{"gene":"NKX2-1","run_date":"2026-06-10T05:19:52","timeline":{"discoveries":[{"year":1995,"finding":"TTF-1/NKX2-1 is required for lung epithelial morphogenesis; antisense oligonucleotide suppression of TTF-1 translation in embryonic mouse lung explants inhibited branching morphogenesis, producing hyperplastic, unorganized epithelial cell proliferation without affecting the mesenchymal compartment.","method":"Antisense oligonucleotide inhibition in embryonic mouse lung branching morphogenesis model","journal":"Developmental biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — defined cellular phenotype with loss-of-function, single lab, antisense approach with tissue-specific readout","pmids":["8612983"],"is_preprint":false},{"year":1999,"finding":"NKX2-1 is required for septation of the anterior foregut into trachea and esophagus, for lung branching morphogenesis, and for pulmonary epithelial cell differentiation (including surfactant protein gene expression); Nkx2.1-/- mice form a common tracheoesophageal lumen, have hypoplastic lungs arrested at pseudoglandular stage, and lack surfactant protein expression. Reduced Bmp-4 expression in mutant lung epithelium provides a mechanistic clue for impaired branching.","method":"Homozygous targeted gene disruption in mice with in situ hybridization and phenotypic analysis","journal":"Developmental biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — clean knockout mouse with multiple specific phenotypic readouts (morphogenesis, differentiation, surfactant expression, Bmp4) replicated across multiple labs","pmids":["10208743"],"is_preprint":false},{"year":2000,"finding":"Two functionally distinct isoforms of NKX2.1 are expressed in pulmonary epithelium: a 371 aa major isoform and a 401 aa minor isoform with a 30 aa N-terminal extension. The longer isoform exhibits reduced transactivation activity on the SP-C promoter compared to the shorter major isoform, as demonstrated by site-directed mutagenesis suggesting the 30 aa extension causes steric interference.","method":"In vitro transcription/translation, co-transfection reporter assays, site-directed mutagenesis","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — in vitro assay with mutagenesis, single lab","pmids":["10753648"],"is_preprint":false},{"year":2003,"finding":"TTF-1/NKX2-1 directly activates transcription of the midkine (MK) gene in lung epithelium by acting on TTF-1 regulatory elements in the 5' region of the MK gene promoter; MK expression was absent in TTF-1 null mouse lungs.","method":"Promoter-reporter transfection assays, TTF-1 null mouse analysis","journal":"Developmental dynamics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — promoter reporter with null mouse validation, single lab, two orthogonal methods","pmids":["12761850"],"is_preprint":false},{"year":2004,"finding":"TAZ (transcriptional co-activator with PDZ-binding motif) directly interacts with the NH2-terminal domain of TTF-1/NKX2-1 and synergistically activates expression of surfactant protein C (SP-C) in the presence of TTF-1, as shown by pull-down and mammalian two-hybrid assays.","method":"Mammalian two-hybrid assay, GST pull-down, co-transfection reporter assays, deletion analysis","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal binding assays with functional reporter, single lab, multiple orthogonal methods","pmids":["14970209"],"is_preprint":false},{"year":2004,"finding":"NKX2-1 directly regulates transcription of the BMP4 gene in lung epithelial cells through specific cis-active NKX2.1-responsive elements on both BMP4 promoters (hBmp4.1 and hBmp4.2); DNA-binding was confirmed by co-transfection assays identifying specific binding sequences.","method":"Co-transfection reporter assays in lung epithelial cells, identification of NKX2.1 binding sites","journal":"Gene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — promoter reporter with binding site identification, single lab","pmids":["14960358"],"is_preprint":false},{"year":2004,"finding":"TTF-1/NKX2-1 binds the RET promoter at a specific site, and activates RET transcription; HSCR-associated RET promoter SNPs overlapping this TTF-1 binding site decrease TTF-1-activated RET transcription. A Gly322Ser TTF-1 mutation found in an HSCR patient compromises activation of transcription from HSCR-associated RET promoter haplotypes.","method":"Luciferase reporter assays, EMSA/binding assays, patient mutation analysis","journal":"Human molecular genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional reporter and binding assay with patient mutation, single lab","pmids":["15548547"],"is_preprint":false},{"year":2006,"finding":"A C-terminal domain deletion mutation of TTF-1/NKX2-1 (825delC) produces a protein with diminished DNA binding that fails to activate Tg, TPO, or SP-B reporter genes. This mutant has a dominant-negative effect specifically on Tg and TPO but not SP-B transcription, and impairs wild-type TTF-1's synergy with PAX8 (which is required for Tg and TPO but not SP-B transcription). The mutant protein does not compete with wild-type for coactivators.","method":"EMSA, transfection reporter assays, Gal4 reporter system, expression vector analysis","journal":"The Journal of clinical endocrinology and metabolism","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — multiple in vitro functional assays with mutagenesis, single lab","pmids":["16507635"],"is_preprint":false},{"year":2007,"finding":"NKX2.1 physically and functionally interacts with FOXA1 through the NKX2.1 homeodomain in a DNA-independent manner. This interaction is inhibitory on the SP-C promoter (which lacks a FOXA1 binding site), where FOXA1 attenuates NKX2.1-dependent transcription by masking the homeodomain DNA-binding function. On the Ccsp promoter (which has both binding sites), FOXA1 and NKX2.1 additively activate transcription.","method":"Co-IP, GST pull-down, EMSA, siRNA knockdown, co-transfection reporter assays","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 1 / Strong — multiple orthogonal methods (pulldown, EMSA, siRNA, reporter), mechanistic dissection with deletion analysis, single rigorous study","pmids":["17220277"],"is_preprint":false},{"year":2007,"finding":"TTF-1 directly activates transcription of growth hormone and prolactin genes in the anterior pituitary; TTF-1 inhibited growth hormone transcription but activated prolactin transcription through direct binding to TTF-1 binding motifs in their respective promoters. Deletion of these motifs abolished the regulatory effects.","method":"In situ hybridization, co-transfection reporter assays, deletion analysis in pituitary cell line","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional reporter with binding site deletion, single lab","pmids":["17706597"],"is_preprint":false},{"year":2008,"finding":"NKX2.1 directly binds a highly conserved sequence in the Lhx6 promoter and activates Lhx6 expression, thereby specifying parvalbumin- and somatostatin-expressing cortical interneuron fate in the medial ganglionic eminence. Rescue of NKX2.1 expression in Nkx2.1-/- slices induced Lhx6; gain- and loss-of-function of Lhx6 were sufficient/necessary to rescue interneuron phenotypes.","method":"Electroporation of cDNA into slice cultures from Nkx2.1-/- embryos, transplantation into neonatal cortex, ChIP, promoter binding assay, gain/loss-of-function","journal":"Development (Cambridge, England)","confidence":"High","confidence_rationale":"Tier 1 / Strong — ChIP confirming direct binding, functional rescue with multiple genetic approaches, single rigorous study","pmids":["18339674"],"is_preprint":false},{"year":2008,"finding":"TTF-1/NKX2-1 directly binds and transcriptionally upregulates the nestin gene in vivo through the NestBS (HRE/CRE-like) site within the CNS-specific nestin enhancer; transgenic mouse analysis confirmed this regulation requires the NestBS site.","method":"Transgenic mouse reporter assay, binding site analysis","journal":"The International journal of developmental biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo transgenic reporter with mutagenesis of binding site, single lab","pmids":["18033672"],"is_preprint":false},{"year":2008,"finding":"TITF1/NKX2-1 is a lineage-specific oncogene amplified at 14q13.3 in lung cancer; siRNA-mediated knockdown of TITF1 in amplified lung cancer cell lines reduced cell proliferation by decreasing cell-cycle progression and increasing apoptosis.","method":"Genomic profiling of 128 cell lines/tumors, siRNA knockdown with proliferation and cell-cycle assays","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — siRNA knockdown with defined cellular phenotype, single lab","pmids":["18212743"],"is_preprint":false},{"year":2009,"finding":"Nkx2-1 acts cooperatively with Phox2b and Sox10 (but not Pax3) to mediate RET transcription in the enteric nervous system, as demonstrated by dual-luciferase reporter studies identifying the Phox2b-responsive region in the RET promoter.","method":"Dual-luciferase reporter assay, immunohistochemistry","journal":"Journal of pediatric surgery","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, luciferase reporter only without direct binding confirmation","pmids":["19853745"],"is_preprint":false},{"year":2009,"finding":"Epigenetic silencing of TTF-1/NKX2-1 in undifferentiated thyroid carcinomas occurs through DNA hypermethylation of CpG islands in the TTF-1 promoter and reduced acetylation of histone H3-lys9; DNA demethylating agents restore TTF-1 expression in thyroid carcinoma cell lines.","method":"Methylation-specific PCR, chromatin immunoprecipitation (ChIP), 5-aza-deoxycytidine treatment","journal":"Laboratory investigation","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP plus functional restoration with demethylating agent, single lab","pmids":["19506552"],"is_preprint":false},{"year":2010,"finding":"TTF-1/NKX2-1 directly activates transcription of the α5 nicotinic acetylcholine receptor (CHRNA5) subunit gene by binding specific TTF-1 response elements in both the 2.0-kb and 850-bp α5 promoters; site-directed mutagenesis of these elements abolished activation.","method":"Reporter assays, site-directed mutagenesis, exogenous TTF-1 expression in lung epithelial cell lines","journal":"Respiratory research","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — reporter with binding site mutagenesis, single lab","pmids":["21143907"],"is_preprint":false},{"year":2012,"finding":"NKX2-1/TTF-1 induces expression of the receptor tyrosine kinase-like orphan receptor ROR1, which sustains prosurvival PI3K-AKT signaling over pro-apoptotic p38 signaling in lung adenocarcinoma, via ROR1 kinase-dependent c-Src activation and kinase-independent sustainment of EGFR-ERBB3 association and ERBB3 phosphorylation.","method":"ROR1 knockdown in lung cancer cell lines, signaling pathway analysis (PI3K-AKT, p38), EGFR status evaluation","journal":"Cancer cell","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — defined signaling pathway placement with knockdown and multiple readouts, single lab","pmids":["22439932"],"is_preprint":false},{"year":2012,"finding":"TTF-1/NKX2-1 directly transactivates the tight junction molecules occludin (OCLN) and claudin-1 (CLDN1) through direct interaction with their promoters; TTF-1 knockdown down-regulated occludin, conferred resistance to anoikis, and occludin restoration reversed this effect, establishing TTF-1-mediated occludin expression as a mechanism of metastasis suppression.","method":"ChIP, promoter reporter assays, siRNA knockdown, anoikis assay, migration assay","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP plus functional readout with siRNA, single lab, multiple methods","pmids":["22761434"],"is_preprint":false},{"year":2012,"finding":"NKX2-1 haploinsufficiency combined with oncogenic KrasG12D (but not EGFRL858R) causes mucinous adenocarcinoma of the lung in mice; NKX2-1 inhibits AP-1 activity and tumor colony formation in vitro. ChIP-seq identified direct association of NKX2-1 with genes induced in mucinous tumors at both AP-1 and canonical NKX2-1 binding elements.","method":"Transgenic mouse model, ChIP-seq, in vitro tumor colony formation, AP-1 reporter assay","journal":"The Journal of clinical investigation","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vivo mouse model with ChIP-seq and in vitro functional assays, genome-wide binding characterization","pmids":["23143308"],"is_preprint":false},{"year":2015,"finding":"NKX2-1 directly regulates p53 transcription; NKX2-1-elevated wild-type p53 down-regulates IKKβ transcription via decreased Sp1 binding to IKKβ promoter, while NKX2-1 with mutant p53 up-regulates IKKβ via mutant p53/NF-Y complex, modulating NF-κB activation and EMT in lung adenocarcinoma in a p53-status-dependent manner.","method":"Promoter reporter assays, ChIP for Sp1 binding, xenograft tumor formation, soft-agar assay","journal":"Oncotarget","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reporter assays with ChIP, functional in vivo and in vitro validation, single lab","pmids":["25881545"],"is_preprint":false},{"year":2015,"finding":"Loss of NKX2-1, FOXA2, and CDX2 together (but not individually) synergistically promotes the metastatic potential of non-metastatic lung adenocarcinoma cells to the level of naturally arising metastatic cells in vivo, and is sufficient to account for a significant fraction of gene expression differences between metastatic and non-metastatic states, including upregulation of Tks5long, Hmga2, and Snail.","method":"Triple knockdown, in vivo transplant metastasis assay, gene expression profiling","journal":"Genes & development","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss-of-function with defined in vivo metastatic phenotype, epistasis between three factors, single lab","pmids":["26341558"],"is_preprint":false},{"year":2017,"finding":"TTF-1/NKX2-1 interacts with DDB1 (damage-specific DNA binding protein 1) and blocks DDB1 binding to CHK1, thereby attenuating ubiquitylation and subsequent degradation of CHK1. TTF-1 overexpression conferred resistance to DNA replication stress and prevented DNA double-strand breaks (reduced pCHK2 and γH2AX), revealing a non-transcriptional function of TTF-1.","method":"Global proteomic interaction screen (MS), co-IP, functional replication stress assays (pCHK2, γH2AX)","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — MS interactome with co-IP validation and functional readout, single lab","pmids":["28192407"],"is_preprint":false},{"year":2017,"finding":"Nkx2.1 directly inhibits NANCI (a cis-acting lncRNA at the same locus) while NANCI in turn promotes Nkx2.1 transcription in cis, forming a feedback loop. Combined heterozygous mutations in both NANCI and Nkx2.1 produce persistent Nkx2.1 deficiency and reprogramming of lung epithelial cells to a posterior endoderm fate, impaired innate immunity, and progressive lung degeneration.","method":"Mouse genetic models, concurrent heterozygous mutations, lung epithelial fate analysis","journal":"Genes & development","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo genetic epistasis between lncRNA and TF, single lab, defined cellular phenotype","pmids":["28546511"],"is_preprint":false},{"year":2017,"finding":"Nkx2.1 binds the GFAP promoter to regulate its expression, thereby controlling astrogliogenesis in the telencephalon; Nkx2.1-/- mice show drastic loss of astrocytes from impaired proliferation and possibly glial specification/differentiation of ventral neural stem cells.","method":"ChIP, co-transfection reporter assay, BrdU proliferation assay, neurosphere assay, knockout mouse analysis","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP with functional reporter and KO mouse phenotype, single lab","pmids":["28266561"],"is_preprint":false},{"year":2017,"finding":"MOB1A/B loss in bronchioalveolar epithelium causes impaired YAP1/TAZ-dependent differentiation and decreased NKX2-1-dependent surfactant protein production. YAP1/TAZ-NKX2.1 axis controls expression of collagen XVII (a hemidesmosome component required for alveolar stem cell niche maintenance); loss of MOB1 decreases collagen XVII expression through this axis.","method":"Conditional knockout mouse model, bronchioalveolar epithelium-specific deletion, cell differentiation and adhesion assays","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — conditional KO with defined cellular phenotype and pathway placement, single lab","pmids":["28346423"],"is_preprint":false},{"year":2019,"finding":"TTF-1/NKX2-1 binding profiles in SCLC vs. lung adenocarcinoma differ substantially (75% distinct binding regions); in SCLC, TTF-1 binds regions enriched for E-box motifs and co-occupies adjacent sites with ASCL1 to cooperatively regulate neuroendocrine and anti-apoptotic (Bcl-2 family) gene expression, whereas in LADC the binding profile and transcriptional targets differ.","method":"ChIP-seq, RNA-seq comparison between SCLC and LADC cell lines","journal":"Molecular oncology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP-seq and RNA-seq with two cell lines, single lab, genome-wide characterization","pmids":["31782890"],"is_preprint":false},{"year":2021,"finding":"NKX2-1 induces the ERK phosphatase DUSP6, which inactivates ERK; loss of NKX2-1 in late-stage lung adenocarcinoma downregulates DUSP6 and unleashes ERK hyperactivation. Re-introduction of NKX2-1 in NKX2-1-silenced tumor cells induced DUSP6 and inhibited tumor growth and metastasis. DUSP6 is necessary for NKX2-1-mediated inhibition of tumor progression in vivo.","method":"Human tissue samples and cell lines, xenografts, genetic mouse models, in vivo rescue experiments","journal":"Oncogene","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple model systems (cell lines, xenograft, GEM, patient tissue), in vivo necessity established, single lab with strong evidence","pmids":["34689179"],"is_preprint":false},{"year":2021,"finding":"NKX2-1 directly inhibits the CXCL1, CXCL2, and CXCL5 promoters, as demonstrated by ATAC-seq; NKX2-1 depletion triggers secretion of these chemokines, recruiting tumor-promoting neutrophils via CXCLs/CXCR2 signaling to promote lung adenocarcinoma progression.","method":"ATAC-seq, chemokine array, qRT-PCR, syngeneic mouse model, CXCR2 antagonist treatment","journal":"Advanced science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ATAC-seq for chromatin accessibility at promoters with functional in vivo mouse model, single lab","pmids":["39113226"],"is_preprint":false},{"year":2021,"finding":"In NKX2-1-positive lung adenocarcinoma, FoxA1/2 loss leads to aberrant NKX2-1 activity and genomic mislocalization, which actively inhibits tumorigenesis and drives alternative non-proliferative cellular identity programs; FoxA1/2 normally guides NKX2-1 to appropriate genomic loci to maintain a dual pulmonary-gastrointestinal identity state.","method":"FoxA1/2 knockout in KRAS-driven mouse models and human cell lines, ChIP-seq for NKX2-1 localization","journal":"Developmental cell","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic KO mouse model with ChIP-seq demonstrating NKX2-1 relocalization, single lab","pmids":["35835117"],"is_preprint":false},{"year":2021,"finding":"PRDM3 and PRDM16 (histone methyltransferases) regulate chromatin accessibility at NKX2-1 transcriptional targets critical for alveolar type 2 (AT2) cell differentiation and surfactant homeostasis; combined deletion of Prdm3/16 in lung endoderm causes perinatal respiratory failure from loss of AT2 cells. PRDM3/16 act as NKX2-1 co-activators, and their loss leads to AT2 cells acquiring partial AT1 fate.","method":"Conditional knockout mice, single-cell RNA-seq, bulk ATAC-seq, CUT&RUN","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1 / Strong — CUT&RUN demonstrating co-occupancy, ATAC-seq showing chromatin changes at NKX2-1 targets, in vivo KO with defined lethal phenotype","pmids":["39284798"],"is_preprint":false},{"year":2021,"finding":"YAP participates with KLF5, NFIB, and NKX2-1 to regulate AGER expression in alveolar epithelial cells; YAP activation increased AT1 cell numbers and altered differentiation via this transcriptional network, while YAP deletion increased mature AT2 cell gene expression.","method":"Transgenic mice with YAP activation or deletion, motif enrichment analysis, promoter accessibility assays","journal":"iScience","confidence":"Low","confidence_rationale":"Tier 3 / Weak — transcriptional network inference from mouse model with motif analysis, direct NKX2-1 binding not directly confirmed by ChIP","pmids":["34466790"],"is_preprint":false},{"year":2021,"finding":"In SCLC, NKX2-1 co-immunoprecipitates with SOX1 as a functional transcriptional partner to maintain neural lineage identity in the SCLC-Aα subtype; NKX2-1 CRISPR deletion inhibited SCLC-Aα cell growth and induced apoptosis; a super-enhancer at the NKX2-1 locus drives its expression in this subtype.","method":"ChIP-seq, co-immunoprecipitation followed by mass spectrometry, CRISPR-Cas9 deletion, xenograft","journal":"American journal of respiratory and critical care medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP/MS for partner identification with CRISPR functional validation, single lab","pmids":["35848993"],"is_preprint":false},{"year":2021,"finding":"In ASCL1-high SCLC, NKX2-1 complexes with ASCL1 and PROX1 to co-occupy super-enhancers and co-regulate genes in NOTCH signaling, catecholamine biosynthesis, and cell cycle; ASCL1 depletion demonstrated its role as a key dependency factor.","method":"ChIP-seq, chromatin landscape analysis, co-immunoprecipitation, ASCL1 depletion","journal":"iScience","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP-seq with co-IP demonstrating complex formation, single lab","pmids":["34466783"],"is_preprint":false},{"year":2021,"finding":"NKX2-1 directly represses Efnb2 (Ephrin-B2) in tracheal endoderm, as demonstrated by ChIP and reporter assays; NKX2-1 loss causes expansion of Efnb2 expression, disrupts EPH/EPHRIN-mediated cell sorting, and causes tracheoesophageal separation failure with misallocation of ventral foregut cells into the esophagus.","method":"ChIP, reporter assays, lineage tracing, genetic loss-of-function mouse model","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 1 / Strong — ChIP and reporter confirming direct repression, in vivo lineage tracing with mechanistic cell-sorting phenotype, single rigorous study","pmids":["35294885"],"is_preprint":false},{"year":2021,"finding":"NKX2-1 loss of function confers Wnt dependency in lung adenocarcinoma regardless of EGFR mutation status; gene engineering of alveolar organoids demonstrated that constitutive EGFR-RAS signaling provides Wnt independence, while NKX2-1 loss overrides this to restore Wnt dependency.","method":"Patient-derived organoid biobank, CRISPR gene engineering, phenotypic screening of niche factor dependency","journal":"Cell reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — CRISPR gene engineering with functional organoid phenotype, single lab","pmids":["36870059"],"is_preprint":false},{"year":2022,"finding":"In NKX2-1-deficient BRAFV600E-driven lung adenocarcinoma, BRAF/MEK inhibitors fail to drive tumor cells into quiescence (unlike NKX2-1-positive cells) and instead induce cell identity switching within the gastric lineage, driven partly by WNT signaling and FoxA1/2. An NKX2-1/ERK/WNT feedback loop exists where NKX2-1 modulates response to targeted therapy.","method":"NKX2-1 deletion in BRAFV600E mouse model, BRAF/MEK inhibitor treatment, cell cycle and identity analysis","journal":"eLife","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo mouse model with defined pharmacological and identity switching phenotype, single lab","pmids":["33821796"],"is_preprint":false},{"year":2023,"finding":"NKX2-1 directly binds and transcriptionally upregulates serine/glycine synthesis enzyme genes (PHGDH, PSAT1, PSPH, SHMT2), enabling NKX2-1-expressing cells to proliferate and invade under serine/glycine depletion. NKX2-1-driven serine/glycine synthesis generates nucleotides and redox molecules, alters cellular lipidome and methylome, and NKX2-1 tumor-bearing mice show enhanced tumor aggressiveness.","method":"ChIP-qPCR, immunoblotting, mass spectrometry metabolomics, NKX2-1 overexpression/knockdown, mouse tumor models","journal":"British journal of cancer","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP-qPCR with metabolomics and in vivo mouse model, single lab, multiple orthogonal methods","pmids":["36932191"],"is_preprint":false},{"year":2025,"finding":"In neuroendocrine prostate cancer, FOXA2 pioneer factor binding at NE enhancers initiates DNA demethylation and induces NKX2-1 expression. NKX2-1 then preferentially binds gene promoters and interacts with enhancer-bound FOXA2 through chromatin looping to drive 3D chromatin remodeling and luminal-to-neuroendocrine transformation. NKX2-1/FOXA2 recruit p300/CBP to activate NE enhancers; pharmacological p300/CBP inhibition blunts NE gene expression and abolishes NEPC tumor growth.","method":"Hi-C/3D chromatin sequencing, isogenic cell lines for NE transformation, ChIP-seq, ATAC-seq, bisulfite sequencing, co-IP, p300/CBP inhibitor treatment in vivo","journal":"Nature genetics","confidence":"High","confidence_rationale":"Tier 1 / Strong — multiple orthogonal genome-wide methods (Hi-C, ChIP-seq, ATAC-seq, bisulfite-seq), co-IP, mechanistic in vivo pharmacological validation, single rigorous study","pmids":["40691407"],"is_preprint":false},{"year":2013,"finding":"Activin-A induces NKX2-1 expression in hESC-derived definitive endoderm through ALK4 receptor-mediated SMAD2 phosphorylation; phospho-SMAD2 directly binds to the NKX2-1 promoter and activates its transcription. GDF11 can substitute for Activin-A, but Wnt3a, SHH, FGF2, or BMP4 cannot.","method":"hESC differentiation, SMAD2 phosphorylation assay, ChIP for SMAD2 at NKX2-1 promoter, signaling pathway inhibition","journal":"Stem cells and development","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP for direct SMAD2 binding at NKX2-1 promoter, multiple pathway tests, single lab","pmids":["23259454"],"is_preprint":false},{"year":2021,"finding":"NKX2-1 functions in an epithelial cell-autonomous manner to establish the proximal-peripheral boundary in developing airways; blastocyst complementation with NKX2-1-sufficient ESCs restored peripheral lung formation and β-catenin signaling in Nkx2-1-/- basal cells, but did not complement most proximal regions, demonstrating a cell-autonomous role in boundary formation.","method":"Blastocyst complementation, chimeric mouse analysis, β-catenin signaling assessment","journal":"Developmental dynamics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — blastocyst complementation as genetic epistasis tool, single lab, defined in vivo phenotypic rescue","pmids":["33428297"],"is_preprint":false},{"year":2022,"finding":"FOXO1 interacts directly with the NKX2.1 homeodomain (via its forkhead domain), disrupting NKX2.1 binding to the SFTPC promoter and causing loss of surfactant gene expression during alveolar epithelial type I differentiation. PI-3K/AKT-mediated phosphorylation of FOXO1 sequesters it from the nucleus, maintaining AT2 identity with high surfactant expression; blocking PI-3K/AKT allows nuclear FOXO1 to interact with NKX2.1 and suppress surfactant expression.","method":"Co-IP between FOXO1 and NKX2.1, ChIP for NKX2.1 at SFTPC promoter, PI-3K/AKT inhibition, KGF treatment, in vitro AEC differentiation","journal":"Cells","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP with ChIP demonstrating disrupted NKX2.1 promoter occupancy, signaling pathway dissection, single lab","pmids":["35406686"],"is_preprint":false}],"current_model":"NKX2-1 (TTF-1) is a homeodomain transcription factor that directly binds promoters of lung-specific genes (SP-B, SP-C, BMP4, occludin, DUSP6, CXCL chemokines, serine/glycine synthesis enzymes) to control lung epithelial morphogenesis, alveolar differentiation, and tracheoesophageal separation; it functions through physical interactions with co-regulators including TAZ, FOXA1/2, PAX8, FOXO1, SMAD2, PRDM3/16, ASCL1, SOX1, and FOXA2, and also exerts non-transcriptional functions by binding DDB1 to protect CHK1 from ubiquitylation, conferring replication stress resistance; in the developing brain it specifies cortical interneuron fate by directly activating Lhx6 and astrogliogenesis by activating GFAP, while in cancer it acts as a lineage-survival oncogene (inducing ROR1-mediated EGFR-PI3K survival signaling and DUSP6-mediated ERK suppression) whose loss unleashes ERK hyperactivation, gastric transdifferentiation, and metastasis through chemokine-mediated neutrophil recruitment."},"narrative":{"mechanistic_narrative":"NKX2-1 (TTF-1) is a homeodomain transcription factor that serves as a master regulator of lung epithelial morphogenesis and differentiation, required for septation of the anterior foregut into trachea and esophagus, for branching morphogenesis, and for surfactant protein expression [PMID:10208743, PMID:8612983]. It executes this program by directly binding cis-elements in target promoters: it activates lung-differentiation and morphogenesis genes including BMP4 [PMID:14960358], midkine [PMID:12761850], and surfactant protein C [PMID:14970209], while directly repressing Efnb2 in tracheal endoderm to enable EPH/EPHRIN-mediated cell sorting during tracheoesophageal separation [PMID:35294885]. Its transcriptional output is shaped by combinatorial partners—it cooperates with TAZ to synergize on SP-C [PMID:14970209], with PAX8 on thyroid genes [PMID:16507635], and is guided to appropriate genomic loci by FOXA1/2, whose loss causes NKX2-1 mislocalization [PMID:35835117, PMID:17220277]; PRDM3/16 act as co-activators that open chromatin at NKX2-1 targets to drive alveolar type 2 cell differentiation [PMID:39284798], and FOXO1 binding to the homeodomain disrupts NKX2-1 occupancy at SFTPC to toggle alveolar epithelial fate [PMID:35406686]. NKX2-1 expression is itself induced via Activin/SMAD2 signaling onto its promoter [PMID:23259454] and is reinforced by a cis-acting lncRNA feedback loop [PMID:28546511]. Beyond the lung, NKX2-1 specifies cortical interneuron fate by directly activating Lhx6 [PMID:18339674] and controls telencephalic astrogliogenesis via the GFAP promoter [PMID:28266561]. In cancer it acts as an amplified lineage-survival oncogene in lung adenocarcinoma [PMID:18212743], inducing ROR1-dependent prosurvival PI3K-AKT signaling [PMID:22439932], while its loss unleashes ERK hyperactivation through downregulation of the phosphatase DUSP6 [PMID:34689179], promotes chemokine-driven neutrophil recruitment by derepressing CXCL1/2/5 [PMID:39113226], and drives metastasis and gastric transdifferentiation cooperatively with FOXA2/CDX2 loss [PMID:26341558, PMID:33821796]. NKX2-1 also exerts a non-transcriptional function by binding DDB1 to protect CHK1 from ubiquitylation, conferring replication-stress resistance [PMID:28192407].","teleology":[{"year":1995,"claim":"Established that NKX2-1 is functionally required for lung epithelial morphogenesis rather than merely a marker, answering whether the factor drives branching.","evidence":"Antisense oligonucleotide suppression in embryonic mouse lung explants","pmids":["8612983"],"confidence":"Medium","gaps":["Did not identify direct transcriptional targets","Antisense approach lacks genetic specificity"]},{"year":1999,"claim":"Genetic knockout defined the full developmental requirement for NKX2-1 in foregut septation, branching, and epithelial differentiation, linking loss to reduced Bmp4 as a mechanistic clue.","evidence":"Homozygous targeted disruption in mice with in situ hybridization and phenotyping","pmids":["10208743"],"confidence":"High","gaps":["Direct binding to target promoters not yet demonstrated","Did not resolve which targets account for each phenotype"]},{"year":2003,"claim":"Identified direct transcriptional targets in lung (midkine, BMP4) establishing NKX2-1 as a sequence-specific activator of differentiation/morphogenesis genes.","evidence":"Promoter-reporter assays and null mouse analysis; binding-site identification","pmids":["12761850","14960358"],"confidence":"Medium","gaps":["Endogenous occupancy by ChIP not shown for all targets","Cofactor requirements undefined"]},{"year":2004,"claim":"Revealed combinatorial control by identifying physical co-regulators (TAZ activates, PAX8 synergy required for thyroid genes), explaining promoter-specific output.","evidence":"Mammalian two-hybrid, GST pull-down, reporter assays; mutant analysis in patient context","pmids":["14970209","16507635"],"confidence":"Medium","gaps":["Structural basis of interactions not resolved","Stoichiometry and genome-wide co-binding unknown"]},{"year":2007,"claim":"Showed that partner binding can inhibit NKX2-1, as FOXA1 masks the homeodomain DNA-binding surface in a promoter-context-dependent manner.","evidence":"Co-IP, GST pull-down, EMSA, siRNA, reporter assays with deletion mapping","pmids":["17220277"],"confidence":"High","gaps":["In vivo relevance of masking versus genomic guidance not yet distinguished"]},{"year":2008,"claim":"Extended NKX2-1 function to neural lineage specification (cortical interneurons via Lhx6) and established it as an amplified lineage-survival oncogene in lung cancer.","evidence":"ChIP and functional rescue in Nkx2.1-/- slices; genomic profiling with siRNA proliferation/cell-cycle assays","pmids":["18339674","18212743"],"confidence":"High","gaps":["Oncogenic downstream effectors not yet identified","Mechanism of survival dependency undefined at the time"]},{"year":2012,"claim":"Placed NKX2-1 in cancer signaling and metastasis circuits—inducing ROR1-PI3K-AKT survival signaling while also activating tight-junction genes that suppress anoikis and metastasis.","evidence":"ROR1 knockdown and signaling analysis; ChIP, reporter, siRNA, anoikis/migration assays","pmids":["22439932","22761434"],"confidence":"Medium","gaps":["Context dependence of pro- versus anti-tumor roles unresolved","Single-lab signaling placements"]},{"year":2013,"claim":"Identified an upstream inductive signal: Activin/GDF11 via ALK4-SMAD2 directly activates the NKX2-1 promoter in definitive endoderm.","evidence":"hESC differentiation, SMAD2 phosphorylation, ChIP at NKX2-1 promoter, pathway inhibition","pmids":["23259454"],"confidence":"Medium","gaps":["Cofactors at the NKX2-1 promoter not defined","Specificity for endoderm versus other lineages untested"]},{"year":2012,"claim":"Genome-wide and genetic studies showed NKX2-1 haploinsufficiency cooperates with oncogenic Kras to drive mucinous adenocarcinoma and that NKX2-1 inhibits AP-1 at shared binding elements.","evidence":"Transgenic mouse model with ChIP-seq and AP-1 reporter/colony assays","pmids":["23143308"],"confidence":"High","gaps":["Mechanism of AP-1 antagonism at the chromatin level not fully resolved"]},{"year":2015,"claim":"Connected NKX2-1 to p53/NF-kB and to multi-factor metastasis suppression, showing loss of NKX2-1 with FOXA2 and CDX2 jointly licenses metastatic identity.","evidence":"Reporter/ChIP for p53-IKKβ axis; triple knockdown with in vivo metastasis and expression profiling","pmids":["25881545","26341558"],"confidence":"Medium","gaps":["Direct versus indirect contributions of each factor not separated","p53-status dependence adds context complexity"]},{"year":2017,"claim":"Uncovered a non-transcriptional function: NKX2-1 binds DDB1 to block CHK1 ubiquitylation and confer replication-stress resistance, broadening its mechanistic repertoire beyond transcription.","evidence":"MS interactome, co-IP, replication-stress assays (pCHK2, γH2AX)","pmids":["28192407"],"confidence":"Medium","gaps":["Structural basis of DDB1 competition unresolved","Physiological contexts where this dominates unclear"]},{"year":2017,"claim":"Defined autoregulatory and co-activator layers controlling NKX2-1 dosage and chromatin access in lung—NANCI lncRNA feedback, PRDM3/16 co-activation, and YAP1/TAZ-MOB1 axis for AT2 differentiation.","evidence":"Mouse genetic epistasis, conditional KO, scRNA-seq, ATAC-seq, CUT&RUN","pmids":["28546511","39284798","28346423","28266561"],"confidence":"High","gaps":["Direct biochemical interaction of PRDM3/16 with NKX2-1 versus chromatin-level cooperation needs further dissection"]},{"year":2021,"claim":"Cell-type-specific ChIP-seq and partner mapping revealed that NKX2-1 rewires its genomic binding and partners across tumor lineages, co-occupying enhancers with ASCL1, SOX1, and PROX1 in SCLC to enforce neuroendocrine identity.","evidence":"ChIP-seq/RNA-seq comparison, co-IP/MS, CRISPR deletion, xenografts","pmids":["31782890","35848993","34466783"],"confidence":"Medium","gaps":["Determinants of lineage-specific binding redistribution incompletely defined","Direct versus assisted recruitment to E-box regions unclear"]},{"year":2021,"claim":"Resolved how NKX2-1 loss promotes tumor progression—derepressing CXCL chemokines to recruit neutrophils, downregulating DUSP6 to unleash ERK, conferring Wnt dependency, and enabling targeted-therapy escape via gastric identity switching.","evidence":"ATAC-seq, syngeneic models, xenografts/GEMs, organoid CRISPR engineering, inhibitor treatments","pmids":["39113226","34689179","36870059","33821796","35835117"],"confidence":"High","gaps":["Hierarchy among these loss-driven programs not established","Reversibility of identity switching in patients untested"]},{"year":2022,"claim":"Identified a metabolic output of NKX2-1: direct activation of serine/glycine synthesis enzymes that supports proliferation under nutrient depletion.","evidence":"ChIP-qPCR, metabolomics, overexpression/knockdown, mouse tumor models","pmids":["36932191"],"confidence":"Medium","gaps":["Whether this drives tumor aggressiveness in patients is untested","Interplay with lineage program unclear"]},{"year":2025,"claim":"Demonstrated a pioneer-factor-driven mechanism in neuroendocrine prostate cancer where FOXA2 induces NKX2-1, which then drives 3D chromatin remodeling and p300/CBP recruitment to enforce neuroendocrine transformation.","evidence":"Hi-C, ChIP-seq, ATAC-seq, bisulfite-seq, co-IP, in vivo p300/CBP inhibition","pmids":["40691407"],"confidence":"High","gaps":["Generalizability of looping mechanism to other lineages untested","Direct contribution of NKX2-1 promoter-binding to looping not fully isolated"]},{"year":null,"claim":"How NKX2-1's combinatorial partner code and chromatin context determine its switch between activator and repressor, and between tumor-suppressive and oncogenic output, remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unified model linking partner identity to activator/repressor mode","Structural basis of homeodomain masking versus genomic guidance unknown","Determinants of lineage-specific genomic redistribution undefined"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[1,5,10,18,25,27,33,36]},{"term_id":"GO:0003677","term_label":"DNA binding","supporting_discovery_ids":[5,7,10,33]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[10,33,40]}],"pathway":[{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[1,5,10,18,33]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[1,10,23,33,39]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[12,16,26,27,35]}],"complexes":[],"partners":["TAZ","FOXA1","FOXA2","PAX8","FOXO1","DDB1","ASCL1","SOX1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P43699","full_name":"Homeobox protein Nkx-2.1","aliases":["Homeobox protein NK-2 homolog A","Thyroid nuclear factor 1","Thyroid transcription factor 1","TTF-1","Thyroid-specific enhancer-binding protein","T/EBP"],"length_aa":371,"mass_kda":38.6,"function":"Transcription factor that binds and activates the promoter of thyroid specific genes such as thyroglobulin, thyroperoxidase, and thyrotropin receptor. Crucial in the maintenance of the thyroid differentiation phenotype. May play a role in lung development and surfactant homeostasis. Forms a regulatory loop with GRHL2 that coordinates lung epithelial cell morphogenesis and differentiation. Activates the transcription of GNRHR and plays a role in enhancing the circadian oscillation of its gene expression. Represses the transcription of the circadian transcriptional repressor NR1D1 (By similarity)","subcellular_location":"Nucleus","url":"https://www.uniprot.org/uniprotkb/P43699/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/NKX2-1","classification":"Not Classified","n_dependent_lines":21,"n_total_lines":1208,"dependency_fraction":0.0173841059602649},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/NKX2-1","total_profiled":1310},"omim":[{"mim_id":"619280","title":"COILED-COIL DOMAIN-CONTAINING PROTEIN 59; CCDC59","url":"https://www.omim.org/entry/619280"},{"mim_id":"616844","title":"DNAJ/HSP40 HOMOLOG, SUBFAMILY C, MEMBER 17; DNAJC17","url":"https://www.omim.org/entry/616844"},{"mim_id":"616741","title":"PR DOMAIN-CONTAINING PROTEIN 13; PRDM13","url":"https://www.omim.org/entry/616741"},{"mim_id":"616534","title":"THYROID CANCER, NONMEDULLARY, 4; NMTC4","url":"https://www.omim.org/entry/616534"},{"mim_id":"610978","title":"CHOREOATHETOSIS AND CONGENITAL HYPOTHYROIDISM WITH OR WITHOUT PULMONARY DYSFUNCTION; CAHTP","url":"https://www.omim.org/entry/610978"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Uncertain","locations":[{"location":"Golgi apparatus","reliability":"Uncertain"},{"location":"Vesicles","reliability":"Uncertain"}],"tissue_specificity":"Group enriched","tissue_distribution":"Detected in some","driving_tissues":[{"tissue":"lung","ntpm":52.0},{"tissue":"thyroid gland","ntpm":162.9}],"url":"https://www.proteinatlas.org/search/NKX2-1"},"hgnc":{"alias_symbol":["TTF-1","TTF1"],"prev_symbol":["NKX2A","BCH","TITF1"]},"alphafold":{"accession":"P43699","domains":[],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P43699","model_url":"https://alphafold.ebi.ac.uk/files/AF-P43699-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P43699-F1-predicted_aligned_error_v6.png","plddt_mean":56.31},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=NKX2-1","jax_strain_url":"https://www.jax.org/strain/search?query=NKX2-1"},"sequence":{"accession":"P43699","fasta_url":"https://rest.uniprot.org/uniprotkb/P43699.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P43699/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P43699"}},"corpus_meta":[{"pmid":"17990269","id":"PMC_17990269","title":"Fate mapping Nkx2.1-lineage cells in the mouse telencephalon.","date":"2008","source":"The Journal of comparative neurology","url":"https://pubmed.ncbi.nlm.nih.gov/17990269","citation_count":457,"is_preprint":false},{"pmid":"10208743","id":"PMC_10208743","title":"Defects in tracheoesophageal and lung morphogenesis in Nkx2.1(-/-) mouse embryos.","date":"1999","source":"Developmental biology","url":"https://pubmed.ncbi.nlm.nih.gov/10208743","citation_count":358,"is_preprint":false},{"pmid":"12023581","id":"PMC_12023581","title":"TTF-1 expression in pulmonary adenocarcinomas.","date":"2002","source":"The American journal of surgical pathology","url":"https://pubmed.ncbi.nlm.nih.gov/12023581","citation_count":296,"is_preprint":false},{"pmid":"11854319","id":"PMC_11854319","title":"Choreoathetosis, hypothyroidism, and pulmonary alterations due to human NKX2-1 haploinsufficiency.","date":"2002","source":"The Journal of clinical investigation","url":"https://pubmed.ncbi.nlm.nih.gov/11854319","citation_count":246,"is_preprint":false},{"pmid":"8062273","id":"PMC_8062273","title":"Expression of thyroid-specific transcription factors TTF-1 and PAX-8 in human thyroid neoplasms.","date":"1994","source":"Cancer research","url":"https://pubmed.ncbi.nlm.nih.gov/8062273","citation_count":222,"is_preprint":false},{"pmid":"22439932","id":"PMC_22439932","title":"NKX2-1/TITF1/TTF-1-Induced ROR1 is required to sustain EGFR survival signaling in lung adenocarcinoma.","date":"2012","source":"Cancer cell","url":"https://pubmed.ncbi.nlm.nih.gov/22439932","citation_count":216,"is_preprint":false},{"pmid":"8675988","id":"PMC_8675988","title":"Expression of thyroid transcription factor-1(TTF-1) in fetal and neonatal human lung.","date":"1996","source":"The journal of histochemistry and cytochemistry : official journal of the Histochemistry Society","url":"https://pubmed.ncbi.nlm.nih.gov/8675988","citation_count":181,"is_preprint":false},{"pmid":"18339674","id":"PMC_18339674","title":"NKX2.1 specifies cortical interneuron fate by activating Lhx6.","date":"2008","source":"Development (Cambridge, England)","url":"https://pubmed.ncbi.nlm.nih.gov/18339674","citation_count":178,"is_preprint":false},{"pmid":"18212743","id":"PMC_18212743","title":"Genomic profiling identifies TITF1 as a lineage-specific oncogene amplified in lung cancer.","date":"2008","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/18212743","citation_count":175,"is_preprint":false},{"pmid":"14970209","id":"PMC_14970209","title":"TAZ interacts with TTF-1 and regulates expression of surfactant protein-C.","date":"2004","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/14970209","citation_count":151,"is_preprint":false},{"pmid":"19037882","id":"PMC_19037882","title":"Thyroid transcription factor-1 (TTF-1/Nkx2.1/TITF1) gene regulation in the lung.","date":"2009","source":"Clinical science (London, England : 1979)","url":"https://pubmed.ncbi.nlm.nih.gov/19037882","citation_count":145,"is_preprint":false},{"pmid":"8612983","id":"PMC_8612983","title":"TTF-1 regulates lung epithelial morphogenesis.","date":"1995","source":"Developmental biology","url":"https://pubmed.ncbi.nlm.nih.gov/8612983","citation_count":145,"is_preprint":false},{"pmid":"23143308","id":"PMC_23143308","title":"Kras(G12D) and Nkx2-1 haploinsufficiency induce mucinous adenocarcinoma of the lung.","date":"2012","source":"The Journal of clinical investigation","url":"https://pubmed.ncbi.nlm.nih.gov/23143308","citation_count":131,"is_preprint":false},{"pmid":"23763999","id":"PMC_23763999","title":"NKX2-1/TTF-1: an enigmatic oncogene that functions as a double-edged sword for cancer cell survival and progression.","date":"2013","source":"Cancer cell","url":"https://pubmed.ncbi.nlm.nih.gov/23763999","citation_count":130,"is_preprint":false},{"pmid":"18520037","id":"PMC_18520037","title":"BCH, an inhibitor of system L amino acid transporters, induces apoptosis in cancer cells.","date":"2008","source":"Biological & pharmaceutical bulletin","url":"https://pubmed.ncbi.nlm.nih.gov/18520037","citation_count":118,"is_preprint":false},{"pmid":"15716236","id":"PMC_15716236","title":"Usefulness of CDX2 and TTF-1 in differentiating gastrointestinal from pulmonary carcinoids.","date":"2005","source":"American journal of clinical pathology","url":"https://pubmed.ncbi.nlm.nih.gov/15716236","citation_count":87,"is_preprint":false},{"pmid":"26341558","id":"PMC_26341558","title":"Foxa2 and Cdx2 cooperate with Nkx2-1 to inhibit lung adenocarcinoma metastasis.","date":"2015","source":"Genes & development","url":"https://pubmed.ncbi.nlm.nih.gov/26341558","citation_count":85,"is_preprint":false},{"pmid":"31811030","id":"PMC_31811030","title":"Npas1+-Nkx2.1+ Neurons Are an Integral Part of the Cortico-pallido-cortical Loop.","date":"2019","source":"The Journal of neuroscience : the official journal of the Society for Neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/31811030","citation_count":76,"is_preprint":false},{"pmid":"26829311","id":"PMC_26829311","title":"KRAS and NKX2-1 Mutations in Invasive Mucinous Adenocarcinoma of the Lung.","date":"2016","source":"Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer","url":"https://pubmed.ncbi.nlm.nih.gov/26829311","citation_count":76,"is_preprint":false},{"pmid":"15548547","id":"PMC_15548547","title":"TTF-1 and RET promoter SNPs: regulation of RET transcription in Hirschsprung's disease.","date":"2004","source":"Human molecular genetics","url":"https://pubmed.ncbi.nlm.nih.gov/15548547","citation_count":74,"is_preprint":false},{"pmid":"22498824","id":"PMC_22498824","title":"PDX-1, CDX-2, TTF-1, and CK7: a reliable immunohistochemical panel for pancreatic neuroendocrine neoplasms.","date":"2012","source":"The American journal of surgical pathology","url":"https://pubmed.ncbi.nlm.nih.gov/22498824","citation_count":72,"is_preprint":false},{"pmid":"30796170","id":"PMC_30796170","title":"Preclinical Evaluation and Pilot Clinical Study of Al18F-PSMA-BCH for Prostate Cancer PET Imaging.","date":"2019","source":"Journal of nuclear medicine : official publication, Society of Nuclear Medicine","url":"https://pubmed.ncbi.nlm.nih.gov/30796170","citation_count":69,"is_preprint":false},{"pmid":"16507635","id":"PMC_16507635","title":"Functional study of a novel single deletion in the TITF1/NKX2.1 homeobox gene that produces congenital hypothyroidism and benign chorea but not pulmonary distress.","date":"2006","source":"The Journal of clinical endocrinology and metabolism","url":"https://pubmed.ncbi.nlm.nih.gov/16507635","citation_count":67,"is_preprint":false},{"pmid":"30475207","id":"PMC_30475207","title":"FoxA1 and FoxA2 drive gastric differentiation and suppress squamous identity in NKX2-1-negative lung cancer.","date":"2018","source":"eLife","url":"https://pubmed.ncbi.nlm.nih.gov/30475207","citation_count":66,"is_preprint":false},{"pmid":"17220277","id":"PMC_17220277","title":"Physical and functional interactions between homeodomain NKX2.1 and winged helix/forkhead FOXA1 in lung epithelial cells.","date":"2007","source":"Molecular and cellular biology","url":"https://pubmed.ncbi.nlm.nih.gov/17220277","citation_count":66,"is_preprint":false},{"pmid":"33619404","id":"PMC_33619404","title":"Sleep down state-active ID2/Nkx2.1 interneurons in the neocortex.","date":"2021","source":"Nature neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/33619404","citation_count":62,"is_preprint":false},{"pmid":"19506552","id":"PMC_19506552","title":"Epigenetic silencing of TTF-1/NKX2-1 through DNA hypermethylation and histone H3 modulation in thyroid carcinomas.","date":"2009","source":"Laboratory investigation; a journal of technical methods and pathology","url":"https://pubmed.ncbi.nlm.nih.gov/19506552","citation_count":62,"is_preprint":false},{"pmid":"36870059","id":"PMC_36870059","title":"Genotype-phenotype mapping of a patient-derived lung cancer organoid biobank identifies NKX2-1-defined Wnt dependency in lung adenocarcinoma.","date":"2023","source":"Cell reports","url":"https://pubmed.ncbi.nlm.nih.gov/36870059","citation_count":60,"is_preprint":false},{"pmid":"9545595","id":"PMC_9545595","title":"Structure of the human Nkx2.1 gene.","date":"1998","source":"Biochimica et biophysica acta","url":"https://pubmed.ncbi.nlm.nih.gov/9545595","citation_count":59,"is_preprint":false},{"pmid":"16138374","id":"PMC_16138374","title":"Cytology applications of p63 and TTF-1 immunostaining in differential diagnosis of lung cancers.","date":"2005","source":"Diagnostic cytopathology","url":"https://pubmed.ncbi.nlm.nih.gov/16138374","citation_count":59,"is_preprint":false},{"pmid":"23351095","id":"PMC_23351095","title":"Derivation and isolation of NKX2.1-positive basal forebrain progenitors from human embryonic stem cells.","date":"2013","source":"Stem cells and development","url":"https://pubmed.ncbi.nlm.nih.gov/23351095","citation_count":55,"is_preprint":false},{"pmid":"18957494","id":"PMC_18957494","title":"Lethal respiratory failure and mild primary hypothyroidism in a term girl with a de novo heterozygous mutation in the TITF1/NKX2.1 gene.","date":"2008","source":"The Journal of clinical endocrinology and metabolism","url":"https://pubmed.ncbi.nlm.nih.gov/18957494","citation_count":54,"is_preprint":false},{"pmid":"34466783","id":"PMC_34466783","title":"ASCL1, NKX2-1, and PROX1 co-regulate subtype-specific genes in small-cell lung cancer.","date":"2021","source":"iScience","url":"https://pubmed.ncbi.nlm.nih.gov/34466783","citation_count":49,"is_preprint":false},{"pmid":"19853745","id":"PMC_19853745","title":"Transcriptional regulation of RET by Nkx2-1, Phox2b, Sox10, and Pax3.","date":"2009","source":"Journal of pediatric surgery","url":"https://pubmed.ncbi.nlm.nih.gov/19853745","citation_count":48,"is_preprint":false},{"pmid":"34466790","id":"PMC_34466790","title":"YAP regulates alveolar epithelial cell differentiation and AGER via NFIB/KLF5/NKX2-1.","date":"2021","source":"iScience","url":"https://pubmed.ncbi.nlm.nih.gov/34466790","citation_count":46,"is_preprint":false},{"pmid":"24743427","id":"PMC_24743427","title":"The relationship between TTF-1 expression and EGFR mutations in lung adenocarcinomas.","date":"2014","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/24743427","citation_count":45,"is_preprint":false},{"pmid":"19279207","id":"PMC_19279207","title":"Characterizing the developmental pathways TTF-1, NKX2-8, and PAX9 in lung cancer.","date":"2009","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/19279207","citation_count":45,"is_preprint":false},{"pmid":"14984578","id":"PMC_14984578","title":"CD117, CK20, TTF-1, and DNA topoisomerase II-alpha antigen expression in small cell tumors.","date":"2004","source":"Journal of cutaneous pathology","url":"https://pubmed.ncbi.nlm.nih.gov/14984578","citation_count":45,"is_preprint":false},{"pmid":"34524427","id":"PMC_34524427","title":"SRGN-Triggered Aggressive and Immunosuppressive Phenotype in a Subset of TTF-1-Negative Lung Adenocarcinomas.","date":"2022","source":"Journal of the National Cancer Institute","url":"https://pubmed.ncbi.nlm.nih.gov/34524427","citation_count":44,"is_preprint":false},{"pmid":"35835117","id":"PMC_35835117","title":"FoxA1 and FoxA2 control growth and cellular identity in NKX2-1-positive lung adenocarcinoma.","date":"2022","source":"Developmental cell","url":"https://pubmed.ncbi.nlm.nih.gov/35835117","citation_count":43,"is_preprint":false},{"pmid":"23701182","id":"PMC_23701182","title":"Update on hypophysitis and TTF-1 expressing sellar region masses.","date":"2013","source":"Brain pathology (Zurich, Switzerland)","url":"https://pubmed.ncbi.nlm.nih.gov/23701182","citation_count":43,"is_preprint":false},{"pmid":"22761434","id":"PMC_22761434","title":"Occludin is a direct target of thyroid transcription factor-1 (TTF-1/NKX2-1).","date":"2012","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/22761434","citation_count":42,"is_preprint":false},{"pmid":"28346423","id":"PMC_28346423","title":"MOB1-YAP1/TAZ-NKX2.1 axis controls bronchioalveolar cell differentiation, adhesion and tumour formation.","date":"2017","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/28346423","citation_count":41,"is_preprint":false},{"pmid":"23125078","id":"PMC_23125078","title":"Nkx2-1: a novel tumor biomarker of lung cancer.","date":"2012","source":"Journal of Zhejiang University. Science. B","url":"https://pubmed.ncbi.nlm.nih.gov/23125078","citation_count":40,"is_preprint":false},{"pmid":"12761850","id":"PMC_12761850","title":"Thyroid transcription factor (TTF) -1 regulates the expression of midkine (MK) during lung morphogenesis.","date":"2003","source":"Developmental dynamics : an official publication of the American Association of Anatomists","url":"https://pubmed.ncbi.nlm.nih.gov/12761850","citation_count":40,"is_preprint":false},{"pmid":"12638129","id":"PMC_12638129","title":"Expression pattern of the homeobox protein NKX2-1 in the developing Xenopus forebrain.","date":"2002","source":"Brain research. Gene expression patterns","url":"https://pubmed.ncbi.nlm.nih.gov/12638129","citation_count":39,"is_preprint":false},{"pmid":"28677170","id":"PMC_28677170","title":"Inactivating mutations and hypermethylation of the NKX2-1/TTF-1 gene in non-terminal respiratory unit-type lung adenocarcinomas.","date":"2017","source":"Cancer science","url":"https://pubmed.ncbi.nlm.nih.gov/28677170","citation_count":35,"is_preprint":false},{"pmid":"10753648","id":"PMC_10753648","title":"Two functionally distinct forms of NKX2.1 protein are expressed in the pulmonary epithelium.","date":"2000","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/10753648","citation_count":35,"is_preprint":false},{"pmid":"28266561","id":"PMC_28266561","title":"Nkx2.1 regulates the generation of telencephalic astrocytes during embryonic development.","date":"2017","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/28266561","citation_count":34,"is_preprint":false},{"pmid":"16220345","id":"PMC_16220345","title":"Nonsense mutation in TITF1 in a Portuguese family with benign hereditary chorea.","date":"2005","source":"Neurogenetics","url":"https://pubmed.ncbi.nlm.nih.gov/16220345","citation_count":34,"is_preprint":false},{"pmid":"19390995","id":"PMC_19390995","title":"Small cell lung cancer: significance of RB alterations and TTF-1 expression in its carcinogenesis, phenotype, and biology.","date":"2009","source":"Endocrine pathology","url":"https://pubmed.ncbi.nlm.nih.gov/19390995","citation_count":34,"is_preprint":false},{"pmid":"16279847","id":"PMC_16279847","title":"Disturbed expression of type 1 and type 2 iodothyronine deiodinase as well as titf1/nkx2-1 and pax-8 transcription factor genes in papillary thyroid cancer.","date":"2005","source":"Thyroid : official journal of the American Thyroid Association","url":"https://pubmed.ncbi.nlm.nih.gov/16279847","citation_count":32,"is_preprint":false},{"pmid":"27573549","id":"PMC_27573549","title":"Induction of TTF-1 or PAX-8 expression on proliferation and tumorigenicity in thyroid carcinomas.","date":"2016","source":"International journal of oncology","url":"https://pubmed.ncbi.nlm.nih.gov/27573549","citation_count":30,"is_preprint":false},{"pmid":"28546511","id":"PMC_28546511","title":"The NANCI-Nkx2.1 gene duplex buffers Nkx2.1 expression to maintain lung development and homeostasis.","date":"2017","source":"Genes & development","url":"https://pubmed.ncbi.nlm.nih.gov/28546511","citation_count":30,"is_preprint":false},{"pmid":"24930029","id":"PMC_24930029","title":"A novel de novo mutation of the TITF1/NKX2-1 gene causing ataxia, benign hereditary chorea, hypothyroidism and a pituitary mass in a UK family and review of the literature.","date":"2014","source":"Cerebellum (London, England)","url":"https://pubmed.ncbi.nlm.nih.gov/24930029","citation_count":27,"is_preprint":false},{"pmid":"25904499","id":"PMC_25904499","title":"Nkx2.1-derived astrocytes and neurons together with Slit2 are indispensable for anterior commissure formation.","date":"2015","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/25904499","citation_count":27,"is_preprint":false},{"pmid":"31782890","id":"PMC_31782890","title":"Comparative analysis of TTF-1 binding DNA regions in small-cell lung cancer and non-small-cell lung cancer.","date":"2019","source":"Molecular oncology","url":"https://pubmed.ncbi.nlm.nih.gov/31782890","citation_count":27,"is_preprint":false},{"pmid":"34689179","id":"PMC_34689179","title":"NKX2-1 controls lung cancer progression by inducing DUSP6 to dampen ERK activity.","date":"2021","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/34689179","citation_count":26,"is_preprint":false},{"pmid":"22046491","id":"PMC_22046491","title":"TTF-1 positive small cell cancers: Don't think they're always primary pulmonary!","date":"2011","source":"World journal of gastrointestinal oncology","url":"https://pubmed.ncbi.nlm.nih.gov/22046491","citation_count":26,"is_preprint":false},{"pmid":"36039869","id":"PMC_36039869","title":"Stable iPSC-derived NKX2-1+ lung bud tip progenitor organoids give rise to airway and alveolar cell types.","date":"2022","source":"Development (Cambridge, England)","url":"https://pubmed.ncbi.nlm.nih.gov/36039869","citation_count":26,"is_preprint":false},{"pmid":"24111789","id":"PMC_24111789","title":"TTF-1 expression in breast carcinoma: an unusual but real phenomenon.","date":"2013","source":"Histopathology","url":"https://pubmed.ncbi.nlm.nih.gov/24111789","citation_count":25,"is_preprint":false},{"pmid":"35848993","id":"PMC_35848993","title":"Transcriptional Circuitry of NKX2-1 and SOX1 Defines an Unrecognized Lineage Subtype of Small-Cell Lung Cancer.","date":"2022","source":"American journal of respiratory and critical care medicine","url":"https://pubmed.ncbi.nlm.nih.gov/35848993","citation_count":24,"is_preprint":false},{"pmid":"28807344","id":"PMC_28807344","title":"Pituicytoma: Review of commonalities and distinguishing features among TTF-1 positive tumors of the central nervous system.","date":"2017","source":"Annals of diagnostic pathology","url":"https://pubmed.ncbi.nlm.nih.gov/28807344","citation_count":23,"is_preprint":false},{"pmid":"38604764","id":"PMC_38604764","title":"68Ga-NC-BCH Whole-Body PET Imaging Rapidly Targets Claudin18.2 in Lesions in Gastrointestinal Cancer Patients.","date":"2024","source":"Journal of nuclear medicine : official publication, Society of Nuclear Medicine","url":"https://pubmed.ncbi.nlm.nih.gov/38604764","citation_count":22,"is_preprint":false},{"pmid":"39284798","id":"PMC_39284798","title":"PRDM3/16 regulate chromatin accessibility required for NKX2-1 mediated alveolar epithelial differentiation and function.","date":"2024","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/39284798","citation_count":22,"is_preprint":false},{"pmid":"22710163","id":"PMC_22710163","title":"Functional plasticity of the BNIP-2 and Cdc42GAP Homology (BCH) domain in cell signaling and cell dynamics.","date":"2012","source":"FEBS letters","url":"https://pubmed.ncbi.nlm.nih.gov/22710163","citation_count":22,"is_preprint":false},{"pmid":"18506088","id":"PMC_18506088","title":"Mutation of a gene for thyroid transcription factor-1 (TITF1) in a patient with clinical features of resistance to thyrotropin.","date":"2008","source":"Endocrine journal","url":"https://pubmed.ncbi.nlm.nih.gov/18506088","citation_count":22,"is_preprint":false},{"pmid":"25982999","id":"PMC_25982999","title":"The expression of TTF-1 and Napsin A in early-stage lung adenocarcinoma correlates with the results of surgical treatment.","date":"2015","source":"Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine","url":"https://pubmed.ncbi.nlm.nih.gov/25982999","citation_count":22,"is_preprint":false},{"pmid":"28192407","id":"PMC_28192407","title":"TTF-1/NKX2-1 binds to DDB1 and confers replication stress resistance to lung adenocarcinomas.","date":"2017","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/28192407","citation_count":21,"is_preprint":false},{"pmid":"33821796","id":"PMC_33821796","title":"An NKX2-1/ERK/WNT feedback loop modulates gastric identity and response to targeted therapy in lung adenocarcinoma.","date":"2021","source":"eLife","url":"https://pubmed.ncbi.nlm.nih.gov/33821796","citation_count":21,"is_preprint":false},{"pmid":"19011567","id":"PMC_19011567","title":"TTF-1 expression in nephroblastoma.","date":"2009","source":"The American journal of surgical pathology","url":"https://pubmed.ncbi.nlm.nih.gov/19011567","citation_count":20,"is_preprint":false},{"pmid":"26799356","id":"PMC_26799356","title":"Utility of TTF-1 and Napsin-A in the work-up of malignant effusions.","date":"2016","source":"Diagnostic cytopathology","url":"https://pubmed.ncbi.nlm.nih.gov/26799356","citation_count":20,"is_preprint":false},{"pmid":"39113226","id":"PMC_39113226","title":"Neutrophils Recruited by NKX2-1 Suppression via Activation of CXCLs/CXCR2 Axis Promote Lung Adenocarcinoma Progression.","date":"2024","source":"Advanced science (Weinheim, Baden-Wurttemberg, Germany)","url":"https://pubmed.ncbi.nlm.nih.gov/39113226","citation_count":19,"is_preprint":false},{"pmid":"33980985","id":"PMC_33980985","title":"CRISPRi-mediated functional analysis of NKX2-1-binding sites in the lung.","date":"2021","source":"Communications biology","url":"https://pubmed.ncbi.nlm.nih.gov/33980985","citation_count":19,"is_preprint":false},{"pmid":"34170361","id":"PMC_34170361","title":"64Cu-PSMA-BCH: a new radiotracer for delayed PET imaging of prostate cancer.","date":"2021","source":"European journal of nuclear medicine and molecular imaging","url":"https://pubmed.ncbi.nlm.nih.gov/34170361","citation_count":19,"is_preprint":false},{"pmid":"36932191","id":"PMC_36932191","title":"Transcription factor NKX2-1 drives serine and glycine synthesis addiction in cancer.","date":"2023","source":"British journal of cancer","url":"https://pubmed.ncbi.nlm.nih.gov/36932191","citation_count":18,"is_preprint":false},{"pmid":"25209726","id":"PMC_25209726","title":"Expression of bkt and bch genes from Haematococcus pluvialis in transgenic Chlamydomonas.","date":"2014","source":"Science China. Life sciences","url":"https://pubmed.ncbi.nlm.nih.gov/25209726","citation_count":18,"is_preprint":false},{"pmid":"27322785","id":"PMC_27322785","title":"TTF-1 and PAX5 Are Frequently Expressed in Combined Merkel Cell Carcinoma.","date":"2016","source":"The American Journal of dermatopathology","url":"https://pubmed.ncbi.nlm.nih.gov/27322785","citation_count":17,"is_preprint":false},{"pmid":"14960358","id":"PMC_14960358","title":"NKX2.1 regulates transcription of the gene for human bone morphogenetic protein-4 in lung epithelial cells.","date":"2004","source":"Gene","url":"https://pubmed.ncbi.nlm.nih.gov/14960358","citation_count":17,"is_preprint":false},{"pmid":"29658609","id":"PMC_29658609","title":"Survivin knockdown induces senescence in TTF‑1-expressing, KRAS-mutant lung adenocarcinomas.","date":"2018","source":"International journal of oncology","url":"https://pubmed.ncbi.nlm.nih.gov/29658609","citation_count":17,"is_preprint":false},{"pmid":"30186310","id":"PMC_30186310","title":"NKX2-1 New Mutation Associated With Myoclonus, Dystonia, and Pituitary Involvement.","date":"2018","source":"Frontiers in genetics","url":"https://pubmed.ncbi.nlm.nih.gov/30186310","citation_count":16,"is_preprint":false},{"pmid":"40691407","id":"PMC_40691407","title":"NKX2-1 drives neuroendocrine transdifferentiation of prostate cancer via epigenetic and 3D chromatin remodeling.","date":"2025","source":"Nature genetics","url":"https://pubmed.ncbi.nlm.nih.gov/40691407","citation_count":15,"is_preprint":false},{"pmid":"25881545","id":"PMC_25881545","title":"NKX2-1-mediated p53 expression modulates lung adenocarcinoma progression via modulating IKKβ/NF-κB activation.","date":"2015","source":"Oncotarget","url":"https://pubmed.ncbi.nlm.nih.gov/25881545","citation_count":15,"is_preprint":false},{"pmid":"31713988","id":"PMC_31713988","title":"Application of GATA 3 and TTF-1 in differentiating parathyroid and thyroid nodules on cytology specimens.","date":"2019","source":"Diagnostic cytopathology","url":"https://pubmed.ncbi.nlm.nih.gov/31713988","citation_count":15,"is_preprint":false},{"pmid":"18033672","id":"PMC_18033672","title":"TTF-1/NKX2.1 up-regulates the in vivo transcription of nestin.","date":"2008","source":"The International journal of developmental biology","url":"https://pubmed.ncbi.nlm.nih.gov/18033672","citation_count":14,"is_preprint":false},{"pmid":"17640327","id":"PMC_17640327","title":"Evaluation of the thyroid transcription factor-1 gene (TITF1) as a Hirschsprung's disease locus.","date":"2007","source":"Annals of human genetics","url":"https://pubmed.ncbi.nlm.nih.gov/17640327","citation_count":13,"is_preprint":false},{"pmid":"33581550","id":"PMC_33581550","title":"SMARCA4 (BRG1) and SMARCB1 (INI1) expression in TTF-1 negative neuroendocrine carcinomas including merkel cell carcinoma.","date":"2021","source":"Pathology, research and practice","url":"https://pubmed.ncbi.nlm.nih.gov/33581550","citation_count":13,"is_preprint":false},{"pmid":"21143907","id":"PMC_21143907","title":"TTF-1 regulates α5 nicotinic acetylcholine receptor (nAChR) subunits in proximal and distal lung epithelium.","date":"2010","source":"Respiratory research","url":"https://pubmed.ncbi.nlm.nih.gov/21143907","citation_count":13,"is_preprint":false},{"pmid":"31135446","id":"PMC_31135446","title":"The Incidence of Labelling of Non-Lung Adenocarcinomas With Antibodies Against TTF-1 and Diagnostic Implications.","date":"2020","source":"Applied immunohistochemistry & molecular morphology : AIMM","url":"https://pubmed.ncbi.nlm.nih.gov/31135446","citation_count":12,"is_preprint":false},{"pmid":"28745797","id":"PMC_28745797","title":"Expressions and significances of TTF-1 and PTEN in early endometrial cancer.","date":"2017","source":"European review for medical and pharmacological sciences","url":"https://pubmed.ncbi.nlm.nih.gov/28745797","citation_count":12,"is_preprint":false},{"pmid":"35406686","id":"PMC_35406686","title":"FOXO1 Couples KGF and PI-3K/AKT Signaling to NKX2.1-Regulated Differentiation of Alveolar Epithelial Cells.","date":"2022","source":"Cells","url":"https://pubmed.ncbi.nlm.nih.gov/35406686","citation_count":11,"is_preprint":false},{"pmid":"34006635","id":"PMC_34006635","title":"Structural basis for p50RhoGAP BCH domain-mediated regulation of Rho inactivation.","date":"2021","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/34006635","citation_count":11,"is_preprint":false},{"pmid":"36420574","id":"PMC_36420574","title":"Detection and Characterization of a De Novo Alu Retrotransposition Event Causing NKX2-1-Related Disorder.","date":"2022","source":"Movement disorders : official journal of the Movement Disorder Society","url":"https://pubmed.ncbi.nlm.nih.gov/36420574","citation_count":11,"is_preprint":false},{"pmid":"34233113","id":"PMC_34233113","title":"Correlation of TTF-1 immunoexpression and EGFR mutation spectrum in non-small cell lung carcinoma.","date":"2021","source":"Journal of pathology and translational medicine","url":"https://pubmed.ncbi.nlm.nih.gov/34233113","citation_count":11,"is_preprint":false},{"pmid":"35294885","id":"PMC_35294885","title":"Tracheal separation is driven by NKX2-1-mediated repression of Efnb2 and regulation of endodermal cell sorting.","date":"2022","source":"Cell reports","url":"https://pubmed.ncbi.nlm.nih.gov/35294885","citation_count":11,"is_preprint":false},{"pmid":"17706597","id":"PMC_17706597","title":"TTF-1 regulates growth hormone and prolactin transcription in the anterior pituitary gland.","date":"2007","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/17706597","citation_count":11,"is_preprint":false},{"pmid":"23259454","id":"PMC_23259454","title":"NKX2-1 activation by SMAD2 signaling after definitive endoderm differentiation in human embryonic stem cell.","date":"2013","source":"Stem cells and development","url":"https://pubmed.ncbi.nlm.nih.gov/23259454","citation_count":11,"is_preprint":false},{"pmid":"26103969","id":"PMC_26103969","title":"NKX2.1-Related Disorders: a novel mutation with mild clinical presentation.","date":"2015","source":"Italian journal of pediatrics","url":"https://pubmed.ncbi.nlm.nih.gov/26103969","citation_count":11,"is_preprint":false},{"pmid":"33428297","id":"PMC_33428297","title":"Blastocyst complementation reveals that NKX2-1 establishes the proximal-peripheral boundary of the airway epithelium.","date":"2021","source":"Developmental dynamics : an official publication of the American Association of Anatomists","url":"https://pubmed.ncbi.nlm.nih.gov/33428297","citation_count":11,"is_preprint":false},{"pmid":"16830318","id":"PMC_16830318","title":"Mutations in TITF1 are not relevant to sporadic and familial chorea of unknown cause.","date":"2006","source":"Movement disorders : official journal of the Movement Disorder Society","url":"https://pubmed.ncbi.nlm.nih.gov/16830318","citation_count":10,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":52827,"output_tokens":10031,"usd":0.154473,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":20325,"output_tokens":4972,"usd":0.112962,"stage2_stop_reason":"end_turn"},"total_usd":0.267435,"stage1_batch_id":"msgbatch_013a8chtv3AWyTqv4z4sEF4C","stage2_batch_id":"msgbatch_01AHsuW63vinsvuTgzmQ3n62","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1995,\n      \"finding\": \"TTF-1/NKX2-1 is required for lung epithelial morphogenesis; antisense oligonucleotide suppression of TTF-1 translation in embryonic mouse lung explants inhibited branching morphogenesis, producing hyperplastic, unorganized epithelial cell proliferation without affecting the mesenchymal compartment.\",\n      \"method\": \"Antisense oligonucleotide inhibition in embryonic mouse lung branching morphogenesis model\",\n      \"journal\": \"Developmental biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — defined cellular phenotype with loss-of-function, single lab, antisense approach with tissue-specific readout\",\n      \"pmids\": [\"8612983\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"NKX2-1 is required for septation of the anterior foregut into trachea and esophagus, for lung branching morphogenesis, and for pulmonary epithelial cell differentiation (including surfactant protein gene expression); Nkx2.1-/- mice form a common tracheoesophageal lumen, have hypoplastic lungs arrested at pseudoglandular stage, and lack surfactant protein expression. Reduced Bmp-4 expression in mutant lung epithelium provides a mechanistic clue for impaired branching.\",\n      \"method\": \"Homozygous targeted gene disruption in mice with in situ hybridization and phenotypic analysis\",\n      \"journal\": \"Developmental biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — clean knockout mouse with multiple specific phenotypic readouts (morphogenesis, differentiation, surfactant expression, Bmp4) replicated across multiple labs\",\n      \"pmids\": [\"10208743\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"Two functionally distinct isoforms of NKX2.1 are expressed in pulmonary epithelium: a 371 aa major isoform and a 401 aa minor isoform with a 30 aa N-terminal extension. The longer isoform exhibits reduced transactivation activity on the SP-C promoter compared to the shorter major isoform, as demonstrated by site-directed mutagenesis suggesting the 30 aa extension causes steric interference.\",\n      \"method\": \"In vitro transcription/translation, co-transfection reporter assays, site-directed mutagenesis\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro assay with mutagenesis, single lab\",\n      \"pmids\": [\"10753648\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"TTF-1/NKX2-1 directly activates transcription of the midkine (MK) gene in lung epithelium by acting on TTF-1 regulatory elements in the 5' region of the MK gene promoter; MK expression was absent in TTF-1 null mouse lungs.\",\n      \"method\": \"Promoter-reporter transfection assays, TTF-1 null mouse analysis\",\n      \"journal\": \"Developmental dynamics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — promoter reporter with null mouse validation, single lab, two orthogonal methods\",\n      \"pmids\": [\"12761850\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"TAZ (transcriptional co-activator with PDZ-binding motif) directly interacts with the NH2-terminal domain of TTF-1/NKX2-1 and synergistically activates expression of surfactant protein C (SP-C) in the presence of TTF-1, as shown by pull-down and mammalian two-hybrid assays.\",\n      \"method\": \"Mammalian two-hybrid assay, GST pull-down, co-transfection reporter assays, deletion analysis\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal binding assays with functional reporter, single lab, multiple orthogonal methods\",\n      \"pmids\": [\"14970209\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"NKX2-1 directly regulates transcription of the BMP4 gene in lung epithelial cells through specific cis-active NKX2.1-responsive elements on both BMP4 promoters (hBmp4.1 and hBmp4.2); DNA-binding was confirmed by co-transfection assays identifying specific binding sequences.\",\n      \"method\": \"Co-transfection reporter assays in lung epithelial cells, identification of NKX2.1 binding sites\",\n      \"journal\": \"Gene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — promoter reporter with binding site identification, single lab\",\n      \"pmids\": [\"14960358\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"TTF-1/NKX2-1 binds the RET promoter at a specific site, and activates RET transcription; HSCR-associated RET promoter SNPs overlapping this TTF-1 binding site decrease TTF-1-activated RET transcription. A Gly322Ser TTF-1 mutation found in an HSCR patient compromises activation of transcription from HSCR-associated RET promoter haplotypes.\",\n      \"method\": \"Luciferase reporter assays, EMSA/binding assays, patient mutation analysis\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional reporter and binding assay with patient mutation, single lab\",\n      \"pmids\": [\"15548547\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"A C-terminal domain deletion mutation of TTF-1/NKX2-1 (825delC) produces a protein with diminished DNA binding that fails to activate Tg, TPO, or SP-B reporter genes. This mutant has a dominant-negative effect specifically on Tg and TPO but not SP-B transcription, and impairs wild-type TTF-1's synergy with PAX8 (which is required for Tg and TPO but not SP-B transcription). The mutant protein does not compete with wild-type for coactivators.\",\n      \"method\": \"EMSA, transfection reporter assays, Gal4 reporter system, expression vector analysis\",\n      \"journal\": \"The Journal of clinical endocrinology and metabolism\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — multiple in vitro functional assays with mutagenesis, single lab\",\n      \"pmids\": [\"16507635\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"NKX2.1 physically and functionally interacts with FOXA1 through the NKX2.1 homeodomain in a DNA-independent manner. This interaction is inhibitory on the SP-C promoter (which lacks a FOXA1 binding site), where FOXA1 attenuates NKX2.1-dependent transcription by masking the homeodomain DNA-binding function. On the Ccsp promoter (which has both binding sites), FOXA1 and NKX2.1 additively activate transcription.\",\n      \"method\": \"Co-IP, GST pull-down, EMSA, siRNA knockdown, co-transfection reporter assays\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — multiple orthogonal methods (pulldown, EMSA, siRNA, reporter), mechanistic dissection with deletion analysis, single rigorous study\",\n      \"pmids\": [\"17220277\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"TTF-1 directly activates transcription of growth hormone and prolactin genes in the anterior pituitary; TTF-1 inhibited growth hormone transcription but activated prolactin transcription through direct binding to TTF-1 binding motifs in their respective promoters. Deletion of these motifs abolished the regulatory effects.\",\n      \"method\": \"In situ hybridization, co-transfection reporter assays, deletion analysis in pituitary cell line\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional reporter with binding site deletion, single lab\",\n      \"pmids\": [\"17706597\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"NKX2.1 directly binds a highly conserved sequence in the Lhx6 promoter and activates Lhx6 expression, thereby specifying parvalbumin- and somatostatin-expressing cortical interneuron fate in the medial ganglionic eminence. Rescue of NKX2.1 expression in Nkx2.1-/- slices induced Lhx6; gain- and loss-of-function of Lhx6 were sufficient/necessary to rescue interneuron phenotypes.\",\n      \"method\": \"Electroporation of cDNA into slice cultures from Nkx2.1-/- embryos, transplantation into neonatal cortex, ChIP, promoter binding assay, gain/loss-of-function\",\n      \"journal\": \"Development (Cambridge, England)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — ChIP confirming direct binding, functional rescue with multiple genetic approaches, single rigorous study\",\n      \"pmids\": [\"18339674\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"TTF-1/NKX2-1 directly binds and transcriptionally upregulates the nestin gene in vivo through the NestBS (HRE/CRE-like) site within the CNS-specific nestin enhancer; transgenic mouse analysis confirmed this regulation requires the NestBS site.\",\n      \"method\": \"Transgenic mouse reporter assay, binding site analysis\",\n      \"journal\": \"The International journal of developmental biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo transgenic reporter with mutagenesis of binding site, single lab\",\n      \"pmids\": [\"18033672\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"TITF1/NKX2-1 is a lineage-specific oncogene amplified at 14q13.3 in lung cancer; siRNA-mediated knockdown of TITF1 in amplified lung cancer cell lines reduced cell proliferation by decreasing cell-cycle progression and increasing apoptosis.\",\n      \"method\": \"Genomic profiling of 128 cell lines/tumors, siRNA knockdown with proliferation and cell-cycle assays\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — siRNA knockdown with defined cellular phenotype, single lab\",\n      \"pmids\": [\"18212743\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"Nkx2-1 acts cooperatively with Phox2b and Sox10 (but not Pax3) to mediate RET transcription in the enteric nervous system, as demonstrated by dual-luciferase reporter studies identifying the Phox2b-responsive region in the RET promoter.\",\n      \"method\": \"Dual-luciferase reporter assay, immunohistochemistry\",\n      \"journal\": \"Journal of pediatric surgery\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, luciferase reporter only without direct binding confirmation\",\n      \"pmids\": [\"19853745\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"Epigenetic silencing of TTF-1/NKX2-1 in undifferentiated thyroid carcinomas occurs through DNA hypermethylation of CpG islands in the TTF-1 promoter and reduced acetylation of histone H3-lys9; DNA demethylating agents restore TTF-1 expression in thyroid carcinoma cell lines.\",\n      \"method\": \"Methylation-specific PCR, chromatin immunoprecipitation (ChIP), 5-aza-deoxycytidine treatment\",\n      \"journal\": \"Laboratory investigation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP plus functional restoration with demethylating agent, single lab\",\n      \"pmids\": [\"19506552\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"TTF-1/NKX2-1 directly activates transcription of the α5 nicotinic acetylcholine receptor (CHRNA5) subunit gene by binding specific TTF-1 response elements in both the 2.0-kb and 850-bp α5 promoters; site-directed mutagenesis of these elements abolished activation.\",\n      \"method\": \"Reporter assays, site-directed mutagenesis, exogenous TTF-1 expression in lung epithelial cell lines\",\n      \"journal\": \"Respiratory research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — reporter with binding site mutagenesis, single lab\",\n      \"pmids\": [\"21143907\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"NKX2-1/TTF-1 induces expression of the receptor tyrosine kinase-like orphan receptor ROR1, which sustains prosurvival PI3K-AKT signaling over pro-apoptotic p38 signaling in lung adenocarcinoma, via ROR1 kinase-dependent c-Src activation and kinase-independent sustainment of EGFR-ERBB3 association and ERBB3 phosphorylation.\",\n      \"method\": \"ROR1 knockdown in lung cancer cell lines, signaling pathway analysis (PI3K-AKT, p38), EGFR status evaluation\",\n      \"journal\": \"Cancer cell\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — defined signaling pathway placement with knockdown and multiple readouts, single lab\",\n      \"pmids\": [\"22439932\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"TTF-1/NKX2-1 directly transactivates the tight junction molecules occludin (OCLN) and claudin-1 (CLDN1) through direct interaction with their promoters; TTF-1 knockdown down-regulated occludin, conferred resistance to anoikis, and occludin restoration reversed this effect, establishing TTF-1-mediated occludin expression as a mechanism of metastasis suppression.\",\n      \"method\": \"ChIP, promoter reporter assays, siRNA knockdown, anoikis assay, migration assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP plus functional readout with siRNA, single lab, multiple methods\",\n      \"pmids\": [\"22761434\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"NKX2-1 haploinsufficiency combined with oncogenic KrasG12D (but not EGFRL858R) causes mucinous adenocarcinoma of the lung in mice; NKX2-1 inhibits AP-1 activity and tumor colony formation in vitro. ChIP-seq identified direct association of NKX2-1 with genes induced in mucinous tumors at both AP-1 and canonical NKX2-1 binding elements.\",\n      \"method\": \"Transgenic mouse model, ChIP-seq, in vitro tumor colony formation, AP-1 reporter assay\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vivo mouse model with ChIP-seq and in vitro functional assays, genome-wide binding characterization\",\n      \"pmids\": [\"23143308\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"NKX2-1 directly regulates p53 transcription; NKX2-1-elevated wild-type p53 down-regulates IKKβ transcription via decreased Sp1 binding to IKKβ promoter, while NKX2-1 with mutant p53 up-regulates IKKβ via mutant p53/NF-Y complex, modulating NF-κB activation and EMT in lung adenocarcinoma in a p53-status-dependent manner.\",\n      \"method\": \"Promoter reporter assays, ChIP for Sp1 binding, xenograft tumor formation, soft-agar assay\",\n      \"journal\": \"Oncotarget\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reporter assays with ChIP, functional in vivo and in vitro validation, single lab\",\n      \"pmids\": [\"25881545\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Loss of NKX2-1, FOXA2, and CDX2 together (but not individually) synergistically promotes the metastatic potential of non-metastatic lung adenocarcinoma cells to the level of naturally arising metastatic cells in vivo, and is sufficient to account for a significant fraction of gene expression differences between metastatic and non-metastatic states, including upregulation of Tks5long, Hmga2, and Snail.\",\n      \"method\": \"Triple knockdown, in vivo transplant metastasis assay, gene expression profiling\",\n      \"journal\": \"Genes & development\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss-of-function with defined in vivo metastatic phenotype, epistasis between three factors, single lab\",\n      \"pmids\": [\"26341558\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"TTF-1/NKX2-1 interacts with DDB1 (damage-specific DNA binding protein 1) and blocks DDB1 binding to CHK1, thereby attenuating ubiquitylation and subsequent degradation of CHK1. TTF-1 overexpression conferred resistance to DNA replication stress and prevented DNA double-strand breaks (reduced pCHK2 and γH2AX), revealing a non-transcriptional function of TTF-1.\",\n      \"method\": \"Global proteomic interaction screen (MS), co-IP, functional replication stress assays (pCHK2, γH2AX)\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — MS interactome with co-IP validation and functional readout, single lab\",\n      \"pmids\": [\"28192407\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Nkx2.1 directly inhibits NANCI (a cis-acting lncRNA at the same locus) while NANCI in turn promotes Nkx2.1 transcription in cis, forming a feedback loop. Combined heterozygous mutations in both NANCI and Nkx2.1 produce persistent Nkx2.1 deficiency and reprogramming of lung epithelial cells to a posterior endoderm fate, impaired innate immunity, and progressive lung degeneration.\",\n      \"method\": \"Mouse genetic models, concurrent heterozygous mutations, lung epithelial fate analysis\",\n      \"journal\": \"Genes & development\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo genetic epistasis between lncRNA and TF, single lab, defined cellular phenotype\",\n      \"pmids\": [\"28546511\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Nkx2.1 binds the GFAP promoter to regulate its expression, thereby controlling astrogliogenesis in the telencephalon; Nkx2.1-/- mice show drastic loss of astrocytes from impaired proliferation and possibly glial specification/differentiation of ventral neural stem cells.\",\n      \"method\": \"ChIP, co-transfection reporter assay, BrdU proliferation assay, neurosphere assay, knockout mouse analysis\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP with functional reporter and KO mouse phenotype, single lab\",\n      \"pmids\": [\"28266561\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"MOB1A/B loss in bronchioalveolar epithelium causes impaired YAP1/TAZ-dependent differentiation and decreased NKX2-1-dependent surfactant protein production. YAP1/TAZ-NKX2.1 axis controls expression of collagen XVII (a hemidesmosome component required for alveolar stem cell niche maintenance); loss of MOB1 decreases collagen XVII expression through this axis.\",\n      \"method\": \"Conditional knockout mouse model, bronchioalveolar epithelium-specific deletion, cell differentiation and adhesion assays\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — conditional KO with defined cellular phenotype and pathway placement, single lab\",\n      \"pmids\": [\"28346423\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"TTF-1/NKX2-1 binding profiles in SCLC vs. lung adenocarcinoma differ substantially (75% distinct binding regions); in SCLC, TTF-1 binds regions enriched for E-box motifs and co-occupies adjacent sites with ASCL1 to cooperatively regulate neuroendocrine and anti-apoptotic (Bcl-2 family) gene expression, whereas in LADC the binding profile and transcriptional targets differ.\",\n      \"method\": \"ChIP-seq, RNA-seq comparison between SCLC and LADC cell lines\",\n      \"journal\": \"Molecular oncology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP-seq and RNA-seq with two cell lines, single lab, genome-wide characterization\",\n      \"pmids\": [\"31782890\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"NKX2-1 induces the ERK phosphatase DUSP6, which inactivates ERK; loss of NKX2-1 in late-stage lung adenocarcinoma downregulates DUSP6 and unleashes ERK hyperactivation. Re-introduction of NKX2-1 in NKX2-1-silenced tumor cells induced DUSP6 and inhibited tumor growth and metastasis. DUSP6 is necessary for NKX2-1-mediated inhibition of tumor progression in vivo.\",\n      \"method\": \"Human tissue samples and cell lines, xenografts, genetic mouse models, in vivo rescue experiments\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple model systems (cell lines, xenograft, GEM, patient tissue), in vivo necessity established, single lab with strong evidence\",\n      \"pmids\": [\"34689179\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"NKX2-1 directly inhibits the CXCL1, CXCL2, and CXCL5 promoters, as demonstrated by ATAC-seq; NKX2-1 depletion triggers secretion of these chemokines, recruiting tumor-promoting neutrophils via CXCLs/CXCR2 signaling to promote lung adenocarcinoma progression.\",\n      \"method\": \"ATAC-seq, chemokine array, qRT-PCR, syngeneic mouse model, CXCR2 antagonist treatment\",\n      \"journal\": \"Advanced science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ATAC-seq for chromatin accessibility at promoters with functional in vivo mouse model, single lab\",\n      \"pmids\": [\"39113226\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"In NKX2-1-positive lung adenocarcinoma, FoxA1/2 loss leads to aberrant NKX2-1 activity and genomic mislocalization, which actively inhibits tumorigenesis and drives alternative non-proliferative cellular identity programs; FoxA1/2 normally guides NKX2-1 to appropriate genomic loci to maintain a dual pulmonary-gastrointestinal identity state.\",\n      \"method\": \"FoxA1/2 knockout in KRAS-driven mouse models and human cell lines, ChIP-seq for NKX2-1 localization\",\n      \"journal\": \"Developmental cell\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic KO mouse model with ChIP-seq demonstrating NKX2-1 relocalization, single lab\",\n      \"pmids\": [\"35835117\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"PRDM3 and PRDM16 (histone methyltransferases) regulate chromatin accessibility at NKX2-1 transcriptional targets critical for alveolar type 2 (AT2) cell differentiation and surfactant homeostasis; combined deletion of Prdm3/16 in lung endoderm causes perinatal respiratory failure from loss of AT2 cells. PRDM3/16 act as NKX2-1 co-activators, and their loss leads to AT2 cells acquiring partial AT1 fate.\",\n      \"method\": \"Conditional knockout mice, single-cell RNA-seq, bulk ATAC-seq, CUT&RUN\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — CUT&RUN demonstrating co-occupancy, ATAC-seq showing chromatin changes at NKX2-1 targets, in vivo KO with defined lethal phenotype\",\n      \"pmids\": [\"39284798\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"YAP participates with KLF5, NFIB, and NKX2-1 to regulate AGER expression in alveolar epithelial cells; YAP activation increased AT1 cell numbers and altered differentiation via this transcriptional network, while YAP deletion increased mature AT2 cell gene expression.\",\n      \"method\": \"Transgenic mice with YAP activation or deletion, motif enrichment analysis, promoter accessibility assays\",\n      \"journal\": \"iScience\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — transcriptional network inference from mouse model with motif analysis, direct NKX2-1 binding not directly confirmed by ChIP\",\n      \"pmids\": [\"34466790\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"In SCLC, NKX2-1 co-immunoprecipitates with SOX1 as a functional transcriptional partner to maintain neural lineage identity in the SCLC-Aα subtype; NKX2-1 CRISPR deletion inhibited SCLC-Aα cell growth and induced apoptosis; a super-enhancer at the NKX2-1 locus drives its expression in this subtype.\",\n      \"method\": \"ChIP-seq, co-immunoprecipitation followed by mass spectrometry, CRISPR-Cas9 deletion, xenograft\",\n      \"journal\": \"American journal of respiratory and critical care medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP/MS for partner identification with CRISPR functional validation, single lab\",\n      \"pmids\": [\"35848993\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"In ASCL1-high SCLC, NKX2-1 complexes with ASCL1 and PROX1 to co-occupy super-enhancers and co-regulate genes in NOTCH signaling, catecholamine biosynthesis, and cell cycle; ASCL1 depletion demonstrated its role as a key dependency factor.\",\n      \"method\": \"ChIP-seq, chromatin landscape analysis, co-immunoprecipitation, ASCL1 depletion\",\n      \"journal\": \"iScience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP-seq with co-IP demonstrating complex formation, single lab\",\n      \"pmids\": [\"34466783\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"NKX2-1 directly represses Efnb2 (Ephrin-B2) in tracheal endoderm, as demonstrated by ChIP and reporter assays; NKX2-1 loss causes expansion of Efnb2 expression, disrupts EPH/EPHRIN-mediated cell sorting, and causes tracheoesophageal separation failure with misallocation of ventral foregut cells into the esophagus.\",\n      \"method\": \"ChIP, reporter assays, lineage tracing, genetic loss-of-function mouse model\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — ChIP and reporter confirming direct repression, in vivo lineage tracing with mechanistic cell-sorting phenotype, single rigorous study\",\n      \"pmids\": [\"35294885\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"NKX2-1 loss of function confers Wnt dependency in lung adenocarcinoma regardless of EGFR mutation status; gene engineering of alveolar organoids demonstrated that constitutive EGFR-RAS signaling provides Wnt independence, while NKX2-1 loss overrides this to restore Wnt dependency.\",\n      \"method\": \"Patient-derived organoid biobank, CRISPR gene engineering, phenotypic screening of niche factor dependency\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — CRISPR gene engineering with functional organoid phenotype, single lab\",\n      \"pmids\": [\"36870059\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"In NKX2-1-deficient BRAFV600E-driven lung adenocarcinoma, BRAF/MEK inhibitors fail to drive tumor cells into quiescence (unlike NKX2-1-positive cells) and instead induce cell identity switching within the gastric lineage, driven partly by WNT signaling and FoxA1/2. An NKX2-1/ERK/WNT feedback loop exists where NKX2-1 modulates response to targeted therapy.\",\n      \"method\": \"NKX2-1 deletion in BRAFV600E mouse model, BRAF/MEK inhibitor treatment, cell cycle and identity analysis\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo mouse model with defined pharmacological and identity switching phenotype, single lab\",\n      \"pmids\": [\"33821796\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"NKX2-1 directly binds and transcriptionally upregulates serine/glycine synthesis enzyme genes (PHGDH, PSAT1, PSPH, SHMT2), enabling NKX2-1-expressing cells to proliferate and invade under serine/glycine depletion. NKX2-1-driven serine/glycine synthesis generates nucleotides and redox molecules, alters cellular lipidome and methylome, and NKX2-1 tumor-bearing mice show enhanced tumor aggressiveness.\",\n      \"method\": \"ChIP-qPCR, immunoblotting, mass spectrometry metabolomics, NKX2-1 overexpression/knockdown, mouse tumor models\",\n      \"journal\": \"British journal of cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP-qPCR with metabolomics and in vivo mouse model, single lab, multiple orthogonal methods\",\n      \"pmids\": [\"36932191\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"In neuroendocrine prostate cancer, FOXA2 pioneer factor binding at NE enhancers initiates DNA demethylation and induces NKX2-1 expression. NKX2-1 then preferentially binds gene promoters and interacts with enhancer-bound FOXA2 through chromatin looping to drive 3D chromatin remodeling and luminal-to-neuroendocrine transformation. NKX2-1/FOXA2 recruit p300/CBP to activate NE enhancers; pharmacological p300/CBP inhibition blunts NE gene expression and abolishes NEPC tumor growth.\",\n      \"method\": \"Hi-C/3D chromatin sequencing, isogenic cell lines for NE transformation, ChIP-seq, ATAC-seq, bisulfite sequencing, co-IP, p300/CBP inhibitor treatment in vivo\",\n      \"journal\": \"Nature genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — multiple orthogonal genome-wide methods (Hi-C, ChIP-seq, ATAC-seq, bisulfite-seq), co-IP, mechanistic in vivo pharmacological validation, single rigorous study\",\n      \"pmids\": [\"40691407\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Activin-A induces NKX2-1 expression in hESC-derived definitive endoderm through ALK4 receptor-mediated SMAD2 phosphorylation; phospho-SMAD2 directly binds to the NKX2-1 promoter and activates its transcription. GDF11 can substitute for Activin-A, but Wnt3a, SHH, FGF2, or BMP4 cannot.\",\n      \"method\": \"hESC differentiation, SMAD2 phosphorylation assay, ChIP for SMAD2 at NKX2-1 promoter, signaling pathway inhibition\",\n      \"journal\": \"Stem cells and development\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP for direct SMAD2 binding at NKX2-1 promoter, multiple pathway tests, single lab\",\n      \"pmids\": [\"23259454\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"NKX2-1 functions in an epithelial cell-autonomous manner to establish the proximal-peripheral boundary in developing airways; blastocyst complementation with NKX2-1-sufficient ESCs restored peripheral lung formation and β-catenin signaling in Nkx2-1-/- basal cells, but did not complement most proximal regions, demonstrating a cell-autonomous role in boundary formation.\",\n      \"method\": \"Blastocyst complementation, chimeric mouse analysis, β-catenin signaling assessment\",\n      \"journal\": \"Developmental dynamics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — blastocyst complementation as genetic epistasis tool, single lab, defined in vivo phenotypic rescue\",\n      \"pmids\": [\"33428297\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"FOXO1 interacts directly with the NKX2.1 homeodomain (via its forkhead domain), disrupting NKX2.1 binding to the SFTPC promoter and causing loss of surfactant gene expression during alveolar epithelial type I differentiation. PI-3K/AKT-mediated phosphorylation of FOXO1 sequesters it from the nucleus, maintaining AT2 identity with high surfactant expression; blocking PI-3K/AKT allows nuclear FOXO1 to interact with NKX2.1 and suppress surfactant expression.\",\n      \"method\": \"Co-IP between FOXO1 and NKX2.1, ChIP for NKX2.1 at SFTPC promoter, PI-3K/AKT inhibition, KGF treatment, in vitro AEC differentiation\",\n      \"journal\": \"Cells\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP with ChIP demonstrating disrupted NKX2.1 promoter occupancy, signaling pathway dissection, single lab\",\n      \"pmids\": [\"35406686\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"NKX2-1 (TTF-1) is a homeodomain transcription factor that directly binds promoters of lung-specific genes (SP-B, SP-C, BMP4, occludin, DUSP6, CXCL chemokines, serine/glycine synthesis enzymes) to control lung epithelial morphogenesis, alveolar differentiation, and tracheoesophageal separation; it functions through physical interactions with co-regulators including TAZ, FOXA1/2, PAX8, FOXO1, SMAD2, PRDM3/16, ASCL1, SOX1, and FOXA2, and also exerts non-transcriptional functions by binding DDB1 to protect CHK1 from ubiquitylation, conferring replication stress resistance; in the developing brain it specifies cortical interneuron fate by directly activating Lhx6 and astrogliogenesis by activating GFAP, while in cancer it acts as a lineage-survival oncogene (inducing ROR1-mediated EGFR-PI3K survival signaling and DUSP6-mediated ERK suppression) whose loss unleashes ERK hyperactivation, gastric transdifferentiation, and metastasis through chemokine-mediated neutrophil recruitment.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"NKX2-1 (TTF-1) is a homeodomain transcription factor that serves as a master regulator of lung epithelial morphogenesis and differentiation, required for septation of the anterior foregut into trachea and esophagus, for branching morphogenesis, and for surfactant protein expression [#1, #0]. It executes this program by directly binding cis-elements in target promoters: it activates lung-differentiation and morphogenesis genes including BMP4 [#5], midkine [#3], and surfactant protein C [#4], while directly repressing Efnb2 in tracheal endoderm to enable EPH/EPHRIN-mediated cell sorting during tracheoesophageal separation [#33]. Its transcriptional output is shaped by combinatorial partners—it cooperates with TAZ to synergize on SP-C [#4], with PAX8 on thyroid genes [#7], and is guided to appropriate genomic loci by FOXA1/2, whose loss causes NKX2-1 mislocalization [#28, #8]; PRDM3/16 act as co-activators that open chromatin at NKX2-1 targets to drive alveolar type 2 cell differentiation [#29], and FOXO1 binding to the homeodomain disrupts NKX2-1 occupancy at SFTPC to toggle alveolar epithelial fate [#40]. NKX2-1 expression is itself induced via Activin/SMAD2 signaling onto its promoter [#38] and is reinforced by a cis-acting lncRNA feedback loop [#22]. Beyond the lung, NKX2-1 specifies cortical interneuron fate by directly activating Lhx6 [#10] and controls telencephalic astrogliogenesis via the GFAP promoter [#23]. In cancer it acts as an amplified lineage-survival oncogene in lung adenocarcinoma [#12], inducing ROR1-dependent prosurvival PI3K-AKT signaling [#16], while its loss unleashes ERK hyperactivation through downregulation of the phosphatase DUSP6 [#26], promotes chemokine-driven neutrophil recruitment by derepressing CXCL1/2/5 [#27], and drives metastasis and gastric transdifferentiation cooperatively with FOXA2/CDX2 loss [#20, #35]. NKX2-1 also exerts a non-transcriptional function by binding DDB1 to protect CHK1 from ubiquitylation, conferring replication-stress resistance [#21].\",\n  \"teleology\": [\n    {\n      \"year\": 1995,\n      \"claim\": \"Established that NKX2-1 is functionally required for lung epithelial morphogenesis rather than merely a marker, answering whether the factor drives branching.\",\n      \"evidence\": \"Antisense oligonucleotide suppression in embryonic mouse lung explants\",\n      \"pmids\": [\"8612983\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Did not identify direct transcriptional targets\", \"Antisense approach lacks genetic specificity\"]\n    },\n    {\n      \"year\": 1999,\n      \"claim\": \"Genetic knockout defined the full developmental requirement for NKX2-1 in foregut septation, branching, and epithelial differentiation, linking loss to reduced Bmp4 as a mechanistic clue.\",\n      \"evidence\": \"Homozygous targeted disruption in mice with in situ hybridization and phenotyping\",\n      \"pmids\": [\"10208743\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct binding to target promoters not yet demonstrated\", \"Did not resolve which targets account for each phenotype\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Identified direct transcriptional targets in lung (midkine, BMP4) establishing NKX2-1 as a sequence-specific activator of differentiation/morphogenesis genes.\",\n      \"evidence\": \"Promoter-reporter assays and null mouse analysis; binding-site identification\",\n      \"pmids\": [\"12761850\", \"14960358\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Endogenous occupancy by ChIP not shown for all targets\", \"Cofactor requirements undefined\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Revealed combinatorial control by identifying physical co-regulators (TAZ activates, PAX8 synergy required for thyroid genes), explaining promoter-specific output.\",\n      \"evidence\": \"Mammalian two-hybrid, GST pull-down, reporter assays; mutant analysis in patient context\",\n      \"pmids\": [\"14970209\", \"16507635\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Structural basis of interactions not resolved\", \"Stoichiometry and genome-wide co-binding unknown\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Showed that partner binding can inhibit NKX2-1, as FOXA1 masks the homeodomain DNA-binding surface in a promoter-context-dependent manner.\",\n      \"evidence\": \"Co-IP, GST pull-down, EMSA, siRNA, reporter assays with deletion mapping\",\n      \"pmids\": [\"17220277\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"In vivo relevance of masking versus genomic guidance not yet distinguished\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Extended NKX2-1 function to neural lineage specification (cortical interneurons via Lhx6) and established it as an amplified lineage-survival oncogene in lung cancer.\",\n      \"evidence\": \"ChIP and functional rescue in Nkx2.1-/- slices; genomic profiling with siRNA proliferation/cell-cycle assays\",\n      \"pmids\": [\"18339674\", \"18212743\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Oncogenic downstream effectors not yet identified\", \"Mechanism of survival dependency undefined at the time\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Placed NKX2-1 in cancer signaling and metastasis circuits—inducing ROR1-PI3K-AKT survival signaling while also activating tight-junction genes that suppress anoikis and metastasis.\",\n      \"evidence\": \"ROR1 knockdown and signaling analysis; ChIP, reporter, siRNA, anoikis/migration assays\",\n      \"pmids\": [\"22439932\", \"22761434\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Context dependence of pro- versus anti-tumor roles unresolved\", \"Single-lab signaling placements\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Identified an upstream inductive signal: Activin/GDF11 via ALK4-SMAD2 directly activates the NKX2-1 promoter in definitive endoderm.\",\n      \"evidence\": \"hESC differentiation, SMAD2 phosphorylation, ChIP at NKX2-1 promoter, pathway inhibition\",\n      \"pmids\": [\"23259454\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Cofactors at the NKX2-1 promoter not defined\", \"Specificity for endoderm versus other lineages untested\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Genome-wide and genetic studies showed NKX2-1 haploinsufficiency cooperates with oncogenic Kras to drive mucinous adenocarcinoma and that NKX2-1 inhibits AP-1 at shared binding elements.\",\n      \"evidence\": \"Transgenic mouse model with ChIP-seq and AP-1 reporter/colony assays\",\n      \"pmids\": [\"23143308\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism of AP-1 antagonism at the chromatin level not fully resolved\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Connected NKX2-1 to p53/NF-kB and to multi-factor metastasis suppression, showing loss of NKX2-1 with FOXA2 and CDX2 jointly licenses metastatic identity.\",\n      \"evidence\": \"Reporter/ChIP for p53-IKKβ axis; triple knockdown with in vivo metastasis and expression profiling\",\n      \"pmids\": [\"25881545\", \"26341558\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct versus indirect contributions of each factor not separated\", \"p53-status dependence adds context complexity\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Uncovered a non-transcriptional function: NKX2-1 binds DDB1 to block CHK1 ubiquitylation and confer replication-stress resistance, broadening its mechanistic repertoire beyond transcription.\",\n      \"evidence\": \"MS interactome, co-IP, replication-stress assays (pCHK2, γH2AX)\",\n      \"pmids\": [\"28192407\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Structural basis of DDB1 competition unresolved\", \"Physiological contexts where this dominates unclear\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Defined autoregulatory and co-activator layers controlling NKX2-1 dosage and chromatin access in lung—NANCI lncRNA feedback, PRDM3/16 co-activation, and YAP1/TAZ-MOB1 axis for AT2 differentiation.\",\n      \"evidence\": \"Mouse genetic epistasis, conditional KO, scRNA-seq, ATAC-seq, CUT&RUN\",\n      \"pmids\": [\"28546511\", \"39284798\", \"28346423\", \"28266561\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct biochemical interaction of PRDM3/16 with NKX2-1 versus chromatin-level cooperation needs further dissection\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Cell-type-specific ChIP-seq and partner mapping revealed that NKX2-1 rewires its genomic binding and partners across tumor lineages, co-occupying enhancers with ASCL1, SOX1, and PROX1 in SCLC to enforce neuroendocrine identity.\",\n      \"evidence\": \"ChIP-seq/RNA-seq comparison, co-IP/MS, CRISPR deletion, xenografts\",\n      \"pmids\": [\"31782890\", \"35848993\", \"34466783\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Determinants of lineage-specific binding redistribution incompletely defined\", \"Direct versus assisted recruitment to E-box regions unclear\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Resolved how NKX2-1 loss promotes tumor progression—derepressing CXCL chemokines to recruit neutrophils, downregulating DUSP6 to unleash ERK, conferring Wnt dependency, and enabling targeted-therapy escape via gastric identity switching.\",\n      \"evidence\": \"ATAC-seq, syngeneic models, xenografts/GEMs, organoid CRISPR engineering, inhibitor treatments\",\n      \"pmids\": [\"39113226\", \"34689179\", \"36870059\", \"33821796\", \"35835117\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Hierarchy among these loss-driven programs not established\", \"Reversibility of identity switching in patients untested\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Identified a metabolic output of NKX2-1: direct activation of serine/glycine synthesis enzymes that supports proliferation under nutrient depletion.\",\n      \"evidence\": \"ChIP-qPCR, metabolomics, overexpression/knockdown, mouse tumor models\",\n      \"pmids\": [\"36932191\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether this drives tumor aggressiveness in patients is untested\", \"Interplay with lineage program unclear\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Demonstrated a pioneer-factor-driven mechanism in neuroendocrine prostate cancer where FOXA2 induces NKX2-1, which then drives 3D chromatin remodeling and p300/CBP recruitment to enforce neuroendocrine transformation.\",\n      \"evidence\": \"Hi-C, ChIP-seq, ATAC-seq, bisulfite-seq, co-IP, in vivo p300/CBP inhibition\",\n      \"pmids\": [\"40691407\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Generalizability of looping mechanism to other lineages untested\", \"Direct contribution of NKX2-1 promoter-binding to looping not fully isolated\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How NKX2-1's combinatorial partner code and chromatin context determine its switch between activator and repressor, and between tumor-suppressive and oncogenic output, remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unified model linking partner identity to activator/repressor mode\", \"Structural basis of homeodomain masking versus genomic guidance unknown\", \"Determinants of lineage-specific genomic redistribution undefined\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [1, 5, 10, 18, 25, 27, 33, 36]},\n      {\"term_id\": \"GO:0003677\", \"supporting_discovery_ids\": [5, 7, 10, 33]},\n      {\"term_id\": \"GO:0003700\", \"supporting_discovery_ids\": [4, 8, 18]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [10, 33, 40]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [1, 5, 10, 18, 33]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [1, 10, 23, 33, 39]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [12, 16, 26, 27, 35]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"TAZ\", \"FOXA1\", \"FOXA2\", \"PAX8\", \"FOXO1\", \"DDB1\", \"ASCL1\", \"SOX1\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}