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Gene Review

Nkx2-1  -  NK2 homeobox 1

Rattus norvegicus

Synonyms: Homeobox protein Nkx-2.1, Nkx-2.1, TTF-1, TTF1, Thyroid nuclear factor 1, ...
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Disease relevance of Titf1


Psychiatry related information on Titf1


High impact information on Titf1

  • A rat thyroglobulin promoter fragment, capable of directing thyroid-specific transcription, binds at least three different factors, TTF-1, TTF-2 and UFA, which are all present in nuclear extracts of the differentiated rat thyroid cell line FRTL-5 [6].
  • TTF-1 and TTF-2 are FRTL-5 specific, as demonstrated by their absence in nuclear extracts prepared from cell lines that do not express any thyroid-differentiated function, while UFA is present in all cell lines tested [6].
  • Major histocompatibility complex class I gene expression, which also is regulated by TTF-1 and Pax-8 in the thyroid, is decreased simultaneously [7].
  • Pendrin is a novel in vivo downstream target gene of the TTF-1/Nkx-2.1 homeodomain transcription factor in differentiated thyroid cells [8].
  • TG mediates the repression of TTF-1 gene expression by decreasing NFI RNA and protein levels, as well as by altering the binding activity of NFI, which is redox controlled [9].

Biological context of Titf1


Anatomical context of Titf1

  • RNase protection assays showed that TTF-1 and PACAP mRNAs have daily fluctuations in the rat hypothalamus [1].
  • We recently found that TTF-1, a homeodomain-containing transcription factor essential for the development of the fetal diencephalon, is postnatally expressed in the hypothalamic area and plays a transcription regulatory role for certain neurohormones [1].
  • In the lung, TTF-1 mRNA and protein are also present at the earliest stages of differentiation and are later confined to the bronchial epithelium [12].
  • In the brain, TTF-1 appears to be restricted to structures of diencephalic origin, including the developing neurohypophysis [12].
  • We now report that the subfornical organ, an important site of angiotensinogen synthesis, is an extra-hypothalamic site of TTF-1 expression [5].

Associations of Titf1 with chemical compounds


Physical interactions of Titf1

  • TTF-1 binding to the proximal region overlaps with that for a novel protein present in FRTL-5 cells which can also recognize the promoter-proximal region of Tg [18].
  • The TTF-1 homeodomain binds to six of the seven putative binding domains observed in the 5'-flanking region of the PACAP gene [1].

Enzymatic interactions of Titf1

  • Transfection of chimeric TSHR-CAT plasmids with the down- and/or up-stream TTF-1 site deleted reveals that the down-stream TTF-1 element functions in the absence of the up-stream element, but function of the up-stream site requires the down-stream TTF-1 element [2].
  • Indeed, ERK directly phosphorylates TTF-1 at three serine residues, and concomitant mutation of these serines to alanines completely abolishes ERK-mediated phosphorylation both in vitro and in vivo [19].

Regulatory relationships of Titf1

  • As one possibility, this suggested there might be a hitherto unrecognized suppressor of TTF-1 RNA levels and TSH-induced Tg synthesis in individual follicles [15].
  • HNF-3 and TTF-1 transcription factors are known to stimulate SP-B transcription [20].

Other interactions of Titf1

  • Regulation of pituitary adenylate cyclase-activating polypeptide gene transcription by TTF-1, a homeodomain-containing transcription factor [1].
  • Protein-DNA binding studies did not reveal any effect of insulin/IGF-I on the ubiquitous transcription factor and the TTF-1 binding capacity [21].
  • Expressions of TTF-1 messenger RNA and protein, which were assessed by Northern blot and Western blot analyses, respectively, were decreased by TNF-alpha treatment of FRTL-5 cells [14].
  • Increased lung distension (due to CDH+TO) reduced expression of SP mRNAs and pro-SP-C and TTF-1 proteins and enhanced expression of RTI(40) (mRNA and protein; P < 0.05 for all) [22].
  • We also investigated gene expression of the transcription factors PCNA, TTF-1, HNF3beta , GATA-6, C/EBPalpha and C/EBPdelta which drive, at least in part, development and differentiation of alveolar epithelium [23].

Analytical, diagnostic and therapeutic context of Titf1


  1. Regulation of pituitary adenylate cyclase-activating polypeptide gene transcription by TTF-1, a homeodomain-containing transcription factor. Kim, M.S., Hur, M.K., Son, Y.J., Park, J.I., Chun, S.Y., D'Elia, A.V., Damante, G., Cho, S., Kim, K., Lee, B.J. J. Biol. Chem. (2002) [Pubmed]
  2. Characterization of an up-stream thyroid transcription factor-1-binding site in the thyrotropin receptor promoter. Ohmori, M., Shimura, H., Shimura, Y., Ikuyama, S., Kohn, L.D. Endocrinology (1995) [Pubmed]
  3. Patterning of the "distal esophagus" in esophageal atresia with tracheo-esophageal fistula: is thyroid transcription factor 1 a player? Crisera, C.A., Maldonado, T.S., Kadison, A.S., Li, M., Longaker, M.T., Gittes, G.K. J. Surg. Res. (2000) [Pubmed]
  4. Expression of the lung-specific thyroid transcription factor (TTF-1) within the tracheoesophageal fistula of embryo rats exposed to Adriamycin. Theodoropoulos, D.S., Ledford, D.K., Lockey, R.F. J. Pediatr. Surg. (2000) [Pubmed]
  5. TTF-1, a homeodomain-containing transcription factor, participates in the control of body fluid homeostasis by regulating angiotensinogen gene transcription in the rat subfornical organ. Son, Y.J., Hur, M.K., Ryu, B.J., Park, S.K., Damante, G., D'Elia, A.V., Costa, M.E., Ojeda, S.R., Lee, B.J. J. Biol. Chem. (2003) [Pubmed]
  6. A thyroid-specific nuclear protein essential for tissue-specific expression of the thyroglobulin promoter. Civitareale, D., Lonigro, R., Sinclair, A.J., Di Lauro, R. EMBO J. (1989) [Pubmed]
  7. Autoregulation of thyroid-specific gene transcription by thyroglobulin. Suzuki, K., Lavaroni, S., Mori, A., Ohta, M., Saito, J., Pietrarelli, M., Singer, D.S., Kimura, S., Katoh, R., Kawaoi, A., Kohn, L.D. Proc. Natl. Acad. Sci. U.S.A. (1998) [Pubmed]
  8. Pendrin is a novel in vivo downstream target gene of the TTF-1/Nkx-2.1 homeodomain transcription factor in differentiated thyroid cells. Dentice, M., Luongo, C., Elefante, A., Ambrosio, R., Salzano, S., Zannini, M., Nitsch, R., Di Lauro, R., Rossi, G., Fenzi, G., Salvatore, D. Mol. Cell. Biol. (2005) [Pubmed]
  9. Thyroglobulin repression of thyroid transcription factor 1 (TTF-1) gene expression is mediated by decreased DNA binding of nuclear factor I proteins which control constitutive TTF-1 expression. Nakazato, M., Chung, H.K., Ulianich, L., Grassadonia, A., Suzuki, K., Kohn, L.D. Mol. Cell. Biol. (2000) [Pubmed]
  10. Structure of the rat thyroid transcription factor-1 (TTF-1) gene. Endo, T., Ohta, K., Saito, T., Haraguchi, K., Nakazato, M., Kogai, T., Onaya, T. Biochem. Biophys. Res. Commun. (1994) [Pubmed]
  11. Thyroid-specific expression and cyclic adenosine 3',5'-monophosphate autoregulation of the thyrotropin receptor gene involves thyroid transcription factor-1. Shimura, H., Okajima, F., Ikuyama, S., Shimura, Y., Kimura, S., Saji, M., Kohn, L.D. Mol. Endocrinol. (1994) [Pubmed]
  12. The transcription factor TTF-1 is expressed at the onset of thyroid and lung morphogenesis and in restricted regions of the foetal brain. Lazzaro, D., Price, M., de Felice, M., Di Lauro, R. Development (1991) [Pubmed]
  13. Bacterial lipopolysaccharide stimulates the thyrotropin-dependent thyroglobulin gene expression at the transcriptional level by involving the transcription factors thyroid transcription factor-1 and paired box domain transcription factor 8. Vélez, M.L., Costamagna, E., Kimura, E.T., Fozzatti, L., Pellizas, C.G., Montesinos, M.M., Lucero, A.M., Coleoni, A.H., Santisteban, P., Masini-Repiso, A.M. Endocrinology (2006) [Pubmed]
  14. Tumor necrosis factor-alpha regulation of thyroid transcription factor-1 and Pax-8 in rat thyroid FRTL-5 cells. Ohmori, M., Harii, N., Endo, T., Onaya, T. Endocrinology (1999) [Pubmed]
  15. In vivo expression of thyroid transcription factor-1 RNA and its relation to thyroid function and follicular heterogeneity: identification of follicular thyroglobulin as a feedback suppressor of thyroid transcription factor-1 RNA levels and thyroglobulin synthesis. Suzuki, K., Mori, A., Lavaroni, S., Miyagi, E., Ulianich, L., Katoh, R., Kawaoi, A., Kohn, L.D. Thyroid (1999) [Pubmed]
  16. Thyroid-specific gene expression is differentially influenced by intracellular glutathione level in FRTL-5 cells. Lonigro, R., Donnini, D., Fabbro, D., Perrella, G., Damante, G., Ambesi Impiombato, F.S., Curcio, F. Endocrinology (2000) [Pubmed]
  17. Transfection of TTF-1 gene induces thyroglobulin gene expression in undifferentiated FRT cells. Mascia, A., De Felice, M., Lipardi, C., Gentile, R., Calì, G., Zannini, M., Di Lauro, R., Nitsch, L. Biochim. Biophys. Acta (1997) [Pubmed]
  18. Cell-type-specific expression of the rat thyroperoxidase promoter indicates common mechanisms for thyroid-specific gene expression. Francis-Lang, H., Price, M., Polycarpou-Schwarz, M., Di Lauro, R. Mol. Cell. Biol. (1992) [Pubmed]
  19. Multiple ras downstream pathways mediate functional repression of the homeobox gene product TTF-1. Missero, C., Pirro, M.T., Di Lauro, R. Mol. Cell. Biol. (2000) [Pubmed]
  20. Activation of surfactant protein-B transcription: signaling through the SP-A receptor utilizing the PI3 kinase pathway. Strayer, D.S., Korutla, L. J. Cell. Physiol. (2000) [Pubmed]
  21. Insulin and insulin-like growth factor I regulate a thyroid-specific nuclear protein that binds to the thyroglobulin promoter. Santisteban, P., Acebrón, A., Polycarpou-Schwarz, M., Di Lauro, R. Mol. Endocrinol. (1992) [Pubmed]
  22. Congenital diaphragmatic hernia, tracheal occlusion, thyroid transcription factor-1, and fetal pulmonary epithelial maturation. Chapin, C.J., Ertsey, R., Yoshizawa, J., Hara, A., Sbragia, L., Greer, J.J., Kitterman, J.A. Am. J. Physiol. Lung Cell Mol. Physiol. (2005) [Pubmed]
  23. Primary rat alveolar epithelial cells for use in biotransformation and toxicity studies. Hansen, T., Blickwede, M., Borlak, J. Toxicology in vitro : an international journal published in association with BIBRA. (2006) [Pubmed]
  24. Thyroid-stimulating hormone-induced down-regulation of thyroid transcription factor 1 in rat thyroid FRTL-5 cells. Saito, T., Endo, T., Nakazato, M., Kogai, T., Onaya, T. Endocrinology (1997) [Pubmed]
  25. Analysis of the conformation and stability of rat TTF-1 homeodomain by circular dichroism. Damante, G., Tell, G., Leonardi, A., Fogolari, F., Bortolotti, N., Di Lauro, R., Formisano, S. FEBS Lett. (1994) [Pubmed]
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