{"gene":"TTF1","run_date":"2026-06-10T10:51:56","timeline":{"discoveries":[{"year":2004,"finding":"TAZ (transcriptional co-activator with PDZ-binding motif) directly interacts with the NH2-terminal domain of TTF-1 and synergistically activates surfactant protein-C (SP-C) promoter activity in the presence of TTF-1, as demonstrated by mammalian two-hybrid assays and pull-down experiments.","method":"Mammalian two-hybrid assay, GST pull-down, deletion analysis, SP-C-luciferase reporter assay","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — reciprocal binding assays (two-hybrid + pull-down) with deletion mapping and functional reporter validation in a single rigorous study","pmids":["14970209"],"is_preprint":false},{"year":2001,"finding":"CBP/p300 and SRC-1 act as coactivators of TTF-1 to regulate surfactant protein-A (SP-A) gene expression. TTF-1 interacts physically with SRC-1 and CBP in vitro; PKA-mediated phosphorylation of TTF-1 facilitates this interaction and leads to TTF-1 acetylation, enhancing its DNA-binding and transcriptional activity on the SP-A promoter.","method":"In vitro pull-down, co-immunoprecipitation (SRC-1 immunodepletion), transient transfection/reporter assay, PKA overexpression, adenoviral E1A competition, cAMP treatment with acetylation detection","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — multiple orthogonal methods (pull-down, immunodepletion, reporter assays, PKA/E1A manipulation) in one study demonstrating physical interaction and functional consequence","pmids":["11713256"],"is_preprint":false},{"year":2006,"finding":"PARP-2 (and PARP-1) physically interact with TTF-1: PARP-2 was co-immunoprecipitated with TTF-1 from lung epithelial cell extracts and identified by mass spectrometry; the E domain of PARP-2 binds the C-terminal domain of TTF-1. Both PARP-1 and PARP-2 selectively enhance surfactant protein-B (SP-B/Sftpb) promoter activity in the presence of TTF-1.","method":"Co-immunoprecipitation from MLE15 cell extracts, mass spectrometry identification, deletion/domain mapping, Sftpb promoter-luciferase reporter assay","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — endogenous co-IP with MS confirmation, domain mapping, and functional promoter assay in one rigorous study","pmids":["16461352"],"is_preprint":false},{"year":1995,"finding":"TTF-1 is required for lung epithelial morphogenesis: antisense oligonucleotide-mediated suppression of TTF-1 translation in embryonic mouse lung explants inhibited branching morphogenesis and caused hyperplastic, disorganized proliferation of airway epithelial cells, while mesenchyme was unaffected.","method":"Antisense oligonucleotide inhibition in embryonic mouse lung branching morphogenesis model","journal":"Developmental biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — clean loss-of-function with specific morphogenetic phenotype; single lab but well-defined cellular readout","pmids":["8612983"],"is_preprint":false},{"year":1995,"finding":"TTF-1 is required for TSH- and IGF-I-stimulated proliferation of thyroid FRTL-5 cells: antisense oligonucleotide blockade of TTF-1 caused ~65% reduction in cell proliferation via the cAMP/PKA pathway. Combined blockade of TTF-1 and Pax-8 did not produce an additive effect.","method":"Antisense oligonucleotide treatment, DNA synthesis measurement, cell counting, forskolin stimulation","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct loss-of-function with quantitative proliferation readout and pathway placement (cAMP), single lab","pmids":["7559458"],"is_preprint":false},{"year":2004,"finding":"TTF-1 binds to a site in the RET promoter that overlaps HSCR-associated SNPs, and TTF-1-activated RET transcription is decreased by HSCR-associated alleles. A patient-derived TTF-1 Gly322Ser mutation compromises activation from HSCR-associated RET promoter haplotypes, and TTF-1 and RET are co-expressed in developing human gut.","method":"Luciferase reporter assay with RET promoter constructs, mutational analysis, identification of patient TTF-1 mutation, immunohistochemistry for co-expression","journal":"Human molecular genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional promoter reporter assays with mutagenesis and patient mutation validation, single lab","pmids":["15548547"],"is_preprint":false},{"year":2001,"finding":"Postnatal TTF-1 expression in hypothalamic neurons is developmentally regulated and cell-specific. TTF-1 binds to and transactivates the erbB-2 and LHRH promoters but represses transcription of the preproenkephalin gene, and hypothalamic TTF-1 mRNA increases transiently preceding puberty initiation.","method":"In situ hybridization, immunohistochemistry, lesion studies, promoter transactivation assays","journal":"Molecular and cellular neurosciences","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — direct binding/transactivation assays for multiple promoters with in vivo expression correlations; single lab","pmids":["11161473"],"is_preprint":false},{"year":2006,"finding":"Conditional deletion of Ttf1 from differentiated neurons in mice caused delayed puberty, reduced reproductive capacity, and shortened reproductive span, associated with reduced hypothalamic expression of pro-reproductive genes, without affecting basal ganglia morphology or function. This places TTF-1 in the transcriptional control of female sexual maturation.","method":"Conditional neuron-specific Ttf1 knockout mice (Cre-lox), gene expression profiling of nonhuman primate hypothalamus, behavioral and hormonal phenotyping","journal":"The Journal of neuroscience","confidence":"High","confidence_rationale":"Tier 2 / Strong — cell-type-specific genetic knockout with defined reproductive phenotype and gene expression evidence, validated across mouse and primate","pmids":["17182767"],"is_preprint":false},{"year":2007,"finding":"A subset of lung adenocarcinoma cell lines expressing TTF-1 exhibit lineage-specific dependency on continued TTF-1 expression: RNAi-mediated TTF-1 knockdown specifically induced growth inhibition and apoptosis only in TTF-1-expressing (TRU lineage) adenocarcinoma lines, not in TTF-1-negative lines.","method":"RNA interference knockdown, cell viability assay, apoptosis assay, FISH for gene copy number in patient samples","journal":"Cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — specific loss-of-function with apoptosis/growth phenotype in multiple cell lines; single lab","pmids":["17616654"],"is_preprint":false},{"year":2011,"finding":"TTF-1 transcriptionally activates MYBPH (myosin binding protein H), which in turn directly binds ROCK1 (not myosin RLC) to inhibit RLC phosphorylation and LIMK activation, thereby reducing actomyosin organization, decreasing single-cell motility, increasing collective migration, and reducing cancer invasion/metastasis.","method":"ChIP and luciferase reporter (TTF-1 → MYBPH), co-immunoprecipitation (MYBPH–ROCK1 interaction), kinase phosphorylation assays, single-cell and collective migration assays, in vivo metastasis models","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — multiple orthogonal methods including ChIP, reciprocal co-IP, kinase assays, and functional migration/metastasis readouts establishing the full TTF-1→MYBPH→ROCK1 pathway","pmids":["22085929"],"is_preprint":false},{"year":2009,"finding":"Three missense mutations in TTF-1/NKX2-1 (L176V, P202L, Q210P) identified in brain-lung-thyroid syndrome patients show loss of transactivation capacity on the human thyroglobulin enhancer/promoter. Importantly, the deficient transcriptional activity of P202L is completely rescued by co-transfected PAX8, whereas L176V and Q210P abolish the PAX8 synergistic effect, demonstrating that TTF-1 and PAX8 cooperate at the thyroglobulin promoter.","method":"Transactivation reporter assay, co-transfection with PAX8, patient mutation identification","journal":"Human molecular genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional assays with multiple patient mutations showing differential PAX8 rescue; single lab with clinical validation","pmids":["19336474"],"is_preprint":false},{"year":2013,"finding":"In small cell lung cancer (SCLC), TTF-1 expression is driven by the neural cell-specific homeoprotein BRN2, which binds to the TTF-1 isoform 2 promoter. BRN2 knockdown markedly reduces TTF-1 expression in SCLC cells; ChIP confirmed BRN2 and FOXA1/2 binding to the TTF-1 promoter. The TTF-1 promoter in SCLC is unmethylated. TTF-1 and BRN2 co-expression is exclusive to SCLC among primary lung tumors.","method":"TTF-1 promoter-luciferase reporter assays, expression vector transfection, siRNA knockdown, chromatin immunoprecipitation (ChIP), bisulfite sequencing, immunohistochemistry","journal":"Laboratory investigation","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — ChIP, promoter assays with mutagenesis-equivalent deletion, and loss-of-function knockdown all concordant, single lab with multiple orthogonal methods","pmids":["23358112"],"is_preprint":false},{"year":2019,"finding":"Genome-wide ChIP-seq reveals that TTF-1 binding regions differ by 75% between SCLC (H209) and lung adenocarcinoma (H441) cells; E-box motifs are enriched exclusively in SCLC TTF-1 binding regions. In SCLC, TTF-1 and ASCL1 are co-expressed and bind adjacent sites on target genes to cooperatively regulate neuroendocrine gene transcription. TTF-1 also regulates Bcl-2 family gene expression and exhibits antiapoptotic function in SCLC.","method":"ChIP-seq, RNA-seq, co-expression analysis, co-occupancy analysis of TTF-1 and ASCL1 binding sites","journal":"Molecular oncology","confidence":"High","confidence_rationale":"Tier 1 / Moderate — genome-wide ChIP-seq with RNA-seq in two cell-line comparisons, identifying cooperative binding with ASCL1; single lab but multiple orthogonal genomic methods","pmids":["31782890"],"is_preprint":false},{"year":2011,"finding":"TNF-α inhibits TTF-1 protein levels in lung epithelial cells by inhibiting TTF-1 gene transcription; TNF-α suppresses TTF-1 DNA binding to its own promoter and inhibits transcriptional activities of Sp1 and TTF-1 without altering their levels, associated with increased threonine phosphorylation of Sp1. Functional ZBP-89, Sp1/Sp3, and TTF-1 binding sites were identified in the TTF-1 proximal promoter by EMSA, ChIP, and mutational analysis.","method":"Deletion analysis of TTF-1 5'-flanking DNA, EMSA, ChIP, mutational analysis, TNF-α treatment, TTF-1 promoter-luciferase reporter assay in H441 and primary alveolar type II cells","journal":"American journal of physiology. Lung cellular and molecular physiology","confidence":"Medium","confidence_rationale":"Tier 1–2 / Moderate — multiple methods (EMSA, ChIP, mutagenesis, reporter assay) identifying promoter elements and cytokine regulation; single lab","pmids":["21784970"],"is_preprint":false},{"year":2008,"finding":"The TTF-1 binding element (TBE) at -171 bp in the hSP-A2 promoter is critical for lung cell-specific, developmental, and hormonal regulation: transgenic mice with TBE mutation showed essentially undetectable fetal lung expression of the hSP-A2 reporter and loss of hormonal (cAMP, IL-1, dexamethasone) regulation, whereas 313-bp wild-type constructs were developmentally regulated and hormonally responsive.","method":"Transgenic mouse reporter assay, site-directed mutagenesis of TBE, lung explant culture with hormonal treatments","journal":"American journal of physiology. Lung cellular and molecular physiology","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vivo transgenic validation with site-directed mutagenesis demonstrating necessity of TTF-1 binding element for developmental and hormonal regulation","pmids":["18487360"],"is_preprint":false},{"year":2014,"finding":"mTOR inhibition promotes TTF-1-dependent redifferentiation of thyroid carcinoma cells: in TTF-1-expressing cell lines, mTOR inhibition upregulates TTF-1 expression and subsequently induces NIS expression and iodine uptake. siRNA knockdown of TTF-1 completely abolishes NIS induction by mTOR inhibition, placing TTF-1 downstream of mTOR and upstream of NIS in this pathway.","method":"mTOR inhibitor treatment, siRNA knockdown of TTF-1, mRNA/protein expression analysis, radioactive iodine uptake assay","journal":"The Journal of clinical endocrinology and metabolism","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — epistasis established by siRNA rescue experiment with functional iodine uptake readout; single lab, two orthogonal methods","pmids":["24712572"],"is_preprint":false},{"year":2010,"finding":"TTF-1 transcriptionally activates the α5 nicotinic acetylcholine receptor (nAChR) subunit gene in lung epithelial cells by binding specific TTF-1 response elements in the α5 promoter, as confirmed by site-directed mutagenesis of those elements.","method":"Luciferase reporter assay with α5 promoter constructs, exogenous TTF-1 overexpression, site-directed mutagenesis of TTF-1 response elements","journal":"Respiratory research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — mutagenesis of binding elements with reporter assay; single lab, two methods","pmids":["21143907"],"is_preprint":false},{"year":2014,"finding":"TTF-1, together with FoxA2 and Gata-6, activates transcription from the Claudin-6 (Cldn6) promoter in proximal and distal lung epithelial cell lines; Cldn6 expression in the developing lung co-localizes with TTF-1 and FoxA2 protein.","method":"Luciferase reporter assay with 0.5, 1.0, and 2.0-kb Cldn6 promoter constructs, co-transfection with TTF-1/FoxA2/Gata-6 expression vectors, immunofluorescence co-localization","journal":"Respiratory research","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — reporter assay with multiple promoter lengths and transcription factors; co-localization supports in vivo relevance; single lab","pmids":["24970044"],"is_preprint":false},{"year":2005,"finding":"TTF-1 and PAX8 cooperate synergistically to activate thyroid-specific gene promoters (thyroglobulin, thyroperoxidase, and NIS regulatory regions) in hepatoma cells; low transcriptional activation occurs with either factor alone, but strong activation requires both together. This functional protein-protein cooperation was imaged in vivo in nude mice.","method":"Luciferase reporter assay with thyroid-specific promoter/enhancer constructs, stable transfection of hepatoma cells, in vivo bioluminescence imaging","journal":"Journal of nuclear medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional reporter assay demonstrating synergy with in vivo imaging; single lab","pmids":["15872358"],"is_preprint":false},{"year":1998,"finding":"Overexpression of TTF-1 together with PAX-8 restores thyroglobulin (Tg) gene promoter activity in TTF-1/PAX-8-deficient thyroid carcinoma cell lines (ARO, WRO); neither factor alone is sufficient, and activity is restricted to thyroid-lineage cells.","method":"Tg promoter-β-galactosidase reporter co-transfection with TTF-1 and PAX-8 expression vectors, RT-PCR","journal":"Surgery","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — functional reporter rescue experiment; single lab, single assay type","pmids":["9854590"],"is_preprint":false},{"year":2017,"finding":"In thyroid carcinoma cell lines, stable transfection of TTF-1 reciprocally induces PAX-8 expression. Induction of TTF-1 affects cell proliferation, migration, and tumorigenicity more than PAX-8, with anti-proliferative and anti-tumorigenic effects observed up to a threshold expression level.","method":"Stable transfection with TTF-1 and PAX-8 expression vectors, cell growth assay, cell cycle analysis, migration assay, in vivo tumorigenicity (xenograft)","journal":"International journal of oncology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — stable overexpression with multiple functional readouts including in vivo; single lab","pmids":["27573549"],"is_preprint":false},{"year":1994,"finding":"TTF-1 and PAX-8 activate transcription from thyroglobulin and thyroperoxidase (TPO) promoters in thyroid follicular cells. TTF-1 mRNA is consistently detectable in papillary thyroid carcinomas but absent in anaplastic carcinomas, suggesting TTF-1 expression is linked to the differentiated thyroid phenotype. Expression of TTF-1 and PAX-8 alone is not sufficient to drive the differentiated thyroid phenotype.","method":"mRNA quantification (Northern/RT-PCR), immunohistochemistry, functional promoter assays referenced as prior work","journal":"Cancer research","confidence":"Low","confidence_rationale":"Tier 3 / Moderate — mechanistic claims about promoter activation are referenced rather than newly demonstrated; primarily expression correlation in this paper","pmids":["8062273"],"is_preprint":false},{"year":2017,"finding":"Iodinated thyroglobulin regulates TTF-1 (and PAX8) expression in thyroid follicular cells through TSH/TSHR-mediated signaling: lowly iodinated TG activates cAMP-PKA to upregulate TTF-1, while highly iodinated TG activates PLC-PKC to suppress TTF-1. Blocking PKC pathway reverses highly-iodinated TG-mediated TTF-1 suppression.","method":"In vitro thyroid follicle model, PKA/PKC agonist and inhibitor treatments, protein/mRNA expression analysis","journal":"Journal of cellular biochemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — pharmacological pathway dissection with multiple agents in a relevant follicular model; single lab","pmids":["28322461"],"is_preprint":false}],"current_model":"TTF-1 (NKX2-1) is a homeodomain transcription factor that directly activates lung-specific genes (surfactant proteins SP-A, SP-B, SP-C; claudin-6; α5 nAChR) and thyroid-specific genes (thyroglobulin, TPO, NIS) through defined promoter binding elements; its transcriptional activity is modulated by coactivators TAZ, CBP/p300, SRC-1, and PARP-1/2 via physical interactions, and by PKA-mediated phosphorylation and acetylation; it cooperates synergistically with PAX8 at thyroid gene promoters; it drives a lineage-survival transcriptional program in lung adenocarcinoma and, in SCLC, is regulated by BRN2 and cooperates with ASCL1 at neuroendocrine gene loci; in the hypothalamus, conditional neuronal deletion impairs female reproductive maturation by altering expression of LHRH, erbB-2, and preproenkephalin; and one downstream target, MYBPH, mediates TTF-1's suppression of cell motility and metastasis by directly inhibiting ROCK1."},"narrative":{"mechanistic_narrative":"TTF-1 (NKX2-1) is a homeodomain transcription factor that establishes and maintains lineage-specific gene programs in lung epithelium, thyroid follicular cells, and hypothalamic neurons by binding defined promoter/enhancer elements in target genes [PMID:18487360, PMID:8062273, PMID:11161473]. In the lung it directly drives surfactant and epithelial differentiation genes—activating SP-A, SP-B, and SP-C promoters, the α5 nicotinic acetylcholine receptor subunit, and (with FoxA2 and Gata-6) Claudin-6—with a TTF-1 binding element being necessary for cell-specific, developmental, and hormonal regulation of surfactant gene expression in vivo [PMID:18487360, PMID:16461352, PMID:21143907, PMID:24970044], and is required for branching morphogenesis of the developing airway [PMID:8612983]. Its transcriptional output is tuned through physical interactions with coactivators TAZ, CBP/p300, SRC-1, and PARP-1/2, and through PKA-mediated phosphorylation and subsequent acetylation that enhance its DNA binding [PMID:14970209, PMID:11713256, PMID:16461352]. In thyroid cells TTF-1 cooperates synergistically with PAX8 to activate thyroglobulin, thyroperoxidase, and NIS, an interaction whose loss in disease-associated mutants abolishes activation [PMID:15872358, PMID:19336474, PMID:24712572]. TTF-1 functions in cancer as a lineage dependency: TTF-1-expressing lung adenocarcinoma lines require it for survival [PMID:17616654], while in small cell lung cancer its expression is driven by BRN2 and it cooperates with ASCL1 at neuroendocrine and Bcl-2 family loci to support an antiapoptotic neuroendocrine program [PMID:23358112, PMID:31782890]. It also suppresses tumor cell motility and metastasis by transactivating MYBPH, which directly binds and inhibits ROCK1 [PMID:22085929]. Conditional neuronal deletion in mice impairs female reproductive maturation, reflecting TTF-1 control of hypothalamic pro-reproductive genes including LHRH, erbB-2, and preproenkephalin [PMID:17182767, PMID:11161473]. A human TTF-1/NKX2-1 missense mutation underlies brain-lung-thyroid syndrome through loss of transactivation capacity [PMID:19336474].","teleology":[{"year":1994,"claim":"Established that TTF-1, alongside PAX-8, is associated with the differentiated thyroid phenotype and activation of thyroid-specific promoters, framing it as a thyroid lineage factor.","evidence":"mRNA quantification, immunohistochemistry, and referenced promoter assays in thyroid carcinomas","pmids":["8062273"],"confidence":"Low","gaps":["Promoter activation claims referenced rather than newly demonstrated here","TTF-1+PAX-8 alone insufficient to drive full differentiated phenotype","no direct binding data in this study"]},{"year":1995,"claim":"Loss-of-function showed TTF-1 is required for lung airway morphogenesis and for thyroid cell proliferation, establishing it as a developmental driver in both lineages.","evidence":"Antisense oligonucleotide suppression in mouse lung explants and in FRTL-5 thyroid cells with proliferation readouts","pmids":["8612983","7559458"],"confidence":"Medium","gaps":["Antisense specificity limited to single lab","direct transcriptional targets mediating morphogenesis not defined","thyroid proliferation effect placed in cAMP/PKA pathway but downstream targets unresolved"]},{"year":1998,"claim":"Demonstrated that TTF-1 and PAX-8 are jointly required, neither alone sufficient, to restore thyroglobulin promoter activity in deficient thyroid carcinoma cells, defining a cooperative thyroid program.","evidence":"Tg promoter reporter rescue by co-transfection in ARO/WRO cells with RT-PCR","pmids":["9854590"],"confidence":"Medium","gaps":["Single assay type","physical basis of cooperation not addressed","lineage restriction mechanism unexplained"]},{"year":2001,"claim":"Identified post-translational and coactivator control of TTF-1, showing PKA phosphorylation promotes CBP/SRC-1 interaction and acetylation to enhance DNA binding, and that hypothalamic TTF-1 transactivates reproductive promoters.","evidence":"Pull-down, immunodepletion, reporter assays with PKA/E1A manipulation (SP-A); in situ hybridization and promoter transactivation (hypothalamus)","pmids":["11713256","11161473"],"confidence":"Medium","gaps":["Acetyltransferase responsible not pinned to a single enzyme","phosphosite mapping incomplete","in vivo relevance of hypothalamic targets not yet genetically tested"]},{"year":2004,"claim":"Expanded the TTF-1 coactivator repertoire and target range, showing TAZ binds its N-terminus to synergize on SP-C and that TTF-1 regulates the RET promoter at HSCR-associated variants.","evidence":"Mammalian two-hybrid, GST pull-down, deletion mapping, SP-C reporter (TAZ); RET promoter reporters with patient mutation and IHC co-expression","pmids":["14970209","15548547"],"confidence":"Medium","gaps":["TAZ interaction validated in reporter context only","RET regulation in enteric development not shown in vivo","Gly322Ser mechanism limited to reporter readout"]},{"year":2006,"claim":"Confirmed PARP-1/2 as physical partners enhancing SP-B activation, and a neuron-specific genetic knockout established TTF-1's causal role in female reproductive maturation.","evidence":"Endogenous co-IP with MS and domain mapping (PARP-2); conditional Cre-lox Ttf1 deletion with hormonal/behavioral phenotyping plus primate expression profiling","pmids":["16461352","17182767"],"confidence":"High","gaps":["PARP enzymatic vs scaffolding contribution to SP-B activation unresolved","specific hypothalamic target gene driving phenotype not isolated genetically"]},{"year":2007,"claim":"Defined TTF-1 as a lineage-survival dependency in lung adenocarcinoma, since RNAi knockdown selectively killed TTF-1-expressing tumor lines.","evidence":"RNAi knockdown, viability/apoptosis assays, FISH in patient samples","pmids":["17616654"],"confidence":"Medium","gaps":["Downstream survival effectors not identified here","single-lab cell line panel","mechanism of selective dependency unexplained"]},{"year":2008,"claim":"Transgenic mutagenesis proved the TTF-1 binding element is necessary in vivo for developmental and hormonal regulation of a surfactant gene, moving beyond cell-culture correlation.","evidence":"Transgenic mouse reporter with site-directed TBE mutation and hormonal lung explant treatments","pmids":["18487360"],"confidence":"High","gaps":["Single target promoter tested","coactivators required in vivo not defined","developmental timing mechanism not dissected"]},{"year":2009,"claim":"Linked TTF-1/NKX2-1 missense mutations to brain-lung-thyroid syndrome and showed PAX8 can rescue some but not all mutant deficits, mechanistically connecting the TTF-1–PAX8 interaction to disease.","evidence":"Transactivation reporter assays with PAX8 co-transfection and patient mutation analysis","pmids":["19336474"],"confidence":"Medium","gaps":["Structural basis of differential PAX8 rescue unresolved","lung/brain phenotype correlation not assayed at promoter level","single lab"]},{"year":2011,"claim":"Resolved a metastasis-suppressive mechanism and a cytokine control loop: TTF-1 activates MYBPH which inhibits ROCK1, and TNF-α suppresses TTF-1 transcription at its own promoter.","evidence":"ChIP, reporter, reciprocal co-IP and kinase assays with migration/metastasis models (MYBPH-ROCK1); EMSA, ChIP, mutagenesis, reporter with TNF-α treatment (promoter regulation)","pmids":["22085929","21784970"],"confidence":"High","gaps":["Whether MYBPH axis operates across all TTF-1 tumor contexts unknown","TNF-α effect on Sp1 phosphorylation mechanism partial","in vivo metastasis suppression generalization untested"]},{"year":2013,"claim":"Defined the upstream driver of TTF-1 in small cell lung cancer, showing BRN2 binds and activates the TTF-1 isoform 2 promoter as a context-specific regulatory input.","evidence":"Reporter assays, siRNA knockdown, ChIP, bisulfite sequencing, IHC in SCLC","pmids":["23358112"],"confidence":"High","gaps":["Why SCLC uses BRN2-driven isoform 2 specifically unresolved","functional consequence of BRN2-driven TTF-1 for SCLC biology not fully tested here"]},{"year":2014,"claim":"Showed context-dependent TTF-1 target reprogramming and pathway placement: it cooperates with FoxA2/Gata-6 on Claudin-6, and lies downstream of mTOR and upstream of NIS in thyroid redifferentiation.","evidence":"Reporter assays and co-localization (Cldn6); mTOR inhibitor treatment with TTF-1 siRNA rescue and iodine uptake (NIS)","pmids":["24970044","24712572"],"confidence":"Medium","gaps":["Direct vs indirect mTOR-to-TTF-1 link not defined","Cldn6 combinatorial logic in vivo not tested","single-lab assays"]},{"year":2019,"claim":"Genome-wide mapping revealed TTF-1's cistrome is rewired between tumor lineages, with SCLC-specific E-box sites and cooperative co-occupancy with ASCL1 driving an antiapoptotic neuroendocrine program.","evidence":"ChIP-seq, RNA-seq, and co-occupancy analysis comparing SCLC and adenocarcinoma lines","pmids":["31782890"],"confidence":"High","gaps":["Mechanism setting lineage-specific binding (chromatin state) not defined","ASCL1-TTF-1 physical interaction not directly shown","Bcl-2 regulation directness untested"]},{"year":2017,"claim":"Showed reciprocal and signal-dependent regulation of TTF-1 levels: TTF-1 induces PAX-8 and has anti-tumorigenic effects up to a threshold, and iodinated thyroglobulin tunes TTF-1 via opposing PKA/PKC signaling.","evidence":"Stable transfection with functional/xenograft readouts (PAX-8); follicle model with PKA/PKC agonist-inhibitor dissection (iodinated TG)","pmids":["27573549","28322461"],"confidence":"Medium","gaps":["Threshold mechanism for anti-tumorigenic switch unexplained","PKC-mediated suppression effector not identified","single-lab models"]},{"year":null,"claim":"How TTF-1's cistrome is selectively reprogrammed across lung adenocarcinoma, SCLC, thyroid, and hypothalamic contexts—and which chromatin or partner inputs dictate target choice—remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unified model linking partner availability to lineage-specific binding","physical interaction with ASCL1 not directly demonstrated","in vivo coactivator requirements largely untested"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[0,1,2,6,9,14,16,17,18]},{"term_id":"GO:0003677","term_label":"DNA binding","supporting_discovery_ids":[1,13,14,16]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[1,6,13]}],"pathway":[{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[14,18,9,12]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[3,7]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[10,5]}],"complexes":[],"partners":["PAX8","TAZ","CBP","SRC-1","PARP-2","PARP-1","ASCL1","BRN2"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q15361","full_name":"Transcription termination factor 1","aliases":["RNA polymerase I termination factor","Transcription termination factor I","TTF-I"],"length_aa":905,"mass_kda":103.1,"function":"Multifunctional nucleolar protein that terminates ribosomal gene transcription, mediates replication fork arrest and regulates RNA polymerase I transcription on chromatin. Plays a dual role in rDNA regulation, being involved in both activation and silencing of rDNA transcription. Interaction with BAZ2A/TIP5 recovers DNA-binding activity","subcellular_location":"Nucleus; Nucleus, nucleolus; Nucleus, nucleoplasm","url":"https://www.uniprot.org/uniprotkb/Q15361/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":true,"resolved_as":"","url":"https://depmap.org/portal/gene/TTF1","classification":"Common Essential","n_dependent_lines":527,"n_total_lines":1208,"dependency_fraction":0.43625827814569534},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/TTF1","total_profiled":1310},"omim":[{"mim_id":"619280","title":"COILED-COIL DOMAIN-CONTAINING PROTEIN 59; CCDC59","url":"https://www.omim.org/entry/619280"},{"mim_id":"610978","title":"CHOREOATHETOSIS AND CONGENITAL HYPOTHYROIDISM WITH OR WITHOUT PULMONARY DYSFUNCTION; CAHTP","url":"https://www.omim.org/entry/610978"},{"mim_id":"609413","title":"ERCC EXCISION REPAIR 6, CHROMATIN REMODELING FACTOR; ERCC6","url":"https://www.omim.org/entry/609413"},{"mim_id":"608144","title":"SAM POINTED DOMAIN-CONTAINING ETS TRANSCRIPTION FACTOR; SPDEF","url":"https://www.omim.org/entry/608144"},{"mim_id":"607808","title":"NK2 HOMEOBOX 4; NKX2-4","url":"https://www.omim.org/entry/607808"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Nucleoli fibrillar center","reliability":"Supported"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/TTF1"},"hgnc":{"alias_symbol":[],"prev_symbol":[]},"alphafold":{"accession":"Q15361","domains":[{"cath_id":"1.10.10.60","chopping":"614-661","consensus_level":"medium","plddt":89.54,"start":614,"end":661},{"cath_id":"-","chopping":"664-749_855-871","consensus_level":"medium","plddt":79.7471,"start":664,"end":871},{"cath_id":"-","chopping":"756-852","consensus_level":"medium","plddt":85.8454,"start":756,"end":852}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q15361","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q15361-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q15361-F1-predicted_aligned_error_v6.png","plddt_mean":57.12},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=TTF1","jax_strain_url":"https://www.jax.org/strain/search?query=TTF1"},"sequence":{"accession":"Q15361","fasta_url":"https://rest.uniprot.org/uniprotkb/Q15361.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q15361/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q15361"}},"corpus_meta":[{"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":"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":"17616654","id":"PMC_17616654","title":"Lineage-specific dependency of lung adenocarcinomas on the lung development regulator TTF-1.","date":"2007","source":"Cancer research","url":"https://pubmed.ncbi.nlm.nih.gov/17616654","citation_count":173,"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":"19336474","id":"PMC_19336474","title":"Five new TTF1/NKX2.1 mutations in brain-lung-thyroid syndrome: rescue by PAX8 synergism in one case.","date":"2009","source":"Human molecular genetics","url":"https://pubmed.ncbi.nlm.nih.gov/19336474","citation_count":151,"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":"22456609","id":"PMC_22456609","title":"Mesonephric adenocarcinomas of the uterine cervix and corpus: HPV-negative neoplasms that are commonly PAX8, CA125, and HMGA2 positive and that may be immunoreactive with TTF1 and hepatocyte nuclear factor 1-β.","date":"2012","source":"The American journal of surgical pathology","url":"https://pubmed.ncbi.nlm.nih.gov/22456609","citation_count":134,"is_preprint":false},{"pmid":"12760288","id":"PMC_12760288","title":"p63 and TTF-1 immunostaining. A useful marker panel for distinguishing small cell carcinoma of lung from poorly differentiated squamous cell carcinoma of lung.","date":"2003","source":"American journal of clinical pathology","url":"https://pubmed.ncbi.nlm.nih.gov/12760288","citation_count":122,"is_preprint":false},{"pmid":"28555282","id":"PMC_28555282","title":"SMARCA4-deficient pulmonary adenocarcinoma: clinicopathological, immunohistochemical, and molecular characteristics of a novel aggressive neoplasm with a consistent TTF1neg/CK7pos/HepPar-1pos immunophenotype.","date":"2017","source":"Virchows Archiv : an international journal of pathology","url":"https://pubmed.ncbi.nlm.nih.gov/28555282","citation_count":117,"is_preprint":false},{"pmid":"20182342","id":"PMC_20182342","title":"An immunohistochemical study of cervical neuroendocrine carcinomas: Neoplasms that are commonly TTF1 positive and which may express CK20 and P63.","date":"2010","source":"The American journal of surgical pathology","url":"https://pubmed.ncbi.nlm.nih.gov/20182342","citation_count":98,"is_preprint":false},{"pmid":"11161473","id":"PMC_11161473","title":"TTF-1, a homeodomain gene required for diencephalic morphogenesis, is postnatally expressed in the neuroendocrine brain in a developmentally regulated and cell-specific fashion.","date":"2001","source":"Molecular and cellular neurosciences","url":"https://pubmed.ncbi.nlm.nih.gov/11161473","citation_count":98,"is_preprint":false},{"pmid":"15279630","id":"PMC_15279630","title":"Expression of TTF-1 and cytokeratins in primary and secondary epithelial lung tumours: correlation with histological type and grade.","date":"2004","source":"Histopathology","url":"https://pubmed.ncbi.nlm.nih.gov/15279630","citation_count":94,"is_preprint":false},{"pmid":"11156325","id":"PMC_11156325","title":"Is TTF1 a good immunohistochemical marker to distinguish primary from metastatic lung adenocarcinomas?","date":"2000","source":"Pathology, research and practice","url":"https://pubmed.ncbi.nlm.nih.gov/11156325","citation_count":88,"is_preprint":false},{"pmid":"19047914","id":"PMC_19047914","title":"TTF-1 expression in ovarian and uterine epithelial neoplasia and its potential significance, an immunohistochemical assessment with multiple monoclonal antibodies and different secondary detection systems.","date":"2009","source":"International journal of gynecological pathology : official journal of the International Society of Gynecological Pathologists","url":"https://pubmed.ncbi.nlm.nih.gov/19047914","citation_count":83,"is_preprint":false},{"pmid":"22085929","id":"PMC_22085929","title":"MYBPH, a transcriptional target of TTF-1, inhibits ROCK1, and reduces cell motility and metastasis.","date":"2011","source":"The EMBO journal","url":"https://pubmed.ncbi.nlm.nih.gov/22085929","citation_count":75,"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":"16680154","id":"PMC_16680154","title":"TTF-1 and p63 for distinguishing pulmonary small-cell carcinoma from poorly differentiated squamous cell carcinoma in previously pap-stained cytologic material.","date":"2006","source":"Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc","url":"https://pubmed.ncbi.nlm.nih.gov/16680154","citation_count":72,"is_preprint":false},{"pmid":"11713256","id":"PMC_11713256","title":"Role of CBP/p300 and SRC-1 in transcriptional regulation of the pulmonary surfactant protein-A (SP-A) gene by thyroid transcription factor-1 (TTF-1).","date":"2001","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/11713256","citation_count":67,"is_preprint":false},{"pmid":"23787483","id":"PMC_23787483","title":"A mutation in TTF1/NKX2.1 is associated with familial neuroendocrine cell hyperplasia of infancy.","date":"2013","source":"Chest","url":"https://pubmed.ncbi.nlm.nih.gov/23787483","citation_count":65,"is_preprint":false},{"pmid":"18932182","id":"PMC_18932182","title":"TTF1 expression in non-small cell lung carcinoma: association with TTF1 gene amplification and improved survival.","date":"2009","source":"The Journal of pathology","url":"https://pubmed.ncbi.nlm.nih.gov/18932182","citation_count":61,"is_preprint":false},{"pmid":"25878335","id":"PMC_25878335","title":"An Integrated Molecular Analysis of Lung Adenocarcinomas Identifies Potential Therapeutic Targets among TTF1-Negative Tumors, Including DNA Repair Proteins and Nrf2.","date":"2015","source":"Clinical cancer research : an official journal of the American Association for Cancer Research","url":"https://pubmed.ncbi.nlm.nih.gov/25878335","citation_count":57,"is_preprint":false},{"pmid":"24746197","id":"PMC_24746197","title":"The utility of a novel triple marker (combination of TTF1, napsin A, and p40) in the subclassification of non-small cell lung cancer.","date":"2014","source":"Human pathology","url":"https://pubmed.ncbi.nlm.nih.gov/24746197","citation_count":55,"is_preprint":false},{"pmid":"20694477","id":"PMC_20694477","title":"TTF1 expression in normal lung neuroendocrine cells and related tumors: immunohistochemical study comparing two different monoclonal antibodies.","date":"2010","source":"Virchows Archiv : an international journal of pathology","url":"https://pubmed.ncbi.nlm.nih.gov/20694477","citation_count":54,"is_preprint":false},{"pmid":"16461352","id":"PMC_16461352","title":"PARP-2 interacts with TTF-1 and regulates expression of surfactant protein-B.","date":"2006","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/16461352","citation_count":49,"is_preprint":false},{"pmid":"17182767","id":"PMC_17182767","title":"Deletion of the Ttf1 gene in differentiated neurons disrupts female reproduction without impairing basal ganglia function.","date":"2006","source":"The Journal of neuroscience : the official journal of the Society for Neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/17182767","citation_count":47,"is_preprint":false},{"pmid":"7559458","id":"PMC_7559458","title":"Function of the homeo and paired domain proteins TTF-1 and Pax-8 in thyroid cell proliferation.","date":"1995","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/7559458","citation_count":47,"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":"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":"30628926","id":"PMC_30628926","title":"SOX10, GATA3, GCDFP15, Androgen Receptor, and Mammaglobin for the Differential Diagnosis Between Triple-negative Breast Cancer and TTF1-negative Lung Adenocarcinoma.","date":"2019","source":"The American journal of surgical pathology","url":"https://pubmed.ncbi.nlm.nih.gov/30628926","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":"17727473","id":"PMC_17727473","title":"Biomarker-assisted diagnosis of ovarian, cervical and pulmonary small cell carcinomas: the role of TTF-1, WT-1 and HPV analysis.","date":"2007","source":"Histopathology","url":"https://pubmed.ncbi.nlm.nih.gov/17727473","citation_count":43,"is_preprint":false},{"pmid":"17497661","id":"PMC_17497661","title":"WT1, monoclonal CEA, TTF1, and CA125 antibodies in the differential diagnosis of lung, breast, and ovarian adenocarcinomas in serous effusions.","date":"2007","source":"Diagnostic cytopathology","url":"https://pubmed.ncbi.nlm.nih.gov/17497661","citation_count":39,"is_preprint":false},{"pmid":"18682709","id":"PMC_18682709","title":"Induction of sodium iodide symporter gene and molecular characterisation of HNF3 beta/FoxA2, TTF-1 and C/EBP beta in thyroid carcinoma cells.","date":"2008","source":"British journal of cancer","url":"https://pubmed.ncbi.nlm.nih.gov/18682709","citation_count":38,"is_preprint":false},{"pmid":"24712572","id":"PMC_24712572","title":"mTOR Inhibition promotes TTF1-dependent redifferentiation and restores iodine uptake in thyroid carcinoma cell lines.","date":"2014","source":"The Journal of clinical endocrinology and metabolism","url":"https://pubmed.ncbi.nlm.nih.gov/24712572","citation_count":37,"is_preprint":false},{"pmid":"26705222","id":"PMC_26705222","title":"Distinct Characteristics of Small Cell Lung Cancer Correlate With Central or Peripheral Origin: Subtyping Based on Location and Expression of Transcription Factor TTF-1.","date":"2015","source":"Medicine","url":"https://pubmed.ncbi.nlm.nih.gov/26705222","citation_count":35,"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":"23573309","id":"PMC_23573309","title":"An immunohistochemical study of primary signet-ring cell carcinoma of the stomach and colorectum: III. Expressions of EMA, CEA, CA19-9, CDX-2, p53, Ki-67 antigen, TTF-1, vimentin, and p63 in normal mucosa and in 42 cases.","date":"2013","source":"International journal of clinical and experimental pathology","url":"https://pubmed.ncbi.nlm.nih.gov/23573309","citation_count":33,"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":"23358112","id":"PMC_23358112","title":"Neural lineage-specific homeoprotein BRN2 is directly involved in TTF1 expression in small-cell lung cancer.","date":"2013","source":"Laboratory investigation; a journal of technical methods and pathology","url":"https://pubmed.ncbi.nlm.nih.gov/23358112","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":"28349943","id":"PMC_28349943","title":"TTF-1- and/or CD56-positive Circulating Tumor Cells in patients with small cell lung cancer (SCLC).","date":"2017","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/28349943","citation_count":26,"is_preprint":false},{"pmid":"23064619","id":"PMC_23064619","title":"Correlation of immunohistochemical staining p63 and TTF-1 with EGFR and K-ras mutational spectrum and diagnostic reproducibility in non small cell lung carcinoma.","date":"2012","source":"Virchows Archiv : an international journal of pathology","url":"https://pubmed.ncbi.nlm.nih.gov/23064619","citation_count":26,"is_preprint":false},{"pmid":"24970044","id":"PMC_24970044","title":"Developmental lung expression and transcriptional regulation of claudin-6 by TTF-1, Gata-6, and FoxA2.","date":"2014","source":"Respiratory research","url":"https://pubmed.ncbi.nlm.nih.gov/24970044","citation_count":25,"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":"31133441","id":"PMC_31133441","title":"Value of SATB2, ISL1, and TTF1 to differentiate rectal from other gastrointestinal and lung well-differentiated neuroendocrine tumors.","date":"2019","source":"Pathology, research and practice","url":"https://pubmed.ncbi.nlm.nih.gov/31133441","citation_count":23,"is_preprint":false},{"pmid":"37854151","id":"PMC_37854151","title":"Thyroid transcription factor-1 (TTF-1) expression and the efficacy of combination therapy with immune checkpoint inhibitors and cytotoxic chemotherapy in non-squamous non-small cell lung cancer.","date":"2023","source":"Translational lung cancer research","url":"https://pubmed.ncbi.nlm.nih.gov/37854151","citation_count":23,"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":"9854590","id":"PMC_9854590","title":"Overexpression of TTF-1 and PAX-8 restores thyroglobulin gene promoter activity in ARO and WRO cell lines.","date":"1998","source":"Surgery","url":"https://pubmed.ncbi.nlm.nih.gov/9854590","citation_count":23,"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":"18067638","id":"PMC_18067638","title":"Immunohistochemical expression of TTF-1 in various cytological subtypes of primary lung adenocarcinoma, with special reference to intratumoral heterogeneity.","date":"2008","source":"Pathology international","url":"https://pubmed.ncbi.nlm.nih.gov/18067638","citation_count":22,"is_preprint":false},{"pmid":"30385371","id":"PMC_30385371","title":"Triple marker composed of p16, CD56, and TTF1 shows higher sensitivity than INSM1 for diagnosis of pulmonary small cell carcinoma: proposal for a rational immunohistochemical algorithm for diagnosis of small cell carcinoma in small biopsy and cytology specimens.","date":"2018","source":"Human pathology","url":"https://pubmed.ncbi.nlm.nih.gov/30385371","citation_count":20,"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":"36519019","id":"PMC_36519019","title":"Association of thyroid transcription factor-1 (TTF-1) expression with efficacy of PD-1/PD-L1 inhibitors plus pemetrexed and platinum chemotherapy in advanced non-squamous non-small cell lung cancer.","date":"2022","source":"Translational lung cancer research","url":"https://pubmed.ncbi.nlm.nih.gov/36519019","citation_count":20,"is_preprint":false},{"pmid":"21784970","id":"PMC_21784970","title":"Thyroid transcription factor-1 (TTF-1) gene: identification of ZBP-89, Sp1, and TTF-1 sites in the promoter and regulation by TNF-α in lung epithelial cells.","date":"2011","source":"American journal of physiology. Lung cellular and molecular physiology","url":"https://pubmed.ncbi.nlm.nih.gov/21784970","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":"36130728","id":"PMC_36130728","title":"Non-small cell lung carcinomas with diffuse coexpression of TTF1 and p40: clinicopathological and genomic features of 14 rare biphenotypic tumours.","date":"2022","source":"Histopathology","url":"https://pubmed.ncbi.nlm.nih.gov/36130728","citation_count":19,"is_preprint":false},{"pmid":"25063315","id":"PMC_25063315","title":"Analysis of clinical characteristics and differential diagnosis of the lung biopsy specimens in 99 adenocarcinoma cases and 111 squamous cell carcinoma cases: utility of an immunohistochemical panel containing CK5/6, CK34βE12, p63, CK7 and TTF-1.","date":"2014","source":"Pathology, research and practice","url":"https://pubmed.ncbi.nlm.nih.gov/25063315","citation_count":19,"is_preprint":false},{"pmid":"30236546","id":"PMC_30236546","title":"The expression of TTF1, CDX2 and ISL1 in 74 poorly differentiated neuroendocrine carcinomas.","date":"2018","source":"Annals of diagnostic pathology","url":"https://pubmed.ncbi.nlm.nih.gov/30236546","citation_count":18,"is_preprint":false},{"pmid":"37020925","id":"PMC_37020925","title":"TTF-1 Expression and Clinical Outcomes of Combined Chemoimmunotherapy in Patients With Advanced Lung Adenocarcinoma: A Prospective Observational Study.","date":"2023","source":"JTO clinical and research reports","url":"https://pubmed.ncbi.nlm.nih.gov/37020925","citation_count":18,"is_preprint":false},{"pmid":"18355939","id":"PMC_18355939","title":"EGFR, TTF-1 and Mdm2 expression in stage III non-small cell lung cancer: a positive association.","date":"2008","source":"Lung cancer (Amsterdam, Netherlands)","url":"https://pubmed.ncbi.nlm.nih.gov/18355939","citation_count":17,"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":"18487360","id":"PMC_18487360","title":"TTF-1 response element is critical for temporal and spatial regulation and necessary for hormonal regulation of human surfactant protein-A2 promoter activity.","date":"2008","source":"American journal of physiology. Lung cellular and molecular physiology","url":"https://pubmed.ncbi.nlm.nih.gov/18487360","citation_count":17,"is_preprint":false},{"pmid":"15872358","id":"PMC_15872358","title":"Effects of Pax8 and TTF-1 thyroid transcription factor gene transfer in hepatoma cells: imaging of functional protein-protein interaction and iodide uptake.","date":"2005","source":"Journal of nuclear medicine : official publication, Society of Nuclear Medicine","url":"https://pubmed.ncbi.nlm.nih.gov/15872358","citation_count":17,"is_preprint":false},{"pmid":"34746884","id":"PMC_34746884","title":"Coexpression of ΔNp63/p40 and TTF1 Within Most of the Same Individual Cells Identifies Life-Threatening NSCLC Featuring Squamous and Glandular Biphenotypic Differentiation: Clinicopathologic Correlations.","date":"2021","source":"JTO clinical and research reports","url":"https://pubmed.ncbi.nlm.nih.gov/34746884","citation_count":16,"is_preprint":false},{"pmid":"23525704","id":"PMC_23525704","title":"EGFR and TTF-1 gene amplification in surgically resected lung adenocarcinomas: clinicopathologic significance and effect on response to EGFR-tyrosine kinase inhibitors in recurred cases.","date":"2013","source":"Annals of surgical oncology","url":"https://pubmed.ncbi.nlm.nih.gov/23525704","citation_count":16,"is_preprint":false},{"pmid":"32411090","id":"PMC_32411090","title":"TTF-1 Positive Primary Small Cell Carcinoma of the Breast: A Case Report and Review of the Literature.","date":"2020","source":"Frontiers in endocrinology","url":"https://pubmed.ncbi.nlm.nih.gov/32411090","citation_count":16,"is_preprint":false},{"pmid":"31388196","id":"PMC_31388196","title":"When tumor doesn't read textbook. Third case of TTF1 and p40 co-expression in the same tumour cells in a non-small cell carcinoma. A potential new entity to consider?","date":"2019","source":"Pathologica","url":"https://pubmed.ncbi.nlm.nih.gov/31388196","citation_count":15,"is_preprint":false},{"pmid":"29956575","id":"PMC_29956575","title":"Immunohistochemical analysis and comparison of napsin A, TTF1, SPA and CK7 expression in primary lung adenocarcinoma.","date":"2018","source":"Biotechnic & histochemistry : official publication of the Biological Stain Commission","url":"https://pubmed.ncbi.nlm.nih.gov/29956575","citation_count":15,"is_preprint":false},{"pmid":"34760996","id":"PMC_34760996","title":"NKX2.1 (TTF1) germline mutation associated with pulmonary fibrosis and lung cancer.","date":"2021","source":"ERJ open research","url":"https://pubmed.ncbi.nlm.nih.gov/34760996","citation_count":15,"is_preprint":false},{"pmid":"29313264","id":"PMC_29313264","title":"Positivity for GATA3 and TTF-1 (SPT24), and Negativity for Monoclonal PAX8 Expand the Biomarker Profile of the Solid Cell Nests of the Thyroid Gland.","date":"2018","source":"Endocrine pathology","url":"https://pubmed.ncbi.nlm.nih.gov/29313264","citation_count":15,"is_preprint":false},{"pmid":"39377914","id":"PMC_39377914","title":"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.","date":"2024","source":"Virchows Archiv : an international journal of pathology","url":"https://pubmed.ncbi.nlm.nih.gov/39377914","citation_count":14,"is_preprint":false},{"pmid":"27834930","id":"PMC_27834930","title":"RETRACTED: TTF1, in the Form of Nanoparticles, Inhibits Angiogenesis, Cell Migration and Cell Invasion In Vitro and In Vivo in Human Hepatoma through STAT3 Regulation.","date":"2016","source":"Molecules (Basel, Switzerland)","url":"https://pubmed.ncbi.nlm.nih.gov/27834930","citation_count":14,"is_preprint":false},{"pmid":"25722034","id":"PMC_25722034","title":"Co-expression of TTF-1 and neuroendocrine markers in the human fetal lung and pulmonary neuroendocrine tumors.","date":"2015","source":"Acta histochemica","url":"https://pubmed.ncbi.nlm.nih.gov/25722034","citation_count":14,"is_preprint":false},{"pmid":"27409604","id":"PMC_27409604","title":"Expression of Tenascin C, EGFR, E-Cadherin, and TTF-1 in Medullary Thyroid Carcinoma and the Correlation with RET Mutation Status.","date":"2016","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/27409604","citation_count":14,"is_preprint":false},{"pmid":"15912575","id":"PMC_15912575","title":"Aberrant expression of TTF-1 and forkhead factor HFH-4 in atrophic gastritis and ciliated metaplasia suggests gastric broncho-pulmonary transdetermination.","date":"2005","source":"The Journal of pathology","url":"https://pubmed.ncbi.nlm.nih.gov/15912575","citation_count":14,"is_preprint":false},{"pmid":"27131317","id":"PMC_27131317","title":"TTF1-NPs Induce ERS-Mediated Apoptosis and Inhibit Human Hepatoma Cell Growth In Vitro and In Vivo.","date":"2016","source":"Oncology research","url":"https://pubmed.ncbi.nlm.nih.gov/27131317","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":"22495359","id":"PMC_22495359","title":"IMP3, NESP55, TTF-1 and CDX2 serve as an immunohistochemical panel in the distinction among small-cell carcinoma, gastrointestinal carcinoid, and pancreatic endocrine tumor metastasized to the liver.","date":"2012","source":"Applied immunohistochemistry & molecular morphology : AIMM","url":"https://pubmed.ncbi.nlm.nih.gov/22495359","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":"33733343","id":"PMC_33733343","title":"An algorithmic approach utilizing CK7, TTF1, beta-catenin, CDX2, and SSTR2A can help differentiate between gastrointestinal and pulmonary neuroendocrine carcinomas.","date":"2021","source":"Virchows Archiv : an international journal of pathology","url":"https://pubmed.ncbi.nlm.nih.gov/33733343","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":"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":"22171128","id":"PMC_22171128","title":"Inhibition of tumor angiogenesis by TTF1 from extract of herbal medicine.","date":"2011","source":"World journal of gastroenterology","url":"https://pubmed.ncbi.nlm.nih.gov/22171128","citation_count":12,"is_preprint":false},{"pmid":"32045390","id":"PMC_32045390","title":"CDX2, SATB2, GATA3, TTF1, and PAX8 Immunohistochemistry in Krukenberg Tumors.","date":"2020","source":"International journal of gynecological pathology : official journal of the International Society of Gynecological Pathologists","url":"https://pubmed.ncbi.nlm.nih.gov/32045390","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":"28811082","id":"PMC_28811082","title":"Correlation between molecular analysis, diagnosis according to the 2015 WHO classification of unresected lung tumours and TTF1 expression in small biopsies and cytology specimens from 344 non-small cell lung carcinoma patients.","date":"2017","source":"Pathology","url":"https://pubmed.ncbi.nlm.nih.gov/28811082","citation_count":11,"is_preprint":false},{"pmid":"21637920","id":"PMC_21637920","title":"TTF1-induced apoptosis of HepG-2 cells through a mitochondrial pathway.","date":"2011","source":"Oncology reports","url":"https://pubmed.ncbi.nlm.nih.gov/21637920","citation_count":11,"is_preprint":false},{"pmid":"29373917","id":"PMC_29373917","title":"Immunohistochemical and Biochemical Expression Patterns of TTF-1, RAGE, GLUT-1 and SOX2 in HCV-Associated Hepatocellular Carcinomas.","date":"2018","source":"Asian Pacific journal of cancer prevention : APJCP","url":"https://pubmed.ncbi.nlm.nih.gov/29373917","citation_count":11,"is_preprint":false},{"pmid":"18626520","id":"PMC_18626520","title":"The value of immunohistochemical expression of TTF-1, CK7 and CK20 in the diagnosis of primary and secondary lung carcinomas.","date":"2008","source":"Saudi medical journal","url":"https://pubmed.ncbi.nlm.nih.gov/18626520","citation_count":11,"is_preprint":false},{"pmid":"26356687","id":"PMC_26356687","title":"Replication and Meta-Analysis of Common Gene Mutations in TTF1 and TTF2 with Papillary Thyroid Cancer.","date":"2015","source":"Medicine","url":"https://pubmed.ncbi.nlm.nih.gov/26356687","citation_count":10,"is_preprint":false},{"pmid":"33585516","id":"PMC_33585516","title":"Differential Expression of PD-L1 in Central and Peripheral and TTF1-Positive and -Negative Small-Cell Lung Cancer.","date":"2021","source":"Frontiers in medicine","url":"https://pubmed.ncbi.nlm.nih.gov/33585516","citation_count":10,"is_preprint":false},{"pmid":"30045295","id":"PMC_30045295","title":"Differential expression of neuroendocrine markers, TTF-1, p53, and Ki-67 in cervical and pulmonary small cell carcinoma.","date":"2018","source":"Medicine","url":"https://pubmed.ncbi.nlm.nih.gov/30045295","citation_count":10,"is_preprint":false},{"pmid":"30631609","id":"PMC_30631609","title":"TTF1 Expression in Pulmonary Metastatic Rectal Adenocarcinoma.","date":"2018","source":"Case reports in gastrointestinal medicine","url":"https://pubmed.ncbi.nlm.nih.gov/30631609","citation_count":10,"is_preprint":false},{"pmid":"31428934","id":"PMC_31428934","title":"REG4 is an indicator for KRAS mutant lung adenocarcinoma with TTF-1 low expression.","date":"2019","source":"Journal of cancer research and clinical oncology","url":"https://pubmed.ncbi.nlm.nih.gov/31428934","citation_count":10,"is_preprint":false},{"pmid":"36745184","id":"PMC_36745184","title":"SOX11 Is an Effective Discriminatory Marker, When Used in Conjunction With CK20 and TTF1, for Merkel Cell Carcinoma: Comparative Analysis of SOX11, CK20, PAX5, and TTF1 Expression in Merkel Cell Carcinoma and Pulmonary Small Cell Carcinoma.","date":"2023","source":"Archives of pathology & laboratory medicine","url":"https://pubmed.ncbi.nlm.nih.gov/36745184","citation_count":9,"is_preprint":false},{"pmid":"28322461","id":"PMC_28322461","title":"Iodinated TG in Thyroid Follicular Lumen Regulates TTF-1 and PAX8 Expression via TSH/TSHR Signaling Pathway.","date":"2017","source":"Journal of cellular biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/28322461","citation_count":9,"is_preprint":false},{"pmid":"38710944","id":"PMC_38710944","title":"Expression patterns of HNF4α, TTF-1, and SMARCA4 in lung adenocarcinomas: impacts on clinicopathological and genetic features.","date":"2024","source":"Virchows Archiv : an international journal of pathology","url":"https://pubmed.ncbi.nlm.nih.gov/38710944","citation_count":8,"is_preprint":false},{"pmid":"32772757","id":"PMC_32772757","title":"Aberrant TTF-1 Expression in Peripheral T-Cell Lymphomas: A Diagnostic Pitfall.","date":"2020","source":"International journal of surgical pathology","url":"https://pubmed.ncbi.nlm.nih.gov/32772757","citation_count":8,"is_preprint":false},{"pmid":"29328481","id":"PMC_29328481","title":"TTF1‑NP induces protective autophagy during apoptosis by inhibiting the Akt/mTOR pathway and activating JNK in human liver cancer cells.","date":"2018","source":"Oncology reports","url":"https://pubmed.ncbi.nlm.nih.gov/29328481","citation_count":8,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":58293,"output_tokens":6232,"usd":0.13418,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":14884,"output_tokens":4942,"usd":0.098985,"stage2_stop_reason":"end_turn"},"total_usd":0.233165,"stage1_batch_id":"msgbatch_017qqVz33Ga63SCDwzb35XPb","stage2_batch_id":"msgbatch_01Scr2Ei9x4HJMiRGxwrmvLK","note":"batch pricing = 50% of standard"},"stage1_raw":"Looking through the abstracts, I need to identify papers about the canonical TTF1 protein (NKX2-1/TITF1, a homeodomain transcription factor expressed in thyroid, lung, and brain). I'll exclude papers about:\n- TTF1 the flavonoid compound from Sorbaria sorbifolia (papers 73, 77, 84, 88, 100 - these are a plant compound, not the protein)\n- Pure IHC/diagnostic/prognostic papers with no mechanistic content\n- Papers about expression correlation without mechanism\n\nNow extracting mechanistic findings:\n\n```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2004,\n      \"finding\": \"TAZ (transcriptional co-activator with PDZ-binding motif) directly interacts with the NH2-terminal domain of TTF-1 and synergistically activates surfactant protein-C (SP-C) promoter activity in the presence of TTF-1, as demonstrated by mammalian two-hybrid assays and pull-down experiments.\",\n      \"method\": \"Mammalian two-hybrid assay, GST pull-down, deletion analysis, SP-C-luciferase reporter assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — reciprocal binding assays (two-hybrid + pull-down) with deletion mapping and functional reporter validation in a single rigorous study\",\n      \"pmids\": [\"14970209\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"CBP/p300 and SRC-1 act as coactivators of TTF-1 to regulate surfactant protein-A (SP-A) gene expression. TTF-1 interacts physically with SRC-1 and CBP in vitro; PKA-mediated phosphorylation of TTF-1 facilitates this interaction and leads to TTF-1 acetylation, enhancing its DNA-binding and transcriptional activity on the SP-A promoter.\",\n      \"method\": \"In vitro pull-down, co-immunoprecipitation (SRC-1 immunodepletion), transient transfection/reporter assay, PKA overexpression, adenoviral E1A competition, cAMP treatment with acetylation detection\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — multiple orthogonal methods (pull-down, immunodepletion, reporter assays, PKA/E1A manipulation) in one study demonstrating physical interaction and functional consequence\",\n      \"pmids\": [\"11713256\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"PARP-2 (and PARP-1) physically interact with TTF-1: PARP-2 was co-immunoprecipitated with TTF-1 from lung epithelial cell extracts and identified by mass spectrometry; the E domain of PARP-2 binds the C-terminal domain of TTF-1. Both PARP-1 and PARP-2 selectively enhance surfactant protein-B (SP-B/Sftpb) promoter activity in the presence of TTF-1.\",\n      \"method\": \"Co-immunoprecipitation from MLE15 cell extracts, mass spectrometry identification, deletion/domain mapping, Sftpb promoter-luciferase reporter assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — endogenous co-IP with MS confirmation, domain mapping, and functional promoter assay in one rigorous study\",\n      \"pmids\": [\"16461352\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1995,\n      \"finding\": \"TTF-1 is required for lung epithelial morphogenesis: antisense oligonucleotide-mediated suppression of TTF-1 translation in embryonic mouse lung explants inhibited branching morphogenesis and caused hyperplastic, disorganized proliferation of airway epithelial cells, while mesenchyme was unaffected.\",\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 — clean loss-of-function with specific morphogenetic phenotype; single lab but well-defined cellular readout\",\n      \"pmids\": [\"8612983\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1995,\n      \"finding\": \"TTF-1 is required for TSH- and IGF-I-stimulated proliferation of thyroid FRTL-5 cells: antisense oligonucleotide blockade of TTF-1 caused ~65% reduction in cell proliferation via the cAMP/PKA pathway. Combined blockade of TTF-1 and Pax-8 did not produce an additive effect.\",\n      \"method\": \"Antisense oligonucleotide treatment, DNA synthesis measurement, cell counting, forskolin stimulation\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct loss-of-function with quantitative proliferation readout and pathway placement (cAMP), single lab\",\n      \"pmids\": [\"7559458\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"TTF-1 binds to a site in the RET promoter that overlaps HSCR-associated SNPs, and TTF-1-activated RET transcription is decreased by HSCR-associated alleles. A patient-derived TTF-1 Gly322Ser mutation compromises activation from HSCR-associated RET promoter haplotypes, and TTF-1 and RET are co-expressed in developing human gut.\",\n      \"method\": \"Luciferase reporter assay with RET promoter constructs, mutational analysis, identification of patient TTF-1 mutation, immunohistochemistry for co-expression\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional promoter reporter assays with mutagenesis and patient mutation validation, single lab\",\n      \"pmids\": [\"15548547\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"Postnatal TTF-1 expression in hypothalamic neurons is developmentally regulated and cell-specific. TTF-1 binds to and transactivates the erbB-2 and LHRH promoters but represses transcription of the preproenkephalin gene, and hypothalamic TTF-1 mRNA increases transiently preceding puberty initiation.\",\n      \"method\": \"In situ hybridization, immunohistochemistry, lesion studies, promoter transactivation assays\",\n      \"journal\": \"Molecular and cellular neurosciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — direct binding/transactivation assays for multiple promoters with in vivo expression correlations; single lab\",\n      \"pmids\": [\"11161473\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"Conditional deletion of Ttf1 from differentiated neurons in mice caused delayed puberty, reduced reproductive capacity, and shortened reproductive span, associated with reduced hypothalamic expression of pro-reproductive genes, without affecting basal ganglia morphology or function. This places TTF-1 in the transcriptional control of female sexual maturation.\",\n      \"method\": \"Conditional neuron-specific Ttf1 knockout mice (Cre-lox), gene expression profiling of nonhuman primate hypothalamus, behavioral and hormonal phenotyping\",\n      \"journal\": \"The Journal of neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — cell-type-specific genetic knockout with defined reproductive phenotype and gene expression evidence, validated across mouse and primate\",\n      \"pmids\": [\"17182767\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"A subset of lung adenocarcinoma cell lines expressing TTF-1 exhibit lineage-specific dependency on continued TTF-1 expression: RNAi-mediated TTF-1 knockdown specifically induced growth inhibition and apoptosis only in TTF-1-expressing (TRU lineage) adenocarcinoma lines, not in TTF-1-negative lines.\",\n      \"method\": \"RNA interference knockdown, cell viability assay, apoptosis assay, FISH for gene copy number in patient samples\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — specific loss-of-function with apoptosis/growth phenotype in multiple cell lines; single lab\",\n      \"pmids\": [\"17616654\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"TTF-1 transcriptionally activates MYBPH (myosin binding protein H), which in turn directly binds ROCK1 (not myosin RLC) to inhibit RLC phosphorylation and LIMK activation, thereby reducing actomyosin organization, decreasing single-cell motility, increasing collective migration, and reducing cancer invasion/metastasis.\",\n      \"method\": \"ChIP and luciferase reporter (TTF-1 → MYBPH), co-immunoprecipitation (MYBPH–ROCK1 interaction), kinase phosphorylation assays, single-cell and collective migration assays, in vivo metastasis models\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — multiple orthogonal methods including ChIP, reciprocal co-IP, kinase assays, and functional migration/metastasis readouts establishing the full TTF-1→MYBPH→ROCK1 pathway\",\n      \"pmids\": [\"22085929\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"Three missense mutations in TTF-1/NKX2-1 (L176V, P202L, Q210P) identified in brain-lung-thyroid syndrome patients show loss of transactivation capacity on the human thyroglobulin enhancer/promoter. Importantly, the deficient transcriptional activity of P202L is completely rescued by co-transfected PAX8, whereas L176V and Q210P abolish the PAX8 synergistic effect, demonstrating that TTF-1 and PAX8 cooperate at the thyroglobulin promoter.\",\n      \"method\": \"Transactivation reporter assay, co-transfection with PAX8, patient mutation identification\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional assays with multiple patient mutations showing differential PAX8 rescue; single lab with clinical validation\",\n      \"pmids\": [\"19336474\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"In small cell lung cancer (SCLC), TTF-1 expression is driven by the neural cell-specific homeoprotein BRN2, which binds to the TTF-1 isoform 2 promoter. BRN2 knockdown markedly reduces TTF-1 expression in SCLC cells; ChIP confirmed BRN2 and FOXA1/2 binding to the TTF-1 promoter. The TTF-1 promoter in SCLC is unmethylated. TTF-1 and BRN2 co-expression is exclusive to SCLC among primary lung tumors.\",\n      \"method\": \"TTF-1 promoter-luciferase reporter assays, expression vector transfection, siRNA knockdown, chromatin immunoprecipitation (ChIP), bisulfite sequencing, immunohistochemistry\",\n      \"journal\": \"Laboratory investigation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — ChIP, promoter assays with mutagenesis-equivalent deletion, and loss-of-function knockdown all concordant, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"23358112\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Genome-wide ChIP-seq reveals that TTF-1 binding regions differ by 75% between SCLC (H209) and lung adenocarcinoma (H441) cells; E-box motifs are enriched exclusively in SCLC TTF-1 binding regions. In SCLC, TTF-1 and ASCL1 are co-expressed and bind adjacent sites on target genes to cooperatively regulate neuroendocrine gene transcription. TTF-1 also regulates Bcl-2 family gene expression and exhibits antiapoptotic function in SCLC.\",\n      \"method\": \"ChIP-seq, RNA-seq, co-expression analysis, co-occupancy analysis of TTF-1 and ASCL1 binding sites\",\n      \"journal\": \"Molecular oncology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — genome-wide ChIP-seq with RNA-seq in two cell-line comparisons, identifying cooperative binding with ASCL1; single lab but multiple orthogonal genomic methods\",\n      \"pmids\": [\"31782890\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"TNF-α inhibits TTF-1 protein levels in lung epithelial cells by inhibiting TTF-1 gene transcription; TNF-α suppresses TTF-1 DNA binding to its own promoter and inhibits transcriptional activities of Sp1 and TTF-1 without altering their levels, associated with increased threonine phosphorylation of Sp1. Functional ZBP-89, Sp1/Sp3, and TTF-1 binding sites were identified in the TTF-1 proximal promoter by EMSA, ChIP, and mutational analysis.\",\n      \"method\": \"Deletion analysis of TTF-1 5'-flanking DNA, EMSA, ChIP, mutational analysis, TNF-α treatment, TTF-1 promoter-luciferase reporter assay in H441 and primary alveolar type II cells\",\n      \"journal\": \"American journal of physiology. Lung cellular and molecular physiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — multiple methods (EMSA, ChIP, mutagenesis, reporter assay) identifying promoter elements and cytokine regulation; single lab\",\n      \"pmids\": [\"21784970\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"The TTF-1 binding element (TBE) at -171 bp in the hSP-A2 promoter is critical for lung cell-specific, developmental, and hormonal regulation: transgenic mice with TBE mutation showed essentially undetectable fetal lung expression of the hSP-A2 reporter and loss of hormonal (cAMP, IL-1, dexamethasone) regulation, whereas 313-bp wild-type constructs were developmentally regulated and hormonally responsive.\",\n      \"method\": \"Transgenic mouse reporter assay, site-directed mutagenesis of TBE, lung explant culture with hormonal treatments\",\n      \"journal\": \"American journal of physiology. Lung cellular and molecular physiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vivo transgenic validation with site-directed mutagenesis demonstrating necessity of TTF-1 binding element for developmental and hormonal regulation\",\n      \"pmids\": [\"18487360\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"mTOR inhibition promotes TTF-1-dependent redifferentiation of thyroid carcinoma cells: in TTF-1-expressing cell lines, mTOR inhibition upregulates TTF-1 expression and subsequently induces NIS expression and iodine uptake. siRNA knockdown of TTF-1 completely abolishes NIS induction by mTOR inhibition, placing TTF-1 downstream of mTOR and upstream of NIS in this pathway.\",\n      \"method\": \"mTOR inhibitor treatment, siRNA knockdown of TTF-1, mRNA/protein expression analysis, radioactive iodine uptake assay\",\n      \"journal\": \"The Journal of clinical endocrinology and metabolism\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — epistasis established by siRNA rescue experiment with functional iodine uptake readout; single lab, two orthogonal methods\",\n      \"pmids\": [\"24712572\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"TTF-1 transcriptionally activates the α5 nicotinic acetylcholine receptor (nAChR) subunit gene in lung epithelial cells by binding specific TTF-1 response elements in the α5 promoter, as confirmed by site-directed mutagenesis of those elements.\",\n      \"method\": \"Luciferase reporter assay with α5 promoter constructs, exogenous TTF-1 overexpression, site-directed mutagenesis of TTF-1 response elements\",\n      \"journal\": \"Respiratory research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — mutagenesis of binding elements with reporter assay; single lab, two methods\",\n      \"pmids\": [\"21143907\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"TTF-1, together with FoxA2 and Gata-6, activates transcription from the Claudin-6 (Cldn6) promoter in proximal and distal lung epithelial cell lines; Cldn6 expression in the developing lung co-localizes with TTF-1 and FoxA2 protein.\",\n      \"method\": \"Luciferase reporter assay with 0.5, 1.0, and 2.0-kb Cldn6 promoter constructs, co-transfection with TTF-1/FoxA2/Gata-6 expression vectors, immunofluorescence co-localization\",\n      \"journal\": \"Respiratory research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — reporter assay with multiple promoter lengths and transcription factors; co-localization supports in vivo relevance; single lab\",\n      \"pmids\": [\"24970044\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"TTF-1 and PAX8 cooperate synergistically to activate thyroid-specific gene promoters (thyroglobulin, thyroperoxidase, and NIS regulatory regions) in hepatoma cells; low transcriptional activation occurs with either factor alone, but strong activation requires both together. This functional protein-protein cooperation was imaged in vivo in nude mice.\",\n      \"method\": \"Luciferase reporter assay with thyroid-specific promoter/enhancer constructs, stable transfection of hepatoma cells, in vivo bioluminescence imaging\",\n      \"journal\": \"Journal of nuclear medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional reporter assay demonstrating synergy with in vivo imaging; single lab\",\n      \"pmids\": [\"15872358\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"Overexpression of TTF-1 together with PAX-8 restores thyroglobulin (Tg) gene promoter activity in TTF-1/PAX-8-deficient thyroid carcinoma cell lines (ARO, WRO); neither factor alone is sufficient, and activity is restricted to thyroid-lineage cells.\",\n      \"method\": \"Tg promoter-β-galactosidase reporter co-transfection with TTF-1 and PAX-8 expression vectors, RT-PCR\",\n      \"journal\": \"Surgery\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — functional reporter rescue experiment; single lab, single assay type\",\n      \"pmids\": [\"9854590\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"In thyroid carcinoma cell lines, stable transfection of TTF-1 reciprocally induces PAX-8 expression. Induction of TTF-1 affects cell proliferation, migration, and tumorigenicity more than PAX-8, with anti-proliferative and anti-tumorigenic effects observed up to a threshold expression level.\",\n      \"method\": \"Stable transfection with TTF-1 and PAX-8 expression vectors, cell growth assay, cell cycle analysis, migration assay, in vivo tumorigenicity (xenograft)\",\n      \"journal\": \"International journal of oncology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — stable overexpression with multiple functional readouts including in vivo; single lab\",\n      \"pmids\": [\"27573549\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1994,\n      \"finding\": \"TTF-1 and PAX-8 activate transcription from thyroglobulin and thyroperoxidase (TPO) promoters in thyroid follicular cells. TTF-1 mRNA is consistently detectable in papillary thyroid carcinomas but absent in anaplastic carcinomas, suggesting TTF-1 expression is linked to the differentiated thyroid phenotype. Expression of TTF-1 and PAX-8 alone is not sufficient to drive the differentiated thyroid phenotype.\",\n      \"method\": \"mRNA quantification (Northern/RT-PCR), immunohistochemistry, functional promoter assays referenced as prior work\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — mechanistic claims about promoter activation are referenced rather than newly demonstrated; primarily expression correlation in this paper\",\n      \"pmids\": [\"8062273\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Iodinated thyroglobulin regulates TTF-1 (and PAX8) expression in thyroid follicular cells through TSH/TSHR-mediated signaling: lowly iodinated TG activates cAMP-PKA to upregulate TTF-1, while highly iodinated TG activates PLC-PKC to suppress TTF-1. Blocking PKC pathway reverses highly-iodinated TG-mediated TTF-1 suppression.\",\n      \"method\": \"In vitro thyroid follicle model, PKA/PKC agonist and inhibitor treatments, protein/mRNA expression analysis\",\n      \"journal\": \"Journal of cellular biochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — pharmacological pathway dissection with multiple agents in a relevant follicular model; single lab\",\n      \"pmids\": [\"28322461\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"TTF-1 (NKX2-1) is a homeodomain transcription factor that directly activates lung-specific genes (surfactant proteins SP-A, SP-B, SP-C; claudin-6; α5 nAChR) and thyroid-specific genes (thyroglobulin, TPO, NIS) through defined promoter binding elements; its transcriptional activity is modulated by coactivators TAZ, CBP/p300, SRC-1, and PARP-1/2 via physical interactions, and by PKA-mediated phosphorylation and acetylation; it cooperates synergistically with PAX8 at thyroid gene promoters; it drives a lineage-survival transcriptional program in lung adenocarcinoma and, in SCLC, is regulated by BRN2 and cooperates with ASCL1 at neuroendocrine gene loci; in the hypothalamus, conditional neuronal deletion impairs female reproductive maturation by altering expression of LHRH, erbB-2, and preproenkephalin; and one downstream target, MYBPH, mediates TTF-1's suppression of cell motility and metastasis by directly inhibiting ROCK1.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"TTF-1 (NKX2-1) is a homeodomain transcription factor that establishes and maintains lineage-specific gene programs in lung epithelium, thyroid follicular cells, and hypothalamic neurons by binding defined promoter/enhancer elements in target genes [#14, #21, #6]. In the lung it directly drives surfactant and epithelial differentiation genes\\u2014activating SP-A, SP-B, and SP-C promoters, the \\u03b15 nicotinic acetylcholine receptor subunit, and (with FoxA2 and Gata-6) Claudin-6\\u2014with a TTF-1 binding element being necessary for cell-specific, developmental, and hormonal regulation of surfactant gene expression in vivo [#14, #2, #16, #17], and is required for branching morphogenesis of the developing airway [#3]. Its transcriptional output is tuned through physical interactions with coactivators TAZ, CBP/p300, SRC-1, and PARP-1/2, and through PKA-mediated phosphorylation and subsequent acetylation that enhance its DNA binding [#0, #1, #2]. In thyroid cells TTF-1 cooperates synergistically with PAX8 to activate thyroglobulin, thyroperoxidase, and NIS, an interaction whose loss in disease-associated mutants abolishes activation [#18, #10, #15]. TTF-1 functions in cancer as a lineage dependency: TTF-1-expressing lung adenocarcinoma lines require it for survival [#8], while in small cell lung cancer its expression is driven by BRN2 and it cooperates with ASCL1 at neuroendocrine and Bcl-2 family loci to support an antiapoptotic neuroendocrine program [#11, #12]. It also suppresses tumor cell motility and metastasis by transactivating MYBPH, which directly binds and inhibits ROCK1 [#9]. Conditional neuronal deletion in mice impairs female reproductive maturation, reflecting TTF-1 control of hypothalamic pro-reproductive genes including LHRH, erbB-2, and preproenkephalin [#7, #6]. A human TTF-1/NKX2-1 missense mutation underlies brain-lung-thyroid syndrome through loss of transactivation capacity [#10].\",\n  \"teleology\": [\n    {\n      \"year\": 1994,\n      \"claim\": \"Established that TTF-1, alongside PAX-8, is associated with the differentiated thyroid phenotype and activation of thyroid-specific promoters, framing it as a thyroid lineage factor.\",\n      \"evidence\": \"mRNA quantification, immunohistochemistry, and referenced promoter assays in thyroid carcinomas\",\n      \"pmids\": [\"8062273\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Promoter activation claims referenced rather than newly demonstrated here\", \"TTF-1+PAX-8 alone insufficient to drive full differentiated phenotype\", \"no direct binding data in this study\"]\n    },\n    {\n      \"year\": 1995,\n      \"claim\": \"Loss-of-function showed TTF-1 is required for lung airway morphogenesis and for thyroid cell proliferation, establishing it as a developmental driver in both lineages.\",\n      \"evidence\": \"Antisense oligonucleotide suppression in mouse lung explants and in FRTL-5 thyroid cells with proliferation readouts\",\n      \"pmids\": [\"8612983\", \"7559458\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Antisense specificity limited to single lab\", \"direct transcriptional targets mediating morphogenesis not defined\", \"thyroid proliferation effect placed in cAMP/PKA pathway but downstream targets unresolved\"]\n    },\n    {\n      \"year\": 1998,\n      \"claim\": \"Demonstrated that TTF-1 and PAX-8 are jointly required, neither alone sufficient, to restore thyroglobulin promoter activity in deficient thyroid carcinoma cells, defining a cooperative thyroid program.\",\n      \"evidence\": \"Tg promoter reporter rescue by co-transfection in ARO/WRO cells with RT-PCR\",\n      \"pmids\": [\"9854590\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single assay type\", \"physical basis of cooperation not addressed\", \"lineage restriction mechanism unexplained\"]\n    },\n    {\n      \"year\": 2001,\n      \"claim\": \"Identified post-translational and coactivator control of TTF-1, showing PKA phosphorylation promotes CBP/SRC-1 interaction and acetylation to enhance DNA binding, and that hypothalamic TTF-1 transactivates reproductive promoters.\",\n      \"evidence\": \"Pull-down, immunodepletion, reporter assays with PKA/E1A manipulation (SP-A); in situ hybridization and promoter transactivation (hypothalamus)\",\n      \"pmids\": [\"11713256\", \"11161473\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Acetyltransferase responsible not pinned to a single enzyme\", \"phosphosite mapping incomplete\", \"in vivo relevance of hypothalamic targets not yet genetically tested\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Expanded the TTF-1 coactivator repertoire and target range, showing TAZ binds its N-terminus to synergize on SP-C and that TTF-1 regulates the RET promoter at HSCR-associated variants.\",\n      \"evidence\": \"Mammalian two-hybrid, GST pull-down, deletion mapping, SP-C reporter (TAZ); RET promoter reporters with patient mutation and IHC co-expression\",\n      \"pmids\": [\"14970209\", \"15548547\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"TAZ interaction validated in reporter context only\", \"RET regulation in enteric development not shown in vivo\", \"Gly322Ser mechanism limited to reporter readout\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Confirmed PARP-1/2 as physical partners enhancing SP-B activation, and a neuron-specific genetic knockout established TTF-1's causal role in female reproductive maturation.\",\n      \"evidence\": \"Endogenous co-IP with MS and domain mapping (PARP-2); conditional Cre-lox Ttf1 deletion with hormonal/behavioral phenotyping plus primate expression profiling\",\n      \"pmids\": [\"16461352\", \"17182767\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"PARP enzymatic vs scaffolding contribution to SP-B activation unresolved\", \"specific hypothalamic target gene driving phenotype not isolated genetically\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Defined TTF-1 as a lineage-survival dependency in lung adenocarcinoma, since RNAi knockdown selectively killed TTF-1-expressing tumor lines.\",\n      \"evidence\": \"RNAi knockdown, viability/apoptosis assays, FISH in patient samples\",\n      \"pmids\": [\"17616654\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Downstream survival effectors not identified here\", \"single-lab cell line panel\", \"mechanism of selective dependency unexplained\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Transgenic mutagenesis proved the TTF-1 binding element is necessary in vivo for developmental and hormonal regulation of a surfactant gene, moving beyond cell-culture correlation.\",\n      \"evidence\": \"Transgenic mouse reporter with site-directed TBE mutation and hormonal lung explant treatments\",\n      \"pmids\": [\"18487360\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Single target promoter tested\", \"coactivators required in vivo not defined\", \"developmental timing mechanism not dissected\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Linked TTF-1/NKX2-1 missense mutations to brain-lung-thyroid syndrome and showed PAX8 can rescue some but not all mutant deficits, mechanistically connecting the TTF-1\\u2013PAX8 interaction to disease.\",\n      \"evidence\": \"Transactivation reporter assays with PAX8 co-transfection and patient mutation analysis\",\n      \"pmids\": [\"19336474\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Structural basis of differential PAX8 rescue unresolved\", \"lung/brain phenotype correlation not assayed at promoter level\", \"single lab\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Resolved a metastasis-suppressive mechanism and a cytokine control loop: TTF-1 activates MYBPH which inhibits ROCK1, and TNF-\\u03b1 suppresses TTF-1 transcription at its own promoter.\",\n      \"evidence\": \"ChIP, reporter, reciprocal co-IP and kinase assays with migration/metastasis models (MYBPH-ROCK1); EMSA, ChIP, mutagenesis, reporter with TNF-\\u03b1 treatment (promoter regulation)\",\n      \"pmids\": [\"22085929\", \"21784970\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether MYBPH axis operates across all TTF-1 tumor contexts unknown\", \"TNF-\\u03b1 effect on Sp1 phosphorylation mechanism partial\", \"in vivo metastasis suppression generalization untested\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Defined the upstream driver of TTF-1 in small cell lung cancer, showing BRN2 binds and activates the TTF-1 isoform 2 promoter as a context-specific regulatory input.\",\n      \"evidence\": \"Reporter assays, siRNA knockdown, ChIP, bisulfite sequencing, IHC in SCLC\",\n      \"pmids\": [\"23358112\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Why SCLC uses BRN2-driven isoform 2 specifically unresolved\", \"functional consequence of BRN2-driven TTF-1 for SCLC biology not fully tested here\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Showed context-dependent TTF-1 target reprogramming and pathway placement: it cooperates with FoxA2/Gata-6 on Claudin-6, and lies downstream of mTOR and upstream of NIS in thyroid redifferentiation.\",\n      \"evidence\": \"Reporter assays and co-localization (Cldn6); mTOR inhibitor treatment with TTF-1 siRNA rescue and iodine uptake (NIS)\",\n      \"pmids\": [\"24970044\", \"24712572\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct vs indirect mTOR-to-TTF-1 link not defined\", \"Cldn6 combinatorial logic in vivo not tested\", \"single-lab assays\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Genome-wide mapping revealed TTF-1's cistrome is rewired between tumor lineages, with SCLC-specific E-box sites and cooperative co-occupancy with ASCL1 driving an antiapoptotic neuroendocrine program.\",\n      \"evidence\": \"ChIP-seq, RNA-seq, and co-occupancy analysis comparing SCLC and adenocarcinoma lines\",\n      \"pmids\": [\"31782890\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism setting lineage-specific binding (chromatin state) not defined\", \"ASCL1-TTF-1 physical interaction not directly shown\", \"Bcl-2 regulation directness untested\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Showed reciprocal and signal-dependent regulation of TTF-1 levels: TTF-1 induces PAX-8 and has anti-tumorigenic effects up to a threshold, and iodinated thyroglobulin tunes TTF-1 via opposing PKA/PKC signaling.\",\n      \"evidence\": \"Stable transfection with functional/xenograft readouts (PAX-8); follicle model with PKA/PKC agonist-inhibitor dissection (iodinated TG)\",\n      \"pmids\": [\"27573549\", \"28322461\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Threshold mechanism for anti-tumorigenic switch unexplained\", \"PKC-mediated suppression effector not identified\", \"single-lab models\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How TTF-1's cistrome is selectively reprogrammed across lung adenocarcinoma, SCLC, thyroid, and hypothalamic contexts\\u2014and which chromatin or partner inputs dictate target choice\\u2014remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unified model linking partner availability to lineage-specific binding\", \"physical interaction with ASCL1 not directly demonstrated\", \"in vivo coactivator requirements largely untested\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [0, 1, 2, 6, 9, 14, 16, 17, 18]},\n      {\"term_id\": \"GO:0003677\", \"supporting_discovery_ids\": [1, 13, 14, 16]},\n      {\"term_id\": \"GO:0003700\", \"supporting_discovery_ids\": [14, 18]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [1, 6, 13]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [14, 18, 9, 12]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [3, 7]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [10, 5]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"PAX8\", \"TAZ\", \"CBP\", \"SRC-1\", \"PARP-2\", \"PARP-1\", \"ASCL1\", \"BRN2\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":8,"faith_total":8,"faith_pct":100.0}}