NKX2.1

Official Full Name

NK2 homeobox 1

Organism

Homo sapiens

GeneID

7080

Background

This gene encodes a protein initially identified as a thyroid-specific transcription factor. The encoded protein binds to the thyroglobulin promoter and regulates the expression of thyroid-specific genes but has also been shown to regulate the expression of genes involved in morphogenesis. Mutations and deletions in this gene are associated with benign hereditary chorea, choreoathetosis, congenital hypothyroidism, and neonatal respiratory distress, and may be associated with thyroid cancer. Multiple transcript variants encoding different isoforms have been found for this gene. This gene shares the symbol/alias 'TTF1' with another gene, transcription termination factor 1, which plays a role in ribosomal gene transcription. [provided by RefSeq, Feb 2014]

Synonyms

NKX2-1; BCH; BHC; NK-2; TEBP; TTF1; NKX2A; NMTC1; T/EBP; TITF1; TTF-1; NKX2.1;

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Detailed Information

Thyroid transcription factor-1 (TITF-1), also known as the thyroid gland-specific enhancer-binding protein (NKx2.1), is one of the homologous transcription factors in the NKx2 gene family. Its expression and absence are closely related to many human diseases. The gene was first discovered as a thyroid-specific DNA functional structure that interacts with rat thyroglobulin and is therefore named the thyroid transcription factor. The human gene, located at 14q13, encodes a nuclear protein with a relative molecular mass of 38 000 and is often expressed in thyroid, lung and forebrain epithelial cells during embryonic development and differentiation.

NKx2.1 and Congenital Hypothyroidism

Congenital hypothyroidism is a common neonatal endocrine metabolic disease. When the NKx2.1 gene was directly sequenced in three patients, it was found that a base mutation from C→A (C609A) occurred on the second base of amino acid 145. This mutation causes a change in the serine to the stop codon (S145X), and the mutant protein accumulates in the cytoplasm and cannot be transferred to the nucleus.

The study mapped a chromosomal region and confirmed that this region is associated with the specificity of cell lines of congenital hypothyroidism in NKx2.1 and PAX8 nonsense heterozygous mice. These two cell lines, which exhibit different susceptibility to congenital hypothyroidism, contain several SNPs in this region, one of which results in a non-synonymous amino acid substitution in a highly conserved region of the Dnajc17 protein. This protein belongs to 40 family members of type III heat shock protein.

Figure 1. NKX2-1/TTF-1-Mediated Transcriptional Regulation and Consequences in Normal and Cancer Cells of the Lung. (Yamaguchi, T., et al. 2013)

NKx2.1 and Tumor

NKx2.1 can be expressed not only in thyroid tissue, but also in some lung cancers, and has potential value in the diagnosis and differential diagnosis of lung cancer. Mutation and expression of NKx2.1 gene in 92 lung cancer patients (including 36 lung adenocarcinoma, 42 lung squamous cell carcinoma, 8 small cell lung cancer, and 6 large cell lung cancer) were studied. The results showed that the total mutation rate of missense mutation and synonymous mutation in NKx2.1 gene in lung cancer patients was as high as 16%, and the expression level of NKx2.1 mRNA and protein in normal lung tissues was higher than that in various lung cancer tissues. In addition, the mutation of NKx2.1 gene is positively correlated with the decrease of the expression level of NKx2.1 mRNA and its protein in lung cancer tissues, which indicates that the synonymous mutation and missense mutation of NKx2.1 in lung cancer tissues can serve as an important molecular pathological basis for the occurrence of lung cancer.

Among all lung cancer cases, lung adenocarcinoma accounts for one-third. Immunohistochemical analysis using NKx2.1 detected approximately 75% of lung adenocarcinoma, suggesting that NKx2.1 can be used as a marker for the identification of primary and metastatic lung adenocarcinoma. Moreover, NKx2.1 has a certain reference value for the differential diagnosis of primary and poorly differentiated adenocarcinoma and squamous cell carcinoma. 54 specimens of surgically resected primary lung adenocarcinoma were stained by immunohistochemical staining and analyzed with clinical pathological data. The results showed that the positive rate of NKx2.1 was 81% in 54 cases of primary lung adenocarcinoma, and the ratio of peripheral type to central type lung adenocarcinoma in positive tumors was 36/41 and 8/13 (P<0.05).

References:

Yamaguchi, T. , Hosono, Y. , Yanagisawa, K. , & Takahashi, T. . (2013). Nkx2-1/ttf-1: an enigmatic oncogene that functions as a double-edged sword for cancer cell survival and progression. Cancer Cell, 23(6), 718-723.
Minocha, S. , & Herr, W. . (2019). Cortical and commissural defects upon hcf-1 loss in nkx2.1-derived embryonic neurons and glia. Developmental Neurobiology, 79(6).
Herriges, M. J. , Tischfield, D. J. , Cui, Z. , Morley, M. P. , Han, Y. , & Babu, A. , et al. (2017). The nanci–nkx2.1 gene duplex buffers nkx2.1 expression to maintain lung development and homeostasis. Genes & Development, genesdev;gad.298018.117v1.

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