1 promoter.\",\n      \"evidence\": \"Co-IP, domain-swap reporter assays, and Cdx1/Wnt3a compound mutant mice\",\n      \"pmids\": [\"15143193\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of the homeodomain\\u2013B box interface unknown\", \"Whether this loop operates identically in intestine vs mesoderm not addressed here\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Demonstrated the functional hierarchy of inputs by showing LEF/TCF element mutation alone phenocopies Cdx1-null defects and is required for RA-induced expression.\",\n      \"evidence\": \"LRE-null and LRE+RARE-null knock-in mice with skeletal and expression analysis\",\n      \"pmids\": [\"17537796\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism by which Wnt input gates RA responsiveness at the locus unclear\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Tested CDX1/CDX2 equivalence by showing Cdx2 knocked into the Cdx1 locus fully complements vertebral patterning, defining context-dependent redundancy.\",\n      \"evidence\": \"Cdx2-into-Cdx1 knock-in mice with full skeletal and Hox phenotyping\",\n      \"pmids\": [\"19328777\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Why redundancy fails in intestine not explained by this study\", \"Target-level differences underlying context dependence not mapped\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Showed CDX1 acts as a direct repressor in addition to an activator by binding Mafb regulatory sequences to refine posterior hindbrain identity.\",\n      \"evidence\": \"ChIP and in situ analysis in Cdx1 mutant mouse neural tube\",\n      \"pmids\": [\"21098558\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Co-repressor partners at the Mafb locus unidentified\", \"Mechanism switching CDX1 between activation and repression unknown\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Provided a biochemical basis for CDX1 promoter-specific activation by demonstrating its homeodomain binds TBP and connects to TFIID/Mediator, a property distinguishing it from CDX2.\",\n      \"evidence\": \"Co-IP, domain swaps, and altered-specificity TBP mutant reporter assays\",\n      \"pmids\": [\"12954759\", \"17158164\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab; structural details of CDX1-TBP contact unresolved\", \"Genome-wide consequence of TBP recruitment not assessed\"]\n    },\n    {\n      \"year\": 2000,\n      \"claim\": \"Defined a core intestinal function for CDX1: enforcing differentiation while restraining cell cycle progression via cyclin D1/D2 downregulation.\",\n      \"evidence\": \"Inducible/stable and adenoviral CDX1 in IEC-6 cells with cell-cycle and differentiation marker readouts\",\n      \"pmids\": [\"10660624\", \"10579974\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct CDX1 targets among cell-cycle genes not all defined\", \"Some studies report opposing proliferation effects across cell contexts\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Connected CDX1 to epithelial adhesion and to antagonism of oncogenic Wnt signaling, showing it induces E-cadherin-dependent adhesion and inhibits \\u03b2-catenin/TCF activity.\",\n      \"evidence\": \"Stable transfection in COLO 205 colon cancer cells, blocking-antibody/EM assays, and TCF/\\u03b2-catenin reporter assays\",\n      \"pmids\": [\"14977637\", \"15215241\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct transcriptional target mediating adhesion not identified in 2004\", \"Mechanism of \\u03b2-catenin/TCF inhibition without altering \\u03b2-catenin levels unclear\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Provided a molecular mechanism for CDX1-driven adhesion via reduced tyrosine phosphorylation of \\u03b2- and p120-catenin, and identified SMAD3 as a direct partner repressing TGF-\\u03b2 transcription.\",\n      \"evidence\": \"Co-IP, phospho-specific Western, PTP1B knockdown rescue, and SMAD3 GST-pulldown/reporter assays\",\n      \"pmids\": [\"17463179\", \"17595234\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"The phosphatase/kinase CDX1 acts through to alter catenin phosphorylation not defined\", \"Single lab for SMAD3 interaction\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Identified the regulatory basis of CDX1 loss in cancer as promoter hypermethylation coupled to HDAC-dependent chromatin silencing, reversible by demethylation.\",\n      \"evidence\": \"Methylation-specific PCR and demethylation rescue across 37 CRC cell lines, plus histone-modification ChIP and HDAC/DNMT inhibitor treatment\",\n      \"pmids\": [\"14704280\", \"21393996\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Trigger initiating de novo methylation in vivo not defined here\", \"Whether silencing is cause or consequence of dedifferentiation unresolved\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Established CDX1 as a tumor suppressor in the distal colon in the APC-mutant context and identified a CDX1\\u2192miR-215\\u2192BMI1 axis suppressing stemness and clonogenicity.\",\n      \"evidence\": \"Compound Cdx1/Cdx2-loss APC(Min/+) tumor model, and ChIP-PCR/promoter reporter with miR-215 gain/loss-of-function\",\n      \"pmids\": [\"25320087\", \"25775580\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Full set of CDX1/miR-215 effector targets incomplete\", \"Region-specificity of tumor suppression mechanistically unexplained\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Defined a physical CDX1\\u2013EHF partnership that cooperatively drives colonic differentiation genes and protects against tumor progression.\",\n      \"evidence\": \"Co-IP mapping the EHF PNT domain, VIL1 transcriptional assays, and Ehf/Cdx1 compound conditional knockout mice\",\n      \"pmids\": [\"35606410\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Genome-wide CDX1\\u2013EHF co-occupancy not fully mapped\", \"Whether EHF cooperation extends beyond colon unknown\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How CDX1 switches between activator and repressor modes and selects target promoters across developmental versus intestinal contexts remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structural model of CDX1 on DNA or with TBP/LEF1/SMAD3/EHF\", \"Genome-wide CDX1 binding atlas across tissues lacking\", \"Mechanistic basis of CDX1 vs CDX2 target specificity incompletely defined\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [0, 1, 2, 14, 20, 27]},\n      {\"term_id\": \"GO:0003677\", \"supporting_discovery_ids\": [0, 14, 20, 32, 35]},\n      {\"term_id\": \"GO:0140097\", \"supporting_discovery_ids\": [16]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [1, 20]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [0, 9, 19, 24]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [14, 16, 20, 27]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [1, 12, 22]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [13, 26, 36]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"LEF1\", \"TBP\", \"SMAD3\", \"EHF\", \"CTNNB1\", \"CEBPA\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":8,"faith_total":8,"faith_pct":100.0}}