NK2 homeobox 1 explained

NK2 homeobox 1 (NKX2-1), also known as thyroid transcription factor 1 (TTF-1), is a protein which in humans is encoded by the NKX2-1 gene.^{[1] [2]}

Function

Thyroid transcription factor-1 (TTF-1) is a protein that regulates transcription of genes specific for the thyroid, lung, and diencephalon. It is also known as thyroid specific enhancer binding protein. It is used in anatomic pathology as a marker to determine if a tumor arises from the lung or thyroid. NKX2.1 can be induced by activin A via SMAD2 signaling in a human embryonic stem cell differentiation model.^[3]

NKX2.1 is key to the fetal development of lung structures. The dorsal-ventral pattern of NKX2.1 expression forms the ventral boundary in the anterior foregut. NKX2.1 is expressed only in select cells in the ventral wall of the anterior foregut, and is not expressed in the dorsal wall, where the esophagus will emerge from. NKX2.1 knockout in mice results in the development of a shortened trachea which is fused to the esophagus, with the bronchi directly connecting this shared tube to the lungs. This resembles a complete tracheoesophageal fistula, which is a rare congenital condition in humans. Furthermore, distal lung structures do not develop in these knockout mice. Branching of the lungs in these mice did not occur past the main-stem bronchi, resulting in lungs that were smaller in size by about 50% compared to the wild-type mice. The epithelial lining of these distal structures did not show evidence of differentiation into specialized cells. This lining is composed of columnar epithelial cells and scattered ciliated epithelial cells.^[4] The proximal epithelium of the lungs showed normal differentiation, indicating that proximal differentiation is independent of NKX2.1. NKX2.1 is initially expressed in the entire epithelium, but is suppressed in a proximal-distal pattern as the lung continues to develop.^[5]

Clinical significance

TTF-1 positive cells are found in the lung as type II pneumocytes and club cells. In the thyroid, follicular and parafollicular cells are also positive for TTF-1.

For lung cancers, adenocarcinomas are usually positive, while squamous cell carcinomas and large cell carcinomas are rarely positive. Small cell carcinomas (of any primary site) are usually positive. TTF1 is more than merely a clinical marker of lung adenocarcinoma. It plays an active role in sustaining lung cancer cells in view of the experimental observation that it is mutated in lung cancer.^{[6] [7] [8] [9]}

It has been observed that a loss of Nkx2-1 allows for deregulation of transcription factors FOXA1/2 (by relaxing histone deacetylation and methylation-mediated repression of Foxa1/2 by Nkx2-1) causing reactivation of an embryonic gastric differentiation program in pulmonary cells. This results in mucinous lung adenocarcinoma, a source of poor clinical outcomes for patients.^[10]

However others have found that TTF-1 staining is often positive in pulmonary adenocarcinomas, large cell carcinomas, small-cell lung carcinomas, neuroendocrine tumors other than small-cell lung carcinomas and extrapulmonary small-cell carcinomas.^[11]

It is also positive in thyroid cancers and is used for monitoring for metastasis and recurrence.^[12]

Interactions

NK2 homeobox 1 has been shown to interact with calreticulin^[13] and PAX8.^[14]

Further reading

• Lau SK, Luthringer DJ, Eisen RN . Thyroid transcription factor-1: a review . Applied Immunohistochemistry & Molecular Morphology . 10 . 2 . 97–102 . June 2002 . 12051643 . 10.1097/00022744-200206000-00001 .
• Guazzi S, Price M, De Felice M, Damante G, Mattei MG, Di Lauro R . Thyroid nuclear factor 1 (TTF-1) contains a homeodomain and displays a novel DNA binding specificity . The EMBO Journal . 9 . 11 . 3631–9 . November 1990 . 1976511 . 552115 . 10.1002/j.1460-2075.1990.tb07574.x .
• Oguchi H, Pan YT, Kimura S . The complete nucleotide sequence of the mouse thyroid-specific enhancer-binding protein (T/EBP) gene: extensive identity of the deduced amino acid sequence with the human protein . Biochimica et Biophysica Acta (BBA) - Gene Structure and Expression . 1261 . 2 . 304–6 . April 1995 . 7711079 . 10.1016/0167-4781(95)00033-D .
• Saiardi A, Tassi V, De Filippis V, Civitareale D . Cloning and sequence analysis of human thyroid transcription factor 1 . Biochimica et Biophysica Acta (BBA) - Gene Structure and Expression . 1261 . 2 . 307–10 . April 1995 . 7711080 . 10.1016/0167-4781(95)00034-E .
• Ikeda K, Clark JC, Shaw-White JR, Stahlman MT, Boutell CJ, Whitsett JA . Gene structure and expression of human thyroid transcription factor-1 in respiratory epithelial cells . The Journal of Biological Chemistry . 270 . 14 . 8108–14 . April 1995 . 7713914 . 10.1074/jbc.270.44.26460 . free .
• Bonaldo MF, Lennon G, Soares MB . Normalization and subtraction: two approaches to facilitate gene discovery . Genome Research . 6 . 9 . 791–806 . September 1996 . 8889548 . 10.1101/gr.6.9.791 . free .
• Ghaffari M, Zeng X, Whitsett JA, Yan C . Nuclear localization domain of thyroid transcription factor-1 in respiratory epithelial cells . The Biochemical Journal . 328 (Pt 3) . 3 . 757–61 . December 1997 . 9396717 . 1218983 . 10.1042/bj3280757 .
• Hamdan H, Liu H, Li C, Jones C, Lee M, deLemos R, Minoo P . Structure of the human Nkx2.1 gene . Biochimica et Biophysica Acta (BBA) - Gene Structure and Expression . 1396 . 3 . 336–48 . March 1998 . 9545595 . 10.1016/S0167-4781(97)00210-8 .
• Perrone L, Tell G, Di Lauro R . Calreticulin enhances the transcriptional activity of thyroid transcription factor-1 by binding to its homeodomain . The Journal of Biological Chemistry . 274 . 8 . 4640–5 . February 1999 . 9988700 . 10.1074/jbc.274.8.4640 . free .
• Naltner A, Ghaffari M, Whitsett JA, Yan C . Retinoic acid stimulation of the human surfactant protein B promoter is thyroid transcription factor 1 site-dependent . The Journal of Biological Chemistry . 275 . 1 . 56–62 . January 2000 . 10617585 . 10.1074/jbc.275.1.56 . free .
• Missero C, Pirro MT, Di Lauro R . Multiple ras downstream pathways mediate functional repression of the homeobox gene product TTF-1 . Molecular and Cellular Biology . 20 . 8 . 2783–93 . April 2000 . 10733581 . 85494 . 10.1128/MCB.20.8.2783-2793.2000 .
• Naltner A, Wert S, Whitsett JA, Yan C . Temporal/spatial expression of nuclear receptor coactivators in the mouse lung . American Journal of Physiology. Lung Cellular and Molecular Physiology . 279 . 6 . L1066-74 . December 2000 . 11076796 . 10.1152/ajplung.2000.279.6.l1066 . 27872061 .
• Yan C, Naltner A, Conkright J, Ghaffari M . Protein-protein interaction of retinoic acid receptor alpha and thyroid transcription factor-1 in respiratory epithelial cells . The Journal of Biological Chemistry . 276 . 24 . 21686–91 . June 2001 . 11274148 . 10.1074/jbc.M011378200 . free .
• Missero C, Pirro MT, Simeone S, Pischetola M, Di Lauro R . The DNA glycosylase T:G mismatch-specific thymine DNA glycosylase represses thyroid transcription factor-1-activated transcription . The Journal of Biological Chemistry . 276 . 36 . 33569–75 . September 2001 . 11438542 . 10.1074/jbc.M104963200 . free .
• Yi M, Tong GX, Murry B, Mendelson CR . 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) . The Journal of Biological Chemistry . 277 . 4 . 2997–3005 . January 2002 . 11713256 . 10.1074/jbc.M109793200 . free .
• Liu C, Glasser SW, Wan H, Whitsett JA . GATA-6 and thyroid transcription factor-1 directly interact and regulate surfactant protein-C gene expression . The Journal of Biological Chemistry . 277 . 6 . 4519–25 . February 2002 . 11733512 . 10.1074/jbc.M107585200 . free .
• Ng WK, Chow JC, Ng PK . Thyroid transcription factor-1 is highly sensitive and specific in differentiating metastatic pulmonary from extrapulmonary adenocarcinoma in effusion fluid cytology specimens . Cancer . 96 . 1 . 43–8 . February 2002 . 11836702 . 10.1002/cncr.10310 . 23626036 . free .
• Pohlenz J, Dumitrescu A, Zundel D, Martiné U, Schönberger W, Koo E, Weiss RE, Cohen RN, Kimura S, Refetoff S . 6 . Partial deficiency of thyroid transcription factor 1 produces predominantly neurological defects in humans and mice . The Journal of Clinical Investigation . 109 . 4 . 469–73 . February 2002 . 11854318 . 150877 . 10.1172/JCI14192 .
• Krude H, Schütz B, Biebermann H, von Moers A, Schnabel D, Neitzel H, Tönnies H, Weise D, Lafferty A, Schwarz S, DeFelice M, von Deimling A, van Landeghem F, DiLauro R, Grüters A . 6 . Choreoathetosis, hypothyroidism, and pulmonary alterations due to human NKX2-1 haploinsufficiency . The Journal of Clinical Investigation . 109 . 4 . 475–80 . February 2002 . 11854319 . 150790 . 10.1172/JCI14341 .
• Miccadei S, De Leo R, Zammarchi E, Natali PG, Civitareale D . The synergistic activity of thyroid transcription factor 1 and Pax 8 relies on the promoter/enhancer interplay . Molecular Endocrinology . 16 . 4 . 837–46 . April 2002 . 11923479 . 10.1210/mend.16.4.0808 . free .

Notes and References

1. Web site: Entrez Gene: NKX2-1 .
2. Guazzi S, Price M, De Felice M, Damante G, Mattei MG, Di Lauro R . Thyroid nuclear factor 1 (TTF-1) contains a homeodomain and displays a novel DNA binding specificity . The EMBO Journal . 9 . 11 . 3631–9 . November 1990 . 1976511 . 552115 . 10.1002/j.1460-2075.1990.tb07574.x .
3. Li Y, Eggermont K, Vanslembrouck V, Verfaillie CM . NKX2-1 activation by SMAD2 signaling after definitive endoderm differentiation in human embryonic stem cell . Stem Cells and Development . 22 . 9 . 1433–42 . May 2013 . 23259454 . 3629846 . 10.1089/scd.2012.0620 .
4. Minoo P, Su G, Drum H, Bringas P, Kimura S . Defects in tracheoesophageal and lung morphogenesis in Nkx2.1(-/-) mouse embryos . Developmental Biology . 209 . 1 . 60–71 . May 1999 . 10208743 . 10.1006/dbio.1999.9234 . free .
5. Yuan B, Li C, Kimura S, Engelhardt RT, Smith BR, Minoo P . Inhibition of distal lung morphogenesis in Nkx2.1(-/-) embryos . Developmental Dynamics . 217 . 2 . 180–90 . February 2000 . 10706142 . 10.1002/(SICI)1097-0177(200002)217:2<180::AID-DVDY5>3.0.CO;2-3 . free .
6. Kendall J, Liu Q, Bakleh A, Krasnitz A, Nguyen KC, Lakshmi B, Gerald WL, Powers S, Mu D . 6 . Oncogenic cooperation and coamplification of developmental transcription factor genes in lung cancer . Proceedings of the National Academy of Sciences of the United States of America . 104 . 42 . 16663–8 . October 2007 . 17925434 . 2034240 . 10.1073/pnas.0708286104 . 2007PNAS..10416663K . free .
7. 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 . 6 . Lineage-specific dependency of lung adenocarcinomas on the lung development regulator TTF-1 . Cancer Research . 67 . 13 . 6007–11 . July 2007 . 17616654 . 10.1158/0008-5472.CAN-06-4774 . free .
8. Weir BA, Woo MS, Getz G, Perner S, Ding L, Beroukhim R, Lin WM, Province MA, Kraja A, Johnson LA, Shah K, Sato M, Thomas RK, Barletta JA, Borecki IB, Broderick S, Chang AC, Chiang DY, Chirieac LR, Cho J, Fujii Y, Gazdar AF, Giordano T, Greulich H, Hanna M, Johnson BE, Kris MG, Lash A, Lin L, Lindeman N, Mardis ER, McPherson JD, Minna JD, Morgan MB, Nadel M, Orringer MB, Osborne JR, Ozenberger B, Ramos AH, Robinson J, Roth JA, Rusch V, Sasaki H, Shepherd F, Sougnez C, Spitz MR, Tsao MS, Twomey D, Verhaak RG, Weinstock GM, Wheeler DA, Winckler W, Yoshizawa A, Yu S, Zakowski MF, Zhang Q, Beer DG, Wistuba II, Watson MA, Garraway LA, Ladanyi M, Travis WD, Pao W, Rubin MA, Gabriel SB, Gibbs RA, Varmus HE, Wilson RK, Lander ES, Meyerson M . 6 . Characterizing the cancer genome in lung adenocarcinoma . Nature . 450 . 7171 . 893–8 . December 2007 . 17982442 . 2538683 . 10.1038/nature06358 . 2007Natur.450..893W .
9. Kwei KA, Kim YH, Girard L, Kao J, Pacyna-Gengelbach M, Salari K, Lee J, Choi YL, Sato M, Wang P, Hernandez-Boussard T, Gazdar AF, Petersen I, Minna JD, Pollack JR . 6 . Genomic profiling identifies TITF1 as a lineage-specific oncogene amplified in lung cancer . Oncogene . 27 . 25 . 3635–40 . June 2008 . 18212743 . 2903002 . 10.1038/sj.onc.1211012 .
10. Snyder EL, Watanabe H, Magendantz M, Hoersch S, Chen TA, Wang DG, Crowley D, Whittaker CA, Meyerson M, Kimura S, Jacks T . 6 . Nkx2-1 represses a latent gastric differentiation program in lung adenocarcinoma . Molecular Cell . 50 . 2 . 185–99 . April 2013 . 23523371 . 3721642 . 10.1016/j.molcel.2013.02.018 .
11. Kalhor N, Zander DS, Liu J . TTF-1 and p63 for distinguishing pulmonary small-cell carcinoma from poorly differentiated squamous cell carcinoma in previously pap-stained cytologic material . Modern Pathology . 19 . 8 . 1117–23 . August 2006 . 16680154 . 10.1038/modpathol.3800629 . free .
12. Espinoza CR, Schmitt TL, Loos U . Thyroid transcription factor 1 and Pax8 synergistically activate the promoter of the human thyroglobulin gene . Journal of Molecular Endocrinology . 27 . 1 . 59–67 . August 2001 . 11463576 . 10.1677/jme.0.0270059 . free .
13. Perrone L, Tell G, Di Lauro R . Calreticulin enhances the transcriptional activity of thyroid transcription factor-1 by binding to its homeodomain . The Journal of Biological Chemistry . 274 . 8 . 4640–5 . February 1999 . 9988700 . 10.1074/jbc.274.8.4640 . free .
14. Di Palma T, Nitsch R, Mascia A, Nitsch L, Di Lauro R, Zannini M . The paired domain-containing factor Pax8 and the homeodomain-containing factor TTF-1 directly interact and synergistically activate transcription . The Journal of Biological Chemistry . 278 . 5 . 3395–402 . January 2003 . 12441357 . 10.1074/jbc.M205977200 . free .