Affinage

NKX2-1

Homeobox protein Nkx-2.1 · UniProt P43699

Round 2 corrected
Length
371 aa
Mass
38.6 kDa
Annotated
2026-04-29
130 papers in source corpus 50 papers cited in narrative 50 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

NKX2-1 (TTF-1) is a homeodomain transcription factor that serves as a master regulator of lineage identity in the lung, thyroid, and forebrain, coordinating morphogenesis, cell-type specification, and differentiated gene expression programs. It binds DNA via an NK-2-type homeodomain preferring 5'-CAAG-3' core motifs and directly activates surfactant protein genes (SP-B, SP-C), thyroglobulin, WNT7b, PACAP, angiotensinogen, ROR1, RET, and serine/glycine biosynthetic enzymes, while repressing Hmga2, CXCL chemokines, Neuropilin-2, and EMT-driving genes through context-dependent recruitment of co-factors including PAX8, TAZ, GATA6, FoxA1/2, LHX6, and HOXB5 (PMID:1976511, PMID:7559607, PMID:12441357, PMID:14970209, PMID:27657450, PMID:39113226). Its transcriptional activity is negatively regulated by Ras/Raf/MEK/ERK-mediated phosphorylation at three serine residues and by TGF-β signaling, and its genomic occupancy is redirected upon loss of pioneer factors FoxA1/2 (PMID:10733581, PMID:18602626, PMID:35835117). Heterozygous loss-of-function mutations cause brain-lung-thyroid syndrome (congenital hypothyroidism, choreoathetosis, and pulmonary disease) and benign hereditary chorea, while in lung adenocarcinoma NKX2-1 functions as a context-dependent lineage-survival oncogene when amplified and a tumor suppressor whose loss unleashes metastatic programs, mucinous differentiation, and CXCR2-dependent neutrophil recruitment (PMID:11854319, PMID:11971878, PMID:21471965, PMID:23143308, PMID:39113226).

Mechanistic history

Synthesis pass · year-by-year structured walk · 15 steps
  1. 1990 High

    Identification of TTF-1 as a homeodomain-containing thyroid/lung nuclear factor established a new tissue-specific transcription factor family and placed NKX2-1 at the intersection of thyroid and pulmonary gene regulation.

    Evidence cDNA cloning, DNA-binding assays with thyroid nuclear extracts, chromosomal mapping to human chr14

    PMID:1976511

    Open questions at the time
    • No in vivo loss-of-function data
    • DNA-binding specificity not yet defined at nucleotide level
    • Lung function of TTF-1 not yet demonstrated
  2. 1993 High

    Structural and biophysical characterization of the TTF-1 homeodomain revealed a canonical helix-turn-helix fold with unusual conformational flexibility, linking structural dynamics to DNA-binding activity.

    Evidence NMR structure determination and CD-monitored thermal/urea unfolding of recombinant TTF-1 homeodomain

    PMID:7957942 PMID:8282100

    Open questions at the time
    • No co-crystal structure with DNA
    • Structural basis for target gene selectivity unknown
  3. 1995 High

    Definition of the 5'-CAAG-3' core binding motif and demonstration that TTF-1 directly transactivates the surfactant protein B gene extended TTF-1 function from thyroid to pulmonary epithelial gene regulation.

    Evidence SELEX-based binding site selection; reporter assays with site-directed mutagenesis of SP-B enhancer TTF-1 sites in lung cells

    PMID:7559607 PMID:7654238

    Open questions at the time
    • Genome-wide binding landscape unknown
    • Mechanism of tissue-selective activation (thyroid vs. lung) not resolved
  4. 1999 High

    Nkx2.1-null mice revealed an essential non-redundant role in foregut septation, distal lung morphogenesis, and surfactant gene expression, establishing NKX2-1 as a master regulator of lung development.

    Evidence Targeted gene disruption in mice; histological and molecular analysis of null embryos showing tracheoesophageal and pulmonary defects

    PMID:10208743 PMID:10706142

    Open questions at the time
    • Downstream transcriptional network in lung morphogenesis largely uncharacterized
    • Mechanism linking NKX2-1 to Bmp-4 regulation not established
  5. 2000 High

    Discovery that the Ras/Raf/MEK/ERK cascade directly phosphorylates TTF-1 at three serine residues to repress its activity identified a key post-translational regulatory axis, connecting oncogenic signaling to loss of differentiated function.

    Evidence In vitro ERK kinase assay, in vivo phosphorylation analysis, serine-to-alanine mutagenesis abolishing phosphorylation, MEK inhibitor rescue

    PMID:10733581

    Open questions at the time
    • Identity of ERK-independent Ras pathway repressing TTF-1 not resolved
    • Structural basis for phosphorylation-mediated repression unknown
  6. 2002 High

    Identification of NKX2-1 loss-of-function mutations in patients with brain-lung-thyroid syndrome and benign hereditary chorea established NKX2-1 haploinsufficiency as the genetic cause of a multi-organ developmental disorder, validated by heterozygous knockout mice.

    Evidence Mutation screening in BHC and congenital hypothyroidism families; heterozygous Ttf1 knockout mouse phenotyping; functional assays showing loss of DNA binding and transactivation

    PMID:11854318 PMID:11854319 PMID:11971878

    Open questions at the time
    • Genotype-phenotype correlations for specific mutations incomplete
    • Mechanism of selective basal ganglia vulnerability unknown
  7. 2002 High

    Demonstration of direct physical interactions between TTF-1 and co-factors PAX8, GATA6, and FoxA2 on thyroid and lung target promoters (thyroglobulin, WNT7b) revealed the combinatorial transcriptional logic underlying tissue-specific gene activation.

    Evidence GST pull-down with purified proteins, co-immunoprecipitation, EMSA, cooperative transactivation assays on thyroglobulin and WNT7b promoters

    PMID:11914369 PMID:12441357

    Open questions at the time
    • Structural basis of TTF-1–PAX8 interaction unknown
    • Relative contributions of each co-factor in vivo not dissected
  8. 2004 High

    Identification of TAZ as a direct co-activator of TTF-1 binding through the N-terminal domain provided a mechanistic link between Hippo pathway effectors and NKX2-1-dependent transcription in lung and thyroid.

    Evidence Mammalian two-hybrid, pull-down domain mapping, cooperative SP-C and thyroglobulin reporter activation

    PMID:14970209 PMID:19010321

    Open questions at the time
    • Whether TAZ modulates NKX2-1 chromatin occupancy genome-wide untested
    • In vivo requirement for TAZ–NKX2-1 interaction not demonstrated genetically
  9. 2008 High

    Conditional knockout studies demonstrated that Nkx2-1 controls temporal specification and migration of cortical interneurons by directly repressing the guidance receptor Neuropilin-2, establishing a postmitotic transcriptional switch governing neuronal fate and migration.

    Evidence Temporally controlled conditional KO in mouse MGE progenitors; ChIP and reporter assays for Neuropilin-2; in utero electroporation migration assays

    PMID:18786356 PMID:18786357

    Open questions at the time
    • Full set of NKX2-1 direct targets in postmitotic interneurons not catalogued
    • Mechanism of Nkx2-1 downregulation in cortex-destined interneurons unknown
  10. 2011 High

    Identification of NKX2-1 as both a lineage-survival oncogene (when amplified) and a metastasis suppressor (through Hmga2 repression) resolved its paradoxical dual role in lung adenocarcinoma and established the concept of context-dependent lineage transcription factor activity in cancer.

    Evidence Lentiviral mouse LUAD model with gain/loss-of-function; siRNA knockdown in amplified cell lines; Hmga2 rescue experiments; genomic profiling of 128 tumors

    PMID:18212743 PMID:21471965

    Open questions at the time
    • Mechanism by which NKX2-1 amplification switches from tumor-suppressive to oncogenic function incompletely defined
    • Patient-level biomarker validation of NKX2-1 status for prognosis limited
  11. 2012 High

    ChIP-seq revealed genome-wide NKX2-1 occupancy at AP-1 elements in mucinous lung tumors and demonstrated that NKX2-1 haploinsufficiency with Kras activation drives mucinous adenocarcinoma, establishing the mechanistic basis of NKX2-1's tumor-suppressive activity against Kras-driven mucinous differentiation.

    Evidence ChIP-seq in Nkx2-1 haploinsufficient/Kras(G12D) mouse models; AP-1 reporter inhibition assays; colony formation assays

    PMID:23143308

    Open questions at the time
    • Whether NKX2-1 directly sequesters AP-1 or modulates its chromatin access unclear
    • Therapeutic strategies to restore NKX2-1 function not explored
  12. 2016 High

    Integrated ChIP-seq and ATAC-seq in the developing forebrain revealed that NKX2-1 acts as a dual-function chromatin regulator — repressing genes by closing chromatin in the ventricular zone while activating genes via permissive chromatin together with LHX6 in migrating interneurons — resolving how a single factor achieves context-dependent transcriptional outcomes.

    Evidence NKX2-1 ChIP-seq, ATAC-seq, RNA-seq in developing mouse forebrain, conditional KO validation

    PMID:27657450

    Open questions at the time
    • Cofactors mediating repressive vs. activating mode in brain not fully identified
    • Whether this dual chromatin mechanism operates similarly in lung and thyroid untested
  13. 2022 High

    FoxA1/2 were shown to direct NKX2-1 genomic localization; their loss causes aberrant NKX2-1 redistribution that paradoxically inhibits tumorigenesis, establishing that pioneer factor availability dictates NKX2-1's oncogenic versus tumor-suppressive output.

    Evidence Conditional Foxa1/2 knockout in Kras-driven mouse LUAD; NKX2-1 ChIP-seq showing genomic relocalization; transcriptomics in mouse and human cells

    PMID:35835117

    Open questions at the time
    • Which chromatin features recruit relocalized NKX2-1 unknown
    • Whether therapeutic modulation of FoxA1/2 can redirect NKX2-1 activity untested
  14. 2023 High

    NKX2-1 was found to directly activate serine/glycine biosynthesis enzyme genes, revealing an unexpected metabolic programming function that creates a therapeutically exploitable metabolic vulnerability in NKX2-1-expressing cancers.

    Evidence ChIP-qPCR for NKX2-1 at PHGDH/PSAT1/PSPH/SHMT promoters; metabolomics; sertraline sensitivity assays in lung cancer and T-ALL models

    PMID:36932191

    Open questions at the time
    • Whether metabolic reprogramming contributes to NKX2-1's developmental functions unknown
    • Clinical validation of sertraline sensitivity in NKX2-1-positive tumors lacking
  15. 2024 High

    NKX2-1 was shown to directly repress CXCL chemokines, and its loss triggers CXCR2-dependent neutrophil recruitment that promotes tumor growth, connecting NKX2-1 loss to immune microenvironment remodeling in lung adenocarcinoma.

    Evidence ATAC-seq showing NKX2-1 occupancy at CXCL promoters; NKX2-1 knockdown in syngeneic mouse LUAD; scRNA-seq; CXCR2 antagonist rescue

    PMID:39113226

    Open questions at the time
    • Whether NKX2-1 regulates other immune cell populations beyond neutrophils untested
    • Interaction between NKX2-1-mediated immune control and checkpoint immunotherapy unknown

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include the structural basis for NKX2-1's context-dependent activator/repressor switching, the full catalog of cofactors determining its mode in each tissue, and whether its metabolic and immune-regulatory functions contribute to developmental morphogenesis beyond cancer.
  • No co-crystal structure of NKX2-1 with DNA or cofactors
  • Comprehensive comparison of NKX2-1 cistrome across lung, thyroid, and brain in matched conditions lacking
  • Therapeutic strategies to restore NKX2-1 function in NKX2-1-loss tumors not established

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140110 transcription regulator activity 11 GO:0003677 DNA binding 5
Localization
GO:0005634 nucleus 4
Pathway
R-HSA-74160 Gene expression (Transcription) 7 R-HSA-1643685 Disease 6 R-HSA-112316 Neuronal System 5 R-HSA-1266738 Developmental Biology 4 R-HSA-162582 Signal Transduction 4 R-HSA-168256 Immune System 1
Partners
FOXA1FOXA2GATA6HOXB5LHX6PAX8TAZ

Evidence

Reading pass · 50 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1990 TTF-1 (NKX2-1) was identified as a thyroid nuclear factor containing a homeodomain with sequence homology to the Drosophila NK-2 homeodomain; the protein binds to promoters of thyroid-specific genes and its mRNA/binding activity is detected in thyroid and lung, with chromosomal localization to human chromosome 14 and mouse chromosome 12. cDNA cloning, DNA-binding assays with nuclear extracts, chromosomal mapping The EMBO journal High 1976511
1992 TTF-1 binds to three specific sites (A, B, C) in the bovine thyroglobulin gene promoter as revealed by DNase I footprinting; mutations reducing TTF-1 binding at A, B, and C sites also decreased promoter activity in transfection assays in primary thyrocytes, demonstrating that TTF-1 binding is functionally required for thyroglobulin gene transcription. DNase I footprinting, site-directed mutagenesis, transient transfection assays in primary dog thyrocytes FEBS letters High 1555648
1993 The NMR structure of the rat TTF-1 homeodomain (TTF-1 HD) was determined, revealing three helices arranged in a helix-turn-helix motif similar to other homeodomains, consistent with its DNA-binding function. 500 MHz 1H NMR spectroscopy, standard 2D NMR methodology, secondary structure determination FEBS letters High 8282100
1994 The conformational stability of the TTF-1 homeodomain was characterized; it has a Tm of 42°C and low Gibbs free energy of stabilization (~1.3–1.4 kcal/mol), indicating it is a mobile, flexible segment folded into loose helices, and small reductions in alpha-helical content significantly modify DNA-binding activity. Circular dichroism-monitored thermal denaturation and urea unfolding, DNA-binding activity assays FEBS letters Medium 7957942
1995 The DNA-binding specificity of the TTF-1 homeodomain preferentially recognizes sequences with the 5'-CAAG-3' core motif, but also binds a wider spectrum of sequences; the 5'-CAAG-3' core is necessary but not sufficient for maximal binding affinity. TTF-1 HD-Sepharose column chromatography, sequential selection and amplification of binding sequences (SELEX-like), binding activity measurement Biochemical and biophysical research communications Medium 7654238
1995 TTF-1 activates transcription of the human surfactant protein B (SP-B) gene through an upstream enhancer element (−439 to −331 bp); three TTF-1 binding sites in this region were identified, purified TTF-1 homeodomain binds this region, co-transfection of TTF-1 transactivates the SP-B promoter, and mutation of TTF-1 binding sites blocks both binding and transactivation. Deletion analysis, luciferase reporter assays, co-transfection, purified TTF-1 binding assays, site-directed mutagenesis of binding sites The Journal of biological chemistry High 7559607
1995 The human NKX2-1/TTF-1 gene was characterized as a single locus spanning ~3.3 kb with two exons and a single intron, encoding a 371 amino acid protein highly conserved with rat TTF-1 (98% identity); the 5'-flanking region directs lung epithelial cell-selective transcription; TTF-1 protein is localized to nuclei of fetal lung epithelial cells from 11 weeks gestation and postnatally in type II epithelial cells and bronchiolar epithelial subsets. Gene cloning and sequencing, immunohistochemistry, luciferase reporter transfection assays The Journal of biological chemistry High 7713914
1998 The human Nkx2.1 gene is organized into three exons and two introns (revising previous reports of two exons); a newly identified exon I contains an ATG codon in-frame with a previously identified initiator codon on the 5E transcript, and in vitro transcription/translation of this 5E cDNA produces a 44 kDa polypeptide; at least two independent regions (within intron 1 and 5' of exon 1) may mediate basal promoter activity in lung epithelial cells. cDNA cloning, genomic cloning, sequencing, Northern blot analysis, in vitro transcription/translation, promoter activity assays Biochimica et biophysica acta Medium 9545595
1999 Nkx2.1 is required for septation of the anterior foregut into trachea and esophagus; homozygous Nkx2.1-null mouse embryos fail to form separate tracheal and esophageal structures, develop profoundly hypoplastic lungs that fail normal branching morphogenesis, and lack pulmonary surfactant protein gene expression; reduced Bmp-4 expression in mutant lung epithelium was identified as a possible mechanistic clue for impaired branching. Targeted gene disruption (knockout mice), in situ hybridization for Bmp-4 and Vegf, histological analysis Developmental biology High 10208743
2000 The two NKX2.1 protein isoforms (371 aa and 401 aa) are functionally distinct: the longer isoform (401 aa, encoded by a transcript including all three exons) exhibits reduced transcriptional activity on an SP-C target promoter compared to the truncated major isoform; the 30 amino acid N-terminal extension likely acts by steric interference, as demonstrated by site-directed mutagenesis. Differential expression analysis of transcripts, transactivation reporter assays, site-directed mutagenesis of the 30 aa extension Biochemical and biophysical research communications Medium 10753648
2000 Distal lung morphogenesis (but not proximal) is strictly dependent on Nkx2.1; Nkx2.1-null lungs show significantly reduced or absent expression of alpha-integrins and collagen type IV (unlike laminin which is maintained), and exhibit predominant Vegf1/reduced Vegf3 expression typical of tracheobronchial epithelium, indicating Nkx2.1 controls the epithelial phenotype required for distal morphogenesis. Analysis of Nkx2.1(-/-) embryos, immunohistochemistry/in situ hybridization for ECM proteins, integrins, and Vegf isoforms Developmental dynamics Medium 10706142
2000 Oncogenic Ras represses TTF-1 transcriptional activity through multiple downstream pathways; the Raf/MEK/ERK cascade directly phosphorylates TTF-1 at three serine residues, and mutation of these serines to alanines abolishes ERK-mediated phosphorylation in vitro and in vivo; a second ERK-independent pathway (activated by V12N38 Ras) also partially represses TTF-1 activity, and combined activation of both pathways nearly completely abolishes TTF-1 function. Transient transfection assays with Ras effector mutants, activated Raf expression, MEK inhibitors (U0126, PD98059), in vitro kinase assay (ERK phosphorylates TTF-1), in vivo phosphorylation analysis, site-directed mutagenesis of serine residues Molecular and cellular biology High 10733581
2002 TTF-1 directly interacts with and synergistically activates transcription with Pax8; GST-Pax8 pull-down captures TTF-1 from thyroid and non-thyroid cell extracts, direct interaction is confirmed using bacterially purified TTF-1, and co-immunoprecipitation demonstrates in vivo interaction in thyroid cells; co-expression in HeLa cells synergistically activates thyroglobulin gene transcription requiring the N-terminal activation domain of TTF-1 and C-terminal domain of Pax8. GST pull-down with purified proteins, co-immunoprecipitation, transactivation reporter assays, deletion analysis The Journal of biological chemistry High 12441357
2002 NKX2-1 haploinsufficiency in humans (heterozygous loss-of-function mutations including deletions, missense, and nonsense mutations) causes a triad of congenital hypothyroidism, choreoathetosis/muscular hypotonia, and pulmonary problems, establishing NKX2-1 as required for thyroid, basal ganglia, and lung development and function in humans. Clinical phenotyping, gene sequencing, identification of heterozygous loss-of-function mutations in five patients The Journal of clinical investigation High 11854319
2002 Heterozygous deletion of the mouse Ttf1 gene (haploinsufficiency) results in predominantly neurological phenotype (poor coordination) and elevated serum thyrotropin, demonstrating that TTF1 haploinsufficiency is sufficient to produce neurological and thyroid axis defects; a mutant human TTF1 (insertion into codon 86) fails to bind its cis-element or transactivate a thyroglobulin promoter reporter, and does not interfere with wild-type TTF1, confirming haploinsufficiency as the mechanism. Heterozygous Ttf1 knockout mouse analysis, reporter gene transactivation assay with mutant vs. wild-type TTF1, competition assay The Journal of clinical investigation High 11854318
2002 TTF-1, GATA6, and Foxa2 directly bind to specific consensus sites within the WNT7b promoter (demonstrated by EMSA) and cooperatively transactivate WNT7b expression in lung epithelial cells; TTF-1 and GATA6 physically interact in vivo and synergistically activate the minimal TTF-1-containing WNT7b promoter region. Electrophoretic mobility shift assay (EMSA), transfection/transactivation assays, truncation mutagenesis of GATA6/Foxa2 binding sites, co-immunoprecipitation (TTF-1 and GATA6 in vivo interaction) The Journal of biological chemistry High 11914369
2002 Mutations in TITF-1 (NKX2-1) are associated with benign hereditary chorea (BHC); a de novo 1.2 Mb deletion harboring TITF-1 was identified in a BHC family, and further TITF-1 mutations in additional BHC families were described, establishing NKX2-1 loss-of-function as the genetic cause of this dominantly inherited movement disorder. Linkage analysis, genomic deletion mapping, mutation screening by sequencing Human molecular genetics High 11971878
2003 In Nkx2.1-null mice, ascending dopaminergic axons from mesencephalic DA cells aberrantly cross the ventral midline and project to the contralateral striatum instead of remaining ipsilateral; this is associated with loss of neuroepithelium in the ventromedial hypothalamus of the third ventricle and markedly reduced expression of semaphorin 3A (and previously reported slit2), indicating that NKX2-1 maintains chemorepulsive axon guidance cues in the hypothalamus. Tyrosine hydroxylase immunostaining in Nkx2.1(-/-) embryos, DiI axon tracing, immunohistochemistry for semaphorin 3A Experimental neurology Medium 12821380
2003 Nkx2.1 and Gsh2 act cooperatively (not through cross-repression) in patterning the ventral telencephalon; however, Gsh2 expression in the MGE after E10.5 may negatively regulate Nkx2.1-dependent oligodendrocyte specification, revealing both integrative and antagonistic interactions in telencephalic patterning. Double-mutant mouse analysis, loss- and gain-of-function genetic experiments, histological/marker analysis Development Medium 12930780
2003 TTF-1 directly regulates PACAP gene transcription in the hypothalamus: the TTF-1 homeodomain binds six of seven putative binding sites in the PACAP 5'-flanking region; TTF-1 dose-dependently activates the PACAP promoter in C6 glioma cells; deletion of the TTF-1 binding motif at −369 abolishes transactivation; intracerebroventricular antisense TTF-1 oligodeoxynucleotide reduces hypothalamic PACAP mRNA in vivo; TTF-1 and PACAP show coordinated daily oscillations in the rat hypothalamus. DNA-binding assays, transactivation reporter assays, deletion mutagenesis, in vivo antisense knockdown, RNase protection assays The Journal of biological chemistry High 12122016
2003 TTF-1 regulates angiotensinogen gene transcription in the rat subfornical organ: TTF-1 mRNA co-localizes with angiotensinogen-producing cells; both mRNAs increase simultaneously upon water deprivation; TTF-1 dose-dependently transactivates the angiotensinogen promoter in C6 glioma cells; deletion of the TTF-1 binding motif at −125 abolishes transactivation; in vivo intracranial antisense TTF-1 oligodeoxynucleotide reduces angiotensinogen mRNA and causes decreased water intake and plasma vasopressin. Double in situ hybridization, RNase protection assays, reporter gene transactivation with deletion analysis, in vivo antisense knockdown The Journal of biological chemistry High 12730191
2004 TAZ (transcriptional co-activator with PDZ-binding motif) directly interacts with TTF-1 and synergistically activates SP-C expression; pull-down experiments demonstrated direct TAZ–TTF-1 interaction; mammalian two-hybrid assays and pull-down experiments mapped TAZ binding to the NH2-terminal domain of TTF-1; co-expression of TAZ and TTF-1 synergistically activated mouse SP-C-luciferase reporter constructs. Mammalian two-hybrid assay, pull-down experiments, co-transfection luciferase reporter assays, immunolocalization The Journal of biological chemistry High 14970209
2004 In vivo promoter analysis of the baboon Nkx2.1 5'-flanking region revealed that proximal and distal promoter fragments direct LacZ expression to brain (including hypothalamus) and two of three fragments direct tracheal epithelial-specific expression in transgenic mice, but parenchymal lung and thyroid expression was not conferred, demonstrating that cis-elements for tracheal vs. lung morphogenesis are distinct and thyroid-directing elements are absent from the tested ~4 kb region. BAC/transgene constructs with LacZ reporter, transgenic mouse analysis at E15 and E18 Gene Medium 15094193
2006 Sonic hedgehog (Shh) maintains Nkx2.1 expression in the MGE during neurogenesis to specify interneurons, but unlike its initial induction of Nkx2.1 (which requires antagonizing Gli3 repressor formation), the Nkx2.1 maintenance function of Shh does not require blocking Gli3R formation, revealing two mechanistically distinct Shh-dependent steps in Nkx2.1 regulation. Genetic mouse models (Shh conditional mutants, Gli3 mutants), immunohistochemistry, in situ hybridization Cerebral cortex Medium 16766713
2006 Conditional deletion of Ttf1 from differentiated neurons causes delayed puberty, reduced reproductive capacity, and a short reproductive span associated with reduced hypothalamic expression of genes required for sexual development, without affecting basal ganglia morphology or function; TTF1 expression in the nonhuman primate hypothalamus increases at puberty, indicating a postdevelopmental role in neuroendocrine control of reproduction. Conditional Ttf1 neuronal knockout mice, gene expression profiling, reproductive phenotyping, extrapyramidal function testing The Journal of neuroscience Medium 17182767
2008 Nkx2.1 is required for the temporal specification of cortical interneuron subtypes: conditional removal of Nkx2.1 at distinct neurogenic time points causes a switch in interneuron subtypes produced, demonstrating a causal link between Nkx2.1 expression in progenitors and the functional identity of their neuronal progeny. Conditional loss-of-function mouse genetics (Cre-mediated deletion at different developmental timepoints), interneuron subtype marker analysis Neuron High 18786356
2008 Postmitotic Nkx2-1 controls interneuron migration by directly repressing the guidance receptor Neuropilin-2: downregulation of Nkx2-1 in postmitotic cells is required for cortical migration while maintenance is required for striatal migration; Nkx2-1 directly regulates Neuropilin-2 expression, which enables interneurons to invade the striatum. Conditional loss-of-function mouse genetics, in utero electroporation, interneuron migration assays, ChIP/reporter assays for Neuropilin-2 direct regulation Neuron High 18786357
2008 TAZ acts as a coactivator for both Pax8 and TTF-1 in thyroid cells: TAZ is present in the nucleus of differentiated thyroid cells; TAZ physically interacts with both Pax8 and TTF-1 in vitro and in vivo; this interaction significantly enhances transcriptional activity on the thyroglobulin promoter, suggesting TAZ modulates thyroid-specific gene expression. Co-immunoprecipitation (in vitro and in vivo), cotransfection reporter assays, immunofluorescence co-localization Experimental cell research Medium 19010321
2009 Five new NKX2-1 mutations causing brain-lung-thyroid syndrome were characterized; functional analysis revealed that three missense mutations (L176V, P202L, Q210P) cause loss of transactivation capacity on the thyroglobulin enhancer/promoter; notably, deficient transcriptional activity of NKX2-1-P202L was completely rescued by co-transfected wild-type PAX8, whereas synergism was abolished by L176V and Q210P mutations, identifying a PAX8-NKX2-1 functional interaction critical for thyroid gene regulation. Mutation identification by sequencing, in vitro transactivation assays, co-transfection rescue experiments with PAX8 Human molecular genetics High 19336474
2009 NKX2-1 directly regulates RET transcription in coordination with Phox2b and Sox10: dual-luciferase reporter studies showed Nkx2-1 works cooperatively with Phox2b and Sox10 (but not Pax3) to activate the RET promoter; HSCR-associated SNPs at the NKX2-1 binding site reduce NKX2-1 binding and abolish synergistic transactivation of RET by HOXB5 and NKX2-1. Dual-luciferase reporter assays, immunohistochemistry for PHOX2B in human gut, SNP functional analysis Journal of pediatric surgery Medium 19853745
2009 TGF-beta inhibits lung endodermal morphogenesis partly through reduction of NKX2.1 protein and its downstream target surfactant protein C; this requires TGFbeta receptor II and is partially dependent on Smad3/Smad4 signaling; increased Pten expression accounts for TGFbeta's anti-proliferative effects but is not sufficient to restore morphogenesis, indicating NKX2.1 is an independent mediator of morphogenetic TGFbeta signaling. Mesenchyme-free embryonic lung endoderm explant model, conditional knockout mice (Smad3(-/-), Smad4Δ/Δ, TGFbetaRII conditional KO, Pten conditional KO), BrdU proliferation assays, protein/mRNA analysis Developmental biology Medium 18602626
2009 TTF-1 inhibits TGF-beta-mediated epithelial-to-mesenchymal transition (EMT) in lung adenocarcinoma cells: TTF-1 expression down-regulates TGF-beta target genes including EMT regulators Snail and Slug; silencing TTF-1 enhances TGF-beta-mediated EMT; TTF-1 down-regulates TGF-beta2 production and TGF-beta conversely decreases TTF-1 expression, creating a reciprocal regulatory loop. TTF-1 overexpression and siRNA knockdown in lung adenocarcinoma cells, EMT marker analysis, invasion assays, gene expression analysis Cancer research High 19293183
2011 NKX2-1 controls tumor differentiation and limits metastatic potential in lung adenocarcinoma in part by repressing the embryonically restricted chromatin regulator Hmga2; gain- and loss-of-function experiments showed Nkx2-1 negativity is pathognomonic of high-grade poorly differentiated tumors, and Nkx2-1 constrains malignant progression through Hmga2 repression. Lentiviral mouse lung adenocarcinoma model, gain- and loss-of-function experiments in tumor cell lines, in vivo transplant experiments, gene expression analysis, functional complementation Nature High 21471965
2011 NKX2-1 is amplified as a lineage-specific oncogene in lung cancer; siRNA-mediated knockdown of NKX2-1/TITF1 in lung cancer cell lines with amplification reduces cell proliferation through decreased cell-cycle progression and increased apoptosis. Genomic profiling of 128 lung cancer cell lines/tumors, siRNA knockdown, cell proliferation and apoptosis assays Oncogene Medium 18212743
2011 Continuous expression of Nkx2-1 is essential for the maturation and maintenance of cholinergic basal forebrain neurons: prenatal deletion of Nkx2-1 in GAD67-expressing neurons causes nearly complete loss of cholinergic and parvalbumin-positive GABAergic neurons in the basal forebrain; postnatal deletion in choline acetyltransferase-expressing cells also causes a striking reduction in cholinergic neuron number, with partial denervation of target structures and discrete spatial memory impairment. Two conditional knockout mouse lines (prenatal GAD67-Cre, postnatal ChAT-Cre), cell counting, denervation analysis, spatial memory behavioral testing The European journal of neuroscience High 22098391
2011 HOXB5 physically interacts with NKX2-1 as a protein complex and synergistically mediates RET expression; HOXB5 binds the RET promoter region 5' upstream of the NKX2-1 binding site; HSCR-associated SNPs at the NKX2-1 binding site abolish this synergistic transactivation; in contrast, HOXB5 cooperates only additively with SOX10, PAX3, and PHOX2B. ChIP, luciferase reporter assays, co-immunoprecipitation of HOXB5-NKX2-1 complex, SNP functional analysis PloS one Medium 21677782
2012 NKX2-1 induces expression of the receptor tyrosine kinase ROR1, which sustains a prosurvival PI3K-AKT/p38 signaling balance in lung adenocarcinoma through ROR1 kinase-dependent c-Src activation and kinase-independent maintenance of EGFR-ERBB3 association, ERBB3 phosphorylation, and PI3K activation; ROR1 knockdown inhibits lung adenocarcinoma cell lines including those with EGFR inhibitor resistance. NKX2-1 gain-of-function, ROR1 siRNA knockdown, signaling pathway analysis (PI3K-AKT, p38, Src, ERBB3), cell line proliferation/apoptosis assays Cancer cell High 22439932
2012 Nkx2-1 haploinsufficiency combined with oncogenic Kras(G12D) causes mucinous pulmonary adenocarcinoma in transgenic mice; NKX2-1 directly associates with AP-1 binding elements and canonical NKX2-1 binding elements at genes induced in mucinous tumors (identified by ChIP-seq); NKX2-1 inhibits AP-1 activity and tumor colony formation in vitro, demonstrating context-dependent tumor suppressor activity against Kras-driven mucinous tumors. Transgenic mouse models (Nkx2-1 haploinsufficiency + Kras(G12D)), ChIP with massively parallel DNA sequencing (ChIP-seq), AP-1 reporter assays, colony formation assays The Journal of clinical investigation High 23143308
2013 MiR-365 directly regulates NKX2-1 protein levels in lung cancer; ectopic miR-365 expression decreased NKX2-1 expression in lung cancer cell lines, reduced cell proliferation, and NKX2-1 overexpression overcame the suppressive effect of miR-365, placing miR-365 as an upstream post-transcriptional regulator of NKX2-1. miR-365 mimic/inhibitor transfection, NKX2-1 overexpression, cell proliferation assays Cancer letters Low 23507558
2014 mTOR inhibition promotes TTF-1-dependent redifferentiation of thyroid carcinoma cells and increases iodine uptake; this redifferentiation is not mediated by autophagy or inflammation but through transcriptional upregulation of TTF-1; siRNA inhibition of TTF-1 completely abrogates mTOR inhibition-induced sodium-iodine symporter expression, placing TTF-1 as the key downstream mediator of mTOR-dependent thyroid differentiation. mTOR inhibitor treatment of thyroid carcinoma cell lines, siRNA knockdown of TTF-1, iodine uptake assays, mRNA/protein expression analysis The Journal of clinical endocrinology and metabolism Medium 24712572
2015 Nkx2-1-derived glia (astrocytes and polydendrocytes) are required for proper formation of the anterior commissure; selective cell ablation showed synergistic roles of Nkx2-1-derived GABAergic interneurons and astroglia in AC formation; Nkx2-1-regulated cells mediate anterior commissure axon guidance through expression of the repellent cue Slit2. Fate mapping, selective cell ablation strategy, Slit2 expression analysis, Nkx2.1 lineage tracing Nature communications Medium 25904499
2015 Loss of Foxa2 and Cdx2 synergizes with loss of Nkx2-1 to fully activate the metastatic program in lung adenocarcinoma; knockdown of all three factors synergistically promotes metastatic potential; this is sufficient to upregulate invadopodia component Tks5long, Hmga2, and Snail, accounting for a significant fraction of gene expression differences between non-metastatic and metastatic states. Knockdown of Foxa2, Cdx2, and Nkx2-1 alone and in combination; in vivo metastasis assays; gene expression analysis Genes & development High 26341558
2016 NKX2-1 controls regional identity and, together with LHX6, is necessary to specify pallidal projection neurons and forebrain interneurons; genome-wide chromosomal binding analysis showed NKX2-1 binding at distal regulatory elements leads to repressed epigenetic state and transcriptional repression in the ventricular zone, while NKX2-1 is also required to establish permissive chromatin and transcriptional activation in the sub-ventricular and mantle zones; combinatorial binding of NKX2-1 and LHX6 promotes permissive chromatin and activates genes in cortical migrating interneurons. ChIP-seq for NKX2-1 binding, ATAC-seq for chromatin state, RNA-seq for gene expression, conditional knockout analysis Neuron High 27657450
2018 Selenbp1 is a direct transcriptional target of Nkx2-1 in lung adenocarcinoma: Nkx2-1 is required and sufficient for Selenbp1 expression; Selenbp1 and Nkx2-1 function in a positive feedback loop (Selenbp1 stabilizes Nkx2-1 protein); Selenbp1 inhibits clonal growth and migration in vitro, suppresses metastasis in an in vivo transplant model, and its CRISPR/Cas9 inactivation enhances primary tumor growth in autochthonous models. Loss- and gain-of-function experiments, CRISPR/Cas9 Selenbp1 knockout, in vivo transplant and autochthonous mouse models, ChIP-seq for direct NKX2-1 binding Molecular cancer research High 30002193
2021 NKX2-1 loss in BRAFV600E-driven lung adenocarcinoma leads to invasive mucinous adenocarcinoma with gastric differentiation; BRAF/MEK inhibitors drive NKX2-1-positive tumor cells into quiescence but fail to induce cell cycle exit in NKX2-1-negative cells; BRAF/MEK inhibitors induce cell identity switching within the gastric lineage in NKX2-1-negative tumors driven partly by WNT signaling and FoxA1/2, revealing a reciprocal NKX2-1/ERK/WNT feedback loop modulating gastric identity. Genetically engineered mouse models (BRAFV600E with/without NKX2-1), BRAF/MEK inhibitor treatment, cell cycle analysis, WNT pathway manipulation, FoxA1/2 expression analysis eLife High 33821796
2021 NKX2-1 positively expresses in deep-layer neocortical neurogliaform cells (ID2+Nkx2.1+ cells) that are active during the down state of non-REM sleep; optogenetic activation of ID2+Nkx2.1+ interneurons in the posterior parietal cortex during NREM sleep interferes with consolidation of cue discrimination memory, demonstrating a physiological role for this NKX2-1-expressing interneuron type in memory consolidation. Single-cell electrophysiology, immunohistochemistry, optogenetic activation of ID2+Nkx2.1+ cells, memory consolidation behavioral assays Nature neuroscience Medium 33619404
2021 CRISPRi-mediated functional analysis of NKX2-1 binding sites revealed that a subset of NKX2-1-binding sites are functionally indispensable while others are dispensable for target gene expression (genes including SFTPB, LAMP3, SFTPA1, SFTPA2, MYBPH, LMO3, CD274/PD-L1); this demonstrates unequal functional roles of NKX2-1 binding sites across proximal and distal genomic regions. CRISPRi (CRISPR/dCas9-KRAB), ChIP-seq, gene expression analysis of 19 NKX2-1-binding regions Communications biology Medium 33980985
2022 FoxA1/2 loss leads to aberrant NKX2-1 activity and genomic relocalization in NKX2-1-positive LUAD; loss of FoxA1/2 collapses a dual pulmonary/gastrointestinal transcriptional identity state, and aberrant NKX2-1 activity actively inhibits tumorigenesis and drives alternative cellular identity programs associated with non-proliferative states. Foxa1/2 conditional knockout in KRAS-driven mouse models, human cell lines, NKX2-1 ChIP-seq to assess genomic relocalization, transcriptomics Developmental cell High 35835117
2023 NKX2-1 directly binds and transcriptionally upregulates serine/glycine synthesis enzyme genes (PHGDH, PSAT1, PSPH, SHMT1/2), driving serine/glycine synthesis addiction in T-cell leukemia and lung cancer cells; NKX2-1-driven serine/glycine synthesis generates nucleotides and redox molecules, alters the cellular lipidome and methylome, and NKX2-1-expressing cells show enhanced sensitivity to serine/glycine conversion inhibition by sertraline. ChIP-qPCR for direct NKX2-1 binding to enzyme gene promoters, NKX2-1 overexpression/knockout models, mass spectrometry metabolomics, proliferation/invasion assays, mouse tumor models British journal of cancer High 36932191
2024 NKX2-1 directly restricts expression of CXCL1, CXCL2, and CXCL5 chemokines in lung adenocarcinoma cells as revealed by ATAC-seq showing NKX2-1 occupancy at their promoters; NKX2-1 depletion triggers CXCL secretion that recruits tumor-promoting neutrophils via CXCR2 signaling, increasing tumor growth that is reversed by CXCR2 antagonist SB225002. ATAC-seq for chromatin accessibility at CXCL promoters, chemokine array, qRT-PCR, NKX2-1 knockdown in LUAD cells, syngeneic mouse model, single-cell RNA-seq, CXCR2 antagonist treatment Advanced science High 39113226

Source papers

Stage 0 corpus · 130 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2002 Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences. Proceedings of the National Academy of Sciences of the United States of America 1479 12477932
2009 A census of human transcription factors: function, expression and evolution. Nature reviews. Genetics 1191 19274049
2011 Phylogenetic-based propagation of functional annotations within the Gene Ontology consortium. Briefings in bioinformatics 656 21873635
1990 Thyroid nuclear factor 1 (TTF-1) contains a homeodomain and displays a novel DNA binding specificity. The EMBO journal 499 1976511
2008 Fate mapping Nkx2.1-lineage cells in the mouse telencephalon. The Journal of comparative neurology 455 17990269
2008 Identification of ten loci associated with height highlights new biological pathways in human growth. Nature genetics 454 18391950
2004 The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC). Genome research 438 15489334
1996 Normalization and subtraction: two approaches to facilitate gene discovery. Genome research 401 8889548
2011 Suppression of lung adenocarcinoma progression by Nkx2-1. Nature 387 21471965
1999 Defects in tracheoesophageal and lung morphogenesis in Nkx2.1(-/-) mouse embryos. Developmental biology 357 10208743
2011 Integrated transcript and genome analyses reveal NKX2-1 and MEF2C as potential oncogenes in T cell acute lymphoblastic leukemia. Cancer cell 323 21481790
2009 Common variants on 9q22.33 and 14q13.3 predispose to thyroid cancer in European populations. Nature genetics 317 19198613
2002 TTF-1 expression in pulmonary adenocarcinomas. The American journal of surgical pathology 296 12023581
2008 The requirement of Nkx2-1 in the temporal specification of cortical interneuron subtypes. Neuron 260 18786356
2000 A clinicopathologic study of 100 cases of pulmonary sclerosing hemangioma with immunohistochemical studies: TTF-1 is expressed in both round and surface cells, suggesting an origin from primitive respiratory epithelium. The American journal of surgical pathology 251 10895813
2009 Napsin A and thyroid transcription factor-1 expression in carcinomas of the lung, breast, pancreas, colon, kidney, thyroid, and malignant mesothelioma. Human pathology 246 19740516
2002 Choreoathetosis, hypothyroidism, and pulmonary alterations due to human NKX2-1 haploinsufficiency. The Journal of clinical investigation 246 11854319
2011 Subclassification of non-small cell lung carcinomas lacking morphologic differentiation on biopsy specimens: Utility of an immunohistochemical panel containing TTF-1, napsin A, p63, and CK5/6. The American journal of surgical pathology 236 21164283
2012 NKX2-1/TITF1/TTF-1-Induced ROR1 is required to sustain EGFR survival signaling in lung adenocarcinoma. Cancer cell 215 22439932
2008 Postmitotic Nkx2-1 controls the migration of telencephalic interneurons by direct repression of guidance receptors. Neuron 192 18786357
2017 Prospective isolation of NKX2-1-expressing human lung progenitors derived from pluripotent stem cells. The Journal of clinical investigation 188 28463226
1996 Expression of thyroid transcription factor-1(TTF-1) in fetal and neonatal human lung. The journal of histochemistry and cytochemistry : official journal of the Histochemistry Society 181 8675988
2008 Genomic profiling identifies TITF1 as a lineage-specific oncogene amplified in lung cancer. Oncogene 175 18212743
2007 Lineage-specific dependency of lung adenocarcinomas on the lung development regulator TTF-1. Cancer research 173 17616654
1995 Gene structure and expression of human thyroid transcription factor-1 in respiratory epithelial cells. The Journal of biological chemistry 166 7713914
2004 PAX8, TITF1, and FOXE1 gene expression patterns during human development: new insights into human thyroid development and thyroid dysgenesis-associated malformations. The Journal of clinical endocrinology and metabolism 162 15494458
2002 Mutations in TITF-1 are associated with benign hereditary chorea. Human molecular genetics 160 11971878
2004 TAZ interacts with TTF-1 and regulates expression of surfactant protein-C. The Journal of biological chemistry 151 14970209
2009 Five new TTF1/NKX2.1 mutations in brain-lung-thyroid syndrome: rescue by PAX8 synergism in one case. Human molecular genetics 150 19336474
2009 Thyroid transcription factor-1 (TTF-1/Nkx2.1/TITF1) gene regulation in the lung. Clinical science (London, England : 1979) 144 19037882
2002 Partial deficiency of thyroid transcription factor 1 produces predominantly neurological defects in humans and mice. The Journal of clinical investigation 142 11854318
2002 Thyroid transcription factor-1: a review. Applied immunohistochemistry & molecular morphology : AIMM 140 12051643
2009 The variant rs1867277 in FOXE1 gene confers thyroid cancer susceptibility through the recruitment of USF1/USF2 transcription factors. PLoS genetics 132 19730683
2007 The diagnostic value of TTF-1, CK 5/6, and p63 immunostaining in classification of lung carcinomas. Applied immunohistochemistry & molecular morphology : AIMM 132 18091384
2012 High incidence of EGFR mutations in Korean men smokers with no intratumoral heterogeneity of lung adenocarcinomas: correlation with histologic subtypes, EGFR/TTF-1 expressions, and clinical features. Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer 131 22237264
2012 Kras(G12D) and Nkx2-1 haploinsufficiency induce mucinous adenocarcinoma of the lung. The Journal of clinical investigation 130 23143308
2013 NKX2-1/TTF-1: an enigmatic oncogene that functions as a double-edged sword for cancer cell survival and progression. Cancer cell 128 23763999
1998 Cloning and functional characterization of PTRF, a novel protein which induces dissociation of paused ternary transcription complexes. The EMBO journal 128 9582279
2018 A Comparison of GATA3, TTF1, CD10, and Calretinin in Identifying Mesonephric and Mesonephric-like Carcinomas of the Gynecologic Tract. The American journal of surgical pathology 124 30148742
2005 Variable sensitivity and specificity of TTF-1 antibodies in lung metastatic adenocarcinoma of colorectal origin. Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc 122 15861215
2009 Thyroid transcription factor-1 inhibits transforming growth factor-beta-mediated epithelial-to-mesenchymal transition in lung adenocarcinoma cells. Cancer research 117 19293183
2002 Expression of thyroid transcription factor-1 in the spectrum of neuroendocrine cell lung proliferations with special interest in carcinoids. Human pathology 117 11957142
2002 The paired domain-containing factor Pax8 and the homeodomain-containing factor TTF-1 directly interact and synergistically activate transcription. The Journal of biological chemistry 117 12441357
2006 Thyroid transcription factor 1--a new prognostic factor in lung cancer: a meta-analysis. Annals of oncology : official journal of the European Society for Medical Oncology 113 16980598
1995 Upstream enhancer activity in the human surfactant protein B gene is mediated by thyroid transcription factor 1. The Journal of biological chemistry 113 7559607
2011 Significance of thymidylate synthase and thyroid transcription factor 1 expression in patients with nonsquamous non-small cell lung cancer treated with pemetrexed-based chemotherapy. Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer 110 21716147
2007 Diagnostic value of CDX-2 and TTF-1 expressions in separating metastatic neuroendocrine neoplasms of unknown origin. Applied immunohistochemistry & molecular morphology : AIMM 109 18091383
2010 A large-scale candidate gene association study of age at menarche and age at natural menopause. Human genetics 106 20734064
2016 Transcriptional Networks Controlled by NKX2-1 in the Development of Forebrain GABAergic Neurons. Neuron 101 27657450
2003 Combinatorial function of the homeodomain proteins Nkx2.1 and Gsh2 in ventral telencephalic patterning. Development (Cambridge, England) 100 12930780
2004 The role of TTF-1 in differentiating primary and metastatic lung adenocarcinomas. Pathology oncology research : POR 98 15188024
2000 Inhibition of distal lung morphogenesis in Nkx2.1(-/-) embryos. Developmental dynamics : an official publication of the American Association of Anatomists 98 10706142
2011 Combination of napsin A and TTF-1 immunohistochemistry helps in differentiating primary lung adenocarcinoma from metastatic carcinoma in the lung. Applied immunohistochemistry & molecular morphology : AIMM 96 21464700
2002 The WNT7b promoter is regulated by TTF-1, GATA6, and Foxa2 in lung epithelium. The Journal of biological chemistry 96 11914369
2000 Pulmonary sclerosing hemangioma consistently expresses thyroid transcription factor-1 (TTF-1): a new clue to its histogenesis. The American journal of surgical pathology 89 11075855
2005 Usefulness of CDX2 and TTF-1 in differentiating gastrointestinal from pulmonary carcinoids. American journal of clinical pathology 87 15716236
2015 Foxa2 and Cdx2 cooperate with Nkx2-1 to inhibit lung adenocarcinoma metastasis. Genes & development 85 26341558
2016 KRAS and NKX2-1 Mutations in Invasive Mucinous Adenocarcinoma of the Lung. Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer 76 26829311
2004 Histopathologic classification of lung cancer: Relevance of cytokeratin and TTF-1 immunophenotyping. Annals of diagnostic pathology 67 15494931
2008 TAZ is a coactivator for Pax8 and TTF-1, two transcription factors involved in thyroid differentiation. Experimental cell research 65 19010321
2021 Sleep down state-active ID2/Nkx2.1 interneurons in the neocortex. Nature neuroscience 62 33619404
2005 Cytology applications of p63 and TTF-1 immunostaining in differential diagnosis of lung cancers. Diagnostic cytopathology 59 16138374
1998 Structure of the human Nkx2.1 gene. Biochimica et biophysica acta 59 9545595
1998 Demarcation of ventral territories by the homeobox gene NKX2.1 during early chick development. Development genes and evolution 58 9601992
2000 Multiple ras downstream pathways mediate functional repression of the homeobox gene product TTF-1. Molecular and cellular biology 54 10733581
2007 Napsin A (TA02) is a useful alternative to thyroid transcription factor-1 (TTF-1) for the identification of pulmonary adenocarcinoma cells in pleural effusions. Diagnostic cytopathology 53 17636482
2011 Diagnostic utility of PAX8, TTF-1 and napsin A for discriminating metastatic carcinoma from primary adenocarcinoma of the lung. Biotechnic & histochemistry : official publication of the Biological Stain Commission 48 21838611
2009 Transcriptional regulation of RET by Nkx2-1, Phox2b, Sox10, and Pax3. Journal of pediatric surgery 48 19853745
2006 Shh maintains Nkx2.1 in the MGE by a Gli3-independent mechanism. Cerebral cortex (New York, N.Y. : 1991) 48 16766713
2006 Deletion of the Ttf1 gene in differentiated neurons disrupts female reproduction without impairing basal ganglia function. The Journal of neuroscience : the official journal of the Society for Neuroscience 47 17182767
2014 Evaluation of napsin A, TTF-1, p63, p40, and CK5/6 immunohistochemical stains in pulmonary neuroendocrine tumors. American journal of clinical pathology 46 25125621
2013 MicroRNA-365 regulates NKX2-1, a key mediator of lung cancer. Cancer letters 46 23507558
2015 Chordoid gliomas of the third ventricle share TTF-1 expression with organum vasculosum of the lamina terminalis. The American journal of surgical pathology 45 25786084
2003 Activation of the KATP channel-independent signaling pathway by the nonhydrolyzable analog of leucine, BCH. American journal of physiology. Endocrinology and metabolism 45 12709398
2013 Update on hypophysitis and TTF-1 expressing sellar region masses. Brain pathology (Zurich, Switzerland) 43 23701182
2013 Benign hereditary chorea related to NKX2.1: expansion of the genotypic and phenotypic spectrum. Developmental medicine and child neurology 43 24171694
2003 Aberrant trajectory of ascending dopaminergic pathway in mice lacking Nkx2.1. Experimental neurology 43 12821380
2022 SRGN-Triggered Aggressive and Immunosuppressive Phenotype in a Subset of TTF-1-Negative Lung Adenocarcinomas. Journal of the National Cancer Institute 42 34524427
2022 FoxA1 and FoxA2 control growth and cellular identity in NKX2-1-positive lung adenocarcinoma. Developmental cell 41 35835117
1993 Analysis of the promoter and regulatory sequences of an oxygen-regulated bch operon in Rhodobacter capsulatus by site-directed mutagenesis. Journal of bacteriology 41 8458846
2008 If it's not CK5/6 positive, TTF-1 negative it's not a squamous cell carcinoma of lung. APMIS : acta pathologica, microbiologica, et immunologica Scandinavica 39 18754327
2003 Dlx2 progenitor migration in wild type and Nkx2.1 mutant telencephalon. Cerebral cortex (New York, N.Y. : 1991) 39 12902388
2008 BNIP2 extra long inhibits RhoA and cellular transformation by Lbc RhoGEF via its BCH domain. Journal of cell science 38 18445682
2014 mTOR Inhibition promotes TTF1-dependent redifferentiation and restores iodine uptake in thyroid carcinoma cell lines. The Journal of clinical endocrinology and metabolism 37 24712572
2018 Tumor Suppressor Activity of Selenbp1, a Direct Nkx2-1 Target, in Lung Adenocarcinoma. Molecular cancer research : MCR 35 30002193
2018 Comparison of Three Different TTF-1 Clones in Resected Primary Lung Cancer and Epithelial Pulmonary Metastases. American journal of clinical pathology 35 30169783
2000 Two functionally distinct forms of NKX2.1 protein are expressed in the pulmonary epithelium. Biochemical and biophysical research communications 35 10753648
2005 Nonsense mutation in TITF1 in a Portuguese family with benign hereditary chorea. Neurogenetics 34 16220345
2009 GCDFP-15 positive and TTF-1 negative primary lung neoplasms: a tissue microarray study of 381 primary lung tumors. Applied immunohistochemistry & molecular morphology : AIMM 28 19620839
2003 TTF-1, a homeodomain-containing transcription factor, participates in the control of body fluid homeostasis by regulating angiotensinogen gene transcription in the rat subfornical organ. The Journal of biological chemistry 28 12730191
1992 Functional role of TTF-1 binding sites in bovine thyroglobulin promoter. FEBS letters 28 1555648
2015 Nkx2.1-derived astrocytes and neurons together with Slit2 are indispensable for anterior commissure formation. Nature communications 27 25904499
2014 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. Cerebellum (London, England) 27 24930029
2012 Opposite roles of FOXA1 and NKX2-1 in lung cancer progression. Genes, chromosomes & cancer 27 22383183
2012 Choreoathetosis, congenital hypothyroidism and neonatal respiratory distress syndrome with intact NKX2-1. American journal of medical genetics. Part A 27 23169673
2011 TTF-1 positive small cell cancers: Don't think they're always primary pulmonary! World journal of gastrointestinal oncology 26 22046491
2011 The integrity of cholinergic basal forebrain neurons depends on expression of Nkx2-1. The European journal of neuroscience 26 22098391
2021 Overexpression of a carrot BCH gene, DcBCH1, improves tolerance to drought in Arabidopsis thaliana. BMC plant biology 25 34663216
2011 HOXB5 cooperates with NKX2-1 in the transcription of human RET. PloS one 25 21677782
2008 Mechanisms of TGFbeta inhibition of LUNG endodermal morphogenesis: the role of TbetaRII, Smads, Nkx2.1 and Pten. Developmental biology 25 18602626
2010 The BNIP-2 and Cdc42GAP homology (BCH) domain of p50RhoGAP/Cdc42GAP sequesters RhoA from inactivation by the adjacent GTPase-activating protein domain. Molecular biology of the cell 24 20660160
2017 Pituicytoma: Review of commonalities and distinguishing features among TTF-1 positive tumors of the central nervous system. Annals of diagnostic pathology 23 28807344
2012 Functional plasticity of the BNIP-2 and Cdc42GAP Homology (BCH) domain in cell signaling and cell dynamics. FEBS letters 22 22710163
2008 Immunohistochemical expression of TTF-1 in various cytological subtypes of primary lung adenocarcinoma, with special reference to intratumoral heterogeneity. Pathology international 22 18067638
2002 Regulation of pituitary adenylate cyclase-activating polypeptide gene transcription by TTF-1, a homeodomain-containing transcription factor. The Journal of biological chemistry 22 12122016
1994 Analysis of the conformation and stability of rat TTF-1 homeodomain by circular dichroism. FEBS letters 22 7957942
2021 An NKX2-1/ERK/WNT feedback loop modulates gastric identity and response to targeted therapy in lung adenocarcinoma. eLife 21 33821796
2016 Utility of TTF-1 and Napsin-A in the work-up of malignant effusions. Diagnostic cytopathology 20 26799356
2012 Cross-species analyses identify the BNIP-2 and Cdc42GAP homology (BCH) domain as a distinct functional subclass of the CRAL_TRIO/Sec14 superfamily. PloS one 20 22479462
2009 TTF-1 expression in nephroblastoma. The American journal of surgical pathology 20 19011567
2013 Ldb1 is essential for development of Nkx2.1 lineage derived GABAergic and cholinergic neurons in the telencephalon. Developmental biology 19 24157949
2011 TITF-1 gene mutation in a case of sporadic non-progressive chorea. Response to levodopa treatment. Brain & development 19 21555194
2021 CRISPRi-mediated functional analysis of NKX2-1-binding sites in the lung. Communications biology 18 33980985
2021 64Cu-PSMA-BCH: a new radiotracer for delayed PET imaging of prostate cancer. European journal of nuclear medicine and molecular imaging 18 34170361
2018 The expression of TTF1, CDX2 and ISL1 in 74 poorly differentiated neuroendocrine carcinomas. Annals of diagnostic pathology 18 30236546
2014 Expression of bkt and bch genes from Haematococcus pluvialis in transgenic Chlamydomonas. Science China. Life sciences 18 25209726
2023 Transcription factor NKX2-1 drives serine and glycine synthesis addiction in cancer. British journal of cancer 17 36932191
1995 Definition of the DNA-binding specificity of TTF-1 homeodomain by chromatographic selection of binding sequences. Biochemical and biophysical research communications 17 7654238
2024 Neutrophils Recruited by NKX2-1 Suppression via Activation of CXCLs/CXCR2 Axis Promote Lung Adenocarcinoma Progression. Advanced science (Weinheim, Baden-Wurttemberg, Germany) 16 39113226
2013 Enhanced derivation of mouse ESC-derived cortical interneurons by expression of Nkx2.1. Stem cell research 16 23672829
2011 Altered surfactant homeostasis and recurrent respiratory failure secondary to TTF-1 nuclear targeting defect. Respiratory research 16 21867529
2014 Recurrent drop attacks in early childhood as presenting symptom of benign hereditary chorea caused by TITF1 gene mutations. Developmental medicine and child neurology 15 25412988
2011 A novel nonsense mutation in the TITF-1 gene in a Japanese family with benign hereditary chorea. Journal of the neurological sciences 15 21982616
2013 Lung metastasis from TTF-1 positive sigmoid adenocarcinoma. pitfalls and management. Pathologica 14 23946985
2004 In vivo characterization of the Nkx2.1 promoter/enhancer elements in transgenic mice. Gene 14 15094193
2017 A further case of brain-lung-thyroid syndrome with deletion proximal to NKX2-1. European journal of medical genetics 13 28286255
2007 Evaluation of the thyroid transcription factor-1 gene (TITF1) as a Hirschsprung's disease locus. Annals of human genetics 13 17640327
1993 Structural study of rat thyroid transcription factor 1 homeodomain (TTF-1 HD) by nuclear magnetic resonance. FEBS letters 13 8282100
2024 TTF-1 is a highly sensitive but not fully specific marker for pulmonary and thyroidal cancer: a tissue microarray study evaluating more than 17,000 tumors from 152 different tumor entities. Virchows Archiv : an international journal of pathology 12 39377914
2020 The Incidence of Labelling of Non-Lung Adenocarcinomas With Antibodies Against TTF-1 and Diagnostic Implications. Applied immunohistochemistry & molecular morphology : AIMM 12 31135446