Biology:NK2 homeobox 1

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Short description: Mammalian protein found in Homo sapiens


A representation of the 3D structure of the protein myoglobin showing turquoise α-helices.
Generic protein structure example

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 needs to have nuclear staining on immunohistochemistry to count as positive. Cytoplasmic staining is disregarded for diagnostic purposes.[6]
Micrograph of a metastatic lung adenocarcinoma (found in the brain) that exhibits nuclear staining (brown) for TTF-1.

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.[7][8][9][10]

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.[11]

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.[12]

It is also positive in thyroid cancers and is used for monitoring for metastasis and recurrence.[13]

Interactions

NK2 homeobox 1 has been shown to interact with calreticulin[14] and PAX8.[15]

References

  1. ↑ "Entrez Gene: NKX2-1". https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=7080. 
  2. ↑ "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. doi:10.1002/j.1460-2075.1990.tb07574.x. PMID 1976511. 
  3. ↑ "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. doi:10.1089/scd.2012.0620. PMID 23259454. 
  4. ↑ "Defects in tracheoesophageal and lung morphogenesis in Nkx2.1(-/-) mouse embryos". Developmental Biology 209 (1): 60–71. May 1999. doi:10.1006/dbio.1999.9234. PMID 10208743. 
  5. ↑ "Inhibition of distal lung morphogenesis in Nkx2.1(-/-) embryos". Developmental Dynamics 217 (2): 180–90. February 2000. doi:10.1002/(SICI)1097-0177(200002)217:2<180::AID-DVDY5>3.0.CO;2-3. PMID 10706142. 
  6. ↑ Image by Mikael Häggström, MD. Source for significance: Bejarano PA, Mousavi F (2003). "Incidence and significance of cytoplasmic thyroid transcription factor-1 immunoreactivity.". Arch Pathol Lab Med 127 (2): 193–5. doi:10.5858/2003-127-193-IASOCT. PMID 12562233. https://pubmed.ncbi.nlm.nih.gov/12562233. 
  7. ↑ "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. doi:10.1073/pnas.0708286104. PMID 17925434. Bibcode: 2007PNAS..10416663K. 
  8. ↑ "Lineage-specific dependency of lung adenocarcinomas on the lung development regulator TTF-1". Cancer Research 67 (13): 6007–11. July 2007. doi:10.1158/0008-5472.CAN-06-4774. PMID 17616654. 
  9. ↑ "Characterizing the cancer genome in lung adenocarcinoma". Nature 450 (7171): 893–8. December 2007. doi:10.1038/nature06358. PMID 17982442. Bibcode: 2007Natur.450..893W. 
  10. ↑ "Genomic profiling identifies TITF1 as a lineage-specific oncogene amplified in lung cancer". Oncogene 27 (25): 3635–40. June 2008. doi:10.1038/sj.onc.1211012. PMID 18212743. 
  11. ↑ "Nkx2-1 represses a latent gastric differentiation program in lung adenocarcinoma". Molecular Cell 50 (2): 185–99. April 2013. doi:10.1016/j.molcel.2013.02.018. PMID 23523371. 
  12. ↑ "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. doi:10.1038/modpathol.3800629. PMID 16680154. 
  13. ↑ "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. doi:10.1677/jme.0.0270059. PMID 11463576. 
  14. ↑ "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. doi:10.1074/jbc.274.8.4640. PMID 9988700. 
  15. ↑ "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. doi:10.1074/jbc.M205977200. PMID 12441357. 

Further reading

External links

This article incorporates text from the United States National Library of Medicine, which is in the public domain.



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