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Gene Review

NKX2-1  -  NK2 homeobox 1

Homo sapiens

Synonyms: BCH, BHC, Homeobox protein NK-2 homolog A, Homeobox protein Nkx-2.1, NK-2, ...
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Disease relevance of TITF1

  • Mutations in PAX8, TITF1, or FOXE1 may account for congenital hypothyroidism in patients with either isolated TD or TD with associated malformations involving kidney, lung, forebrain, and palate [1].
  • UGRP1 is a downstream target gene for homeodomain transcription factor T/EBP/NKX2.1, which is predominantly expressed in lung epithelial cells, and may play an anti-inflammatory role in lung inflammation [2].
  • Variable expression of keratins and nearly uniform lack of thyroid transcription factor 1 in thyroid anaplastic carcinoma [3].
  • RESULTS: TSHR, TTF-1 and TRbeta1 levels were significantly lower in oncocytic tumours than in papillary carcinomas, as a result of specific biological changes in oncocytic tumours [4].
  • Since a positive immunostaining for TTF-1 in cystic lesions of the neck was not only found in metastases of PTC, but also in non-malignant branchiogenic cysts, additional investigations, e.g. an immunostaining for TG, should be added in difficult cases [5].
  • These findings strongly suggest that in addition to the development and maintenance of TRU lineages in normal lung, sustained TTF-1 expression may be crucial for the survival of a subset of adenocarcinomas that express TTF-1, providing credence for the lineage-specific dependency model [6].
  • This is the first reported case of a heterozygous TITF1/NKX2.1 mutation leading to neonatal death from respiratory failure [7].

Psychiatry related information on TITF1


High impact information on TITF1

  • Deletion of thyroid transcription factor-1 gene in an infant with neonatal thyroid dysfunction and respiratory failure [10].
  • The first of these hypotheses is apparently supported by the fact the nonmetabolized amino acids, especially the L-leucine analogue b(-)2-amino-bicyclo[2,2,1]heptane-2-carbocyclic acid (BCH), stimulate insulin release [11].
  • A clone of hybrid myelomas (NK2), secreting a mouse monoclonal antibody to human leukocyte interferon, has been isolated [12].
  • Here, we report that t(2;3)(q13;p25), a translocation identified in a subset of human thyroid follicular carcinomas, results in fusion of the DNA binding domains of the thyroid transcription factor PAX8 to domains A to F of the peroxisome proliferator-activated receptor (PPAR) gamma1 [13].
  • We present data confirming that the NK1 specificity depended on Lys80 (and not on Asn77); however recognition of NK2 ligands by NK cells was also controlled by the amino acid at position 80 (Asn), and mutation of Ser77 had no effect [14].

Chemical compound and disease context of TITF1


Biological context of TITF1

  • The transcription factor thyroid transcription factor-1 (TTF-1) is a homeodomain-containing protein that belongs to the NK2 family of genes involved in organogenesis [20].
  • A -199-bp promoter construct showed the greatest suppression by IFN gamma whereas a -177-bp construct, in which the TTF-1 binding site was deleted, showed less suppressibility [21].
  • The synergistic activity of thyroid transcription factor 1 and Pax 8 relies on the promoter/enhancer interplay [22].
  • Our results describe the first dominant negative missense mutation in a paired domain and provide evidence for a crucial role of the p300 coactivator in mediating the functional synergism between PAX8 and TTF-1 in thyroid-specific gene expression [23].
  • Conclusion: These results are concordant with the phenotype of the two sisters studied and demonstrate a differential role for TTF1 in the different tissues in which it is expressed [24].

Anatomical context of TITF1


Associations of TITF1 with chemical compounds


Physical interactions of TITF1

  • Calreticulin binds to the TTF-1 homeodomain and promotes its folding, suggesting that the mechanism involved in stimulation of transcriptional activity is an increase of the steady-state concentration of active TTF-1 protein in the cell [32].
  • We suggest that a PKA-induced increase of TTF-1 phosphorylation and TBE binding activity mediates cyclic AMP-induced expression of the SP-A gene in lung type II cells [33].
  • Hypophosphorylated TTF-1 is still able to bind its DNA consensus sequence within the thyroglobulin promoter, although a reporter construct whose expression is exclusively dependent on TTF-1 is not transactivated [34].
  • The TTF-1/TAP26 complex differentially modulates surfactant protein-B (SP-B) and -C (SP-C) promoters in lung cells [35].
  • By electromobility shift assay we demonstrated that NKX3.1 preferentially binds the TAAGTA sequence rather than the binding site for Nkx2.1 (CAAGTG) or Msx1 (TAATTG) [36].
  • 1 interacts physically and functionally with FOXA1 [37].

Regulatory relationships of TITF1


Other interactions of TITF1


Analytical, diagnostic and therapeutic context of TITF1


  1. PAX8, TITF1, and FOXE1 gene expression patterns during human development: new insights into human thyroid development and thyroid dysgenesis-associated malformations. Trueba, S.S., Augé, J., Mattei, G., Etchevers, H., Martinovic, J., Czernichow, P., Vekemans, M., Polak, M., Attié-Bitach, T. J. Clin. Endocrinol. Metab. (2005) [Pubmed]
  2. Interleukin-10 induces uteroglobin-related protein (UGRP) 1 gene expression in lung epithelial cells through homeodomain transcription factor T/EBP/NKX2.1. Srisodsai, A., Kurotani, R., Chiba, Y., Sheikh, F., Young, H.A., Donnelly, R.P., Kimura, S. J. Biol. Chem. (2004) [Pubmed]
  3. Variable expression of keratins and nearly uniform lack of thyroid transcription factor 1 in thyroid anaplastic carcinoma. Miettinen, M., Franssila, K.O. Hum. Pathol. (2000) [Pubmed]
  4. Decreased expression of thyrotropin receptor gene suggests a high-risk subgroup for oncocytic adenoma. Mirebeau-Prunier, D., Guyétant, S., Rodien, P., Franc, B., Baris, O., Rohmer, V., Reynier, P., Tourmen, Y., Malthièry, Y., Savagner, F. Eur. J. Endocrinol. (2004) [Pubmed]
  5. Thyroid transcription factor 1 expression in cystic lesions of the neck: an immunohistochemical investigation of thyroglossal duct cysts, branchial cleft cysts and metastatic papillary thyroid cancer. Kreft, A., Hansen, T., Kirkpatrick, C.J. Virchows Arch. (2005) [Pubmed]
  6. Lineage-specific dependency of lung adenocarcinomas on the lung development regulator TTF-1. Tanaka, H., Yanagisawa, K., Shinjo, K., Taguchi, A., Maeno, K., Tomida, S., Shimada, Y., Osada, H., Kosaka, T., Matsubara, H., Mitsudomi, T., Sekido, Y., Tanimoto, M., Yatabe, Y., Takahashi, T. Cancer Res. (2007) [Pubmed]
  7. Lethal respiratory failure and mild primary hypothyroidism in a term girl with a de novo heterozygous mutation in the TITF1/NKX2.1 gene. Maquet, E., Costagliola, S., Parma, J., Christophe-Hobertus, C., Oligny, L.L., Fournet, J.C., Robitaille, Y., Vuissoz, J.M., Payot, A., Laberge, S., Vassart, G., Van Vliet, G., Deladoëy, J. J. Clin. Endocrinol. Metab. (2009) [Pubmed]
  8. Brain-Thyroid-Lung syndrome: a patient with a severe multi-system disorder due to a de novo mutation in the thyroid transcription factor 1 gene. Willemsen, M.A., Breedveld, G.J., Wouda, S., Otten, B.J., Yntema, J.L., Lammens, M., de Vries, B.B. Eur. J. Pediatr. (2005) [Pubmed]
  9. TTF-1, a homeodomain-containing transcription factor, regulates feeding behavior in the rat hypothalamus. Kim, J.G., Nam-Goong, I.S., Yun, C.H., Jeong, J.K., Kim, E.S., Park, J.J., Lee, Y.C., Kim, Y.I., Lee, B.J. Biochem. Biophys. Res. Commun. (2006) [Pubmed]
  10. Deletion of thyroid transcription factor-1 gene in an infant with neonatal thyroid dysfunction and respiratory failure. Devriendt, K., Vanhole, C., Matthijs, G., de Zegher, F. N. Engl. J. Med. (1998) [Pubmed]
  11. L-leucine and a nonmetabolized analogue activate pancreatic islet glutamate dehydrogenase. Sener, A., Malaisse, W.J. Nature (1980) [Pubmed]
  12. A monoclonal antibody for large-scale purification of human leukocyte interferon. Secher, D.S., Burke, D.C. Nature (1980) [Pubmed]
  13. PAX8-PPARgamma1 fusion oncogene in human thyroid carcinoma [corrected]. Kroll, T.G., Sarraf, P., Pecciarini, L., Chen, C.J., Mueller, E., Spiegelman, B.M., Fletcher, J.A. Science (2000) [Pubmed]
  14. Protection from lysis by natural killer cells of group 1 and 2 specificity is mediated by residue 80 in human histocompatibility leukocyte antigen C alleles and also occurs with empty major histocompatibility complex molecules. Mandelboim, O., Reyburn, H.T., Valés-Gómez, M., Pazmany, L., Colonna, M., Borsellino, G., Strominger, J.L. J. Exp. Med. (1996) [Pubmed]
  15. A novel TITF-1 mutation causes benign hereditary chorea with response to levodopa. Asmus, F., Horber, V., Pohlenz, J., Schwabe, D., Zimprich, A., Munz, M., Schöning, M., Gasser, T. Neurology (2005) [Pubmed]
  16. Suppression of cyclooxygenase-2 overexpression by 15S-hydroxyeicosatrienoic acid in androgen-dependent prostatic adenocarcinoma cells. Pham, H., Banerjee, T., Ziboh, V.A. Int. J. Cancer (2004) [Pubmed]
  17. L-type amino acid transporter 1 as a potential molecular target in human astrocytic tumors. Nawashiro, H., Otani, N., Shinomiya, N., Fukui, S., Ooigawa, H., Shima, K., Matsuo, H., Kanai, Y., Endou, H. Int. J. Cancer (2006) [Pubmed]
  18. Experimental studies on insecticides commonly used in India. Nigam, S.K., Bhatt, D.K., Karnik, A.B., Thakore, K.N., Aravinda Babu, K., Lakkad, B.C., Kashyap, S.K., Chatterjee, S.K. J. Cancer Res. Clin. Oncol. (1981) [Pubmed]
  19. Toxicity and bioconcentration of BHC and lindane in selected estuarine animals. Schimmel, S.C., Patrick, J.M., Forester, J. Arch. Environ. Contam. Toxicol. (1977) [Pubmed]
  20. The DNA glycosylase T:G mismatch-specific thymine DNA glycosylase represses thyroid transcription factor-1-activated transcription. Missero, C., Pirro, M.T., Simeone, S., Pischetola, M., Di Lauro, R. J. Biol. Chem. (2001) [Pubmed]
  21. Interferon-gamma suppresses thyrotropin receptor promoter activity by reducing thyroid transcription factor-1 (TTF-1) binding to its recognition site. Ohe, K., Ikuyama, S., Takayanagi, R., Kohn, L.D., Nawata, H. Mol. Endocrinol. (1996) [Pubmed]
  22. The synergistic activity of thyroid transcription factor 1 and Pax 8 relies on the promoter/enhancer interplay. Miccadei, S., De Leo, R., Zammarchi, E., Natali, P.G., Civitareale, D. Mol. Endocrinol. (2002) [Pubmed]
  23. Thyroid transcription factor 1 rescues PAX8/p300 synergism impaired by a natural PAX8 paired domain mutation with dominant negative activity. Grasberger, H., Ringkananont, U., Lefrancois, P., Abramowicz, M., Vassart, G., Refetoff, S. Mol. Endocrinol. (2005) [Pubmed]
  24. Functional Study of a Novel Single Deletion in the TITF1/NKX2.1 Homeobox Gene That Produces Congenital Hypothyroidism and Benign Chorea But Not Pulmonary Distress. Moya, C.M., Perez de Nanclares, G., Castaño, L., Potau, N., Bilbao, J.R., Carrascosa, A., Bargadá, M., Coya, R., Martul, P., Vicens-Calvet, E., Santisteban, P. J. Clin. Endocrinol. Metab. (2006) [Pubmed]
  25. Thyroid transcription factor 1 and Pax8 synergistically activate the promoter of the human thyroglobulin gene. Espinoza, C.R., Schmitt, T.L., Loos, U. J. Mol. Endocrinol. (2001) [Pubmed]
  26. Thyroid transcription factor-1 in orbital adipose tissues: potential role in orbital thyrotropin receptor expression. Bhattacharyya, K.K., Coenen, M.J., Bahn, R.S. Thyroid (2005) [Pubmed]
  27. Retinoic acid stimulation of the human surfactant protein B promoter is thyroid transcription factor 1 site-dependent. Naltner, A., Ghaffari, M., Whitsett, J.A., Yan, C. J. Biol. Chem. (2000) [Pubmed]
  28. Thyroglobulin regulates follicular function and heterogeneity by suppressing thyroid-specific gene expression. Suzuki, K., Mori, A., Lavaroni, S., Ulianich, L., Miyagi, E., Saito, J., Nakazato, M., Pietrarelli, M., Shafran, N., Grassadonia, A., Kim, W.B., Consiglio, E., Formisano, S., Kohn, L.D. Biochimie (1999) [Pubmed]
  29. HEX, PAX-8 and TTF-1 gene expression in human thyroid tissues: a comparative analysis with other genes involved in iodide metabolism. Lacroix, L., Michiels, S., Mian, C., Arturi, F., Caillou, B., Filetti, S., Schlumberger, M., Bidart, J.M. Clin. Endocrinol. (Oxf) (2006) [Pubmed]
  30. Effects of nitrofen and vitamins A, C and E on maturation of cultured human H441 pneumocytes. Gonzalez-Reyes, S., Martinez, L., Martinez-Calonge, W., Fernandez-Dumont, V., Tovar, J.A. Biol. Neonate (2006) [Pubmed]
  31. Nonsense mutation in TITF1 in a Portuguese family with benign hereditary chorea. do Carmo Costa, M., Costa, C., Silva, A.P., Evangelista, P., Santos, L., Ferro, A., Sequeiros, J., Maciel, P. Neurogenetics (2005) [Pubmed]
  32. Calreticulin enhances the transcriptional activity of thyroid transcription factor-1 by binding to its homeodomain. Perrone, L., Tell, G., Di Lauro, R. J. Biol. Chem. (1999) [Pubmed]
  33. Cyclic AMP-responsive expression of the surfactant protein-A gene is mediated by increased DNA binding and transcriptional activity of thyroid transcription factor-1. Li, J., Gao, E., Mendelson, C.R. J. Biol. Chem. (1998) [Pubmed]
  34. Ha-ras interference with thyroid cell differentiation is associated with a down-regulation of thyroid transcription factor-1 phosphorylation. Velasco, J.A., Acebrón, A., Zannini, M., Martín-Pérez, J., Di Lauro, R., Santisteban, P. Endocrinology (1998) [Pubmed]
  35. The TTF-1/TAP26 complex differentially modulates surfactant protein-B (SP-B) and -C (SP-C) promoters in lung cells. Yang, M.C., Guo, Y., Liu, C.C., Weissler, J.C., Yang, Y.S. Biochem. Biophys. Res. Commun. (2006) [Pubmed]
  36. DNA-binding sequence of the human prostate-specific homeodomain protein NKX3.1. Steadman, D.J., Giuffrida, D., Gelmann, E.P. Nucleic Acids Res. (2000) [Pubmed]
  37. Physical and functional interactions between homeodomain NKX2.1 and winged helix/forkhead FOXA1 in lung epithelial cells. Minoo, P., Hu, L., Xing, Y., Zhu, N.L., Chen, H., Li, M., Borok, Z., Li, C. Mol. Cell. Biol. (2007) [Pubmed]
  38. Expression of ABCA3 in Developing Lung and Other Tissues. Stahlman, M.T., Besnard, V., Wert, S.E., Weaver, T.E., Dingle, S., Xu, Y., von Zychlin, K., Olson, S.J., Whitsett, J.A. J. Histochem. Cytochem. (2007) [Pubmed]
  39. Upstream enhancer activity in the human surfactant protein B gene is mediated by thyroid transcription factor 1. Yan, C., Sever, Z., Whitsett, J.A. J. Biol. Chem. (1995) [Pubmed]
  40. Follicular thyroid tumors with the PAX8-PPARgamma1 rearrangement display characteristic genetic alterations. Lacroix, L., Lazar, V., Michiels, S., Ripoche, H., Dessen, P., Talbot, M., Caillou, B., Levillain, J.P., Schlumberger, M., Bidart, J.M. Am. J. Pathol. (2005) [Pubmed]
  41. NKX2.1 regulates transcription of the gene for human bone morphogenetic protein-4 in lung epithelial cells. Zhu, N.L., Li, C., Xiao, J., Minoo, P. Gene (2004) [Pubmed]
  42. Transforming growth factor-beta inhibits pulmonary surfactant protein B gene transcription through SMAD3 interactions with NKX2.1 and HNF-3 transcription factors. Li, C., Zhu, N.L., Tan, R.C., Ballard, P.L., Derynck, R., Minoo, P. J. Biol. Chem. (2002) [Pubmed]
  43. Absence of mutations in the gene encoding thyroid transcription factor-1 (TTF-1) in patients with thyroid dysgenesis. Perna, M.G., Civitareale, D., De Filippis, V., Sacco, M., Cisternino, C., Tassi, V. Thyroid (1997) [Pubmed]
  44. Nuclear localization of thyroid transcription factor-1 correlates with serum thyrotropin activity and may be increased in differentiated thyroid carcinomas with aggressive clinical course. Fenton, C.L., Patel, A., Burch, H.B., Tuttle, R.M., Francis, G.L. Ann. Clin. Lab. Sci. (2001) [Pubmed]
  45. Expression of thyroid transcription factor-1 in 16 human lung cancer cell lines. Fujita, J., Ohtsuki, Y., Bandoh, S., Ueda, Y., Kubo, A., Tojo, Y., Yamaji, Y., Ishida, T. Lung Cancer (2003) [Pubmed]
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