Written | 2010-04 | Theresia Wilbertz, Sebastian Maier, Sven Perner |
Institute of Pathology, University Hospital Tubingen, Germany |
Identity |
Alias (NCBI) | BCH | BHC | NK-2 | NKX2.1 | NKX2A | TEBP | TITF1 | TTF-1 | TTF1 |
HGNC (Hugo) | NKX2-1 |
HGNC Alias symb | TTF-1 | TTF1 |
HGNC Previous name | NKX2A | BCH | TITF1 |
HGNC Previous name | benign chorea | thyroid transcription factor 1 |
LocusID (NCBI) | 7080 |
Atlas_Id | 44015 |
Location | 14q13.3 [Link to chromosome band 14q13] |
Location_base_pair | Starts at 36516399 and ends at 36519556 bp from pter ( according to GRCh38/hg38-Dec_2013) [Mapping NKX2-1.png] |
Fusion genes (updated 2017) | Data from Atlas, Mitelman, Cosmic Fusion, Fusion Cancer, TCGA fusion databases with official HUGO symbols (see references in chromosomal bands) |
BAZ1A (14q13.1) / NKX2-1 (14q13.3) | NKX2-1 (14q13.3) / SFTA3 (14q13.3) | NKX2-1 (14q13.3) / SLC25A21 (14q13.3) | |
SFTA3 (14q13.3) / NKX2-1 (14q13.3) |
DNA/RNA |
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Figure 1. NKX2-1 gene and NKX2-1 mRNA. | |
Description | NKX2-1 is regulated by two promoter regions: the first one is located in intron 1 (5' of exon 1, regulation of NKX2-1 in lung and thyroid cells). The second one is situated in the 5' flanking region of exon 1, it is a 330 bp TATA-less region containing multiple palindromes and G/C-rich elements. It regulates NKX2-1 in lung epithelial cells responding to transcription factors sp1 and sp3. |
Transcription | NKX2-1 is transcribed in two highly conserved forms: mRNA-isoform 1 contains exon 1, exon 2, and exon 3, it is translated into a 401 amino acid protein and represents the minor transcript. mRNA-isoform 2 is the predominant transcript containing exon 2 and exon 3. It is translated into a 371 aa protein. |
Protein |
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Figure 2. Upstream and downstream targets of NKX2-1. | |
Description | The NKX2-1 protein includes three functional domains: an N-terminal transactivation domain, a DNA-binding transactivation domain and a C-terminal transactivation domain. |
Expression | In the lung, expression of NKX2-1 is consistent throughout all life stages from fetal to adult tissue. It is expressed in conducting airways type II alveolar epithelial cells and Clara cells and uniformly in the terminal respiratory unit. NKX2-1 expression is also found in thyroid follicular cells and both normal and hyperplastic C cells where it activates calcitonin gene expression. NKX2-1 is not expressed in adult neurons of the basal ganglia. During embryonic and fetal development, NKX2-1 expression is found in various tissues (e.g. brain, lung, thyroid), for details see "function" → "Embryonic and fetal development". |
Localisation | NKX2-1 is a nuclear transcription factor. |
Function | In the lung, NKX2-1 regulates the expression of the lung-specific genes: surfactant protein SP-A, SP-B, SP-C and Clara cell secretory protein (CCSP). It cooperates with C/EBPalpha in transactivating CCSP. In the transcription of SP-C, NKX2-1 interacts with nuclear factor I to differentially regulate the transcription. The longer NKX2-1 isoform reduces transactivation of SP-C, probably due to some kind of interference. NKX2-1 is a key activator of SP-B gene expression having at least two binding sites at the SP-B promoter and enhancer. The transactivation capacity of NKX2-1 regarding the expression of SP-B is controlled by the sphingolipid ceramide which is produced in inflammation and reduces NKX2-1 binding capacity to the SP-B promoter. SP-B transcription is also inhibited by TGFbeta1-mediated interaction of smad3 with NKX2-1. Moreover, NKX2-1 interacts with retinoic acid receptor (RAR), nuclear receptor coactivators (p160, CBP/p300) and signal transducers and activators of transcription 3 (STAT3) in regulation of SP-B expression. Furthermore, NKX2-1 regulates the expression of the secretoglobulin 3A2 gene (SCGB3A2) in mouse airways in cooperation with CAATT/enhancer binding proteins alpha and delta as well as the expression of ABCA3 which encodes for a lipid transporter critical for surfactant function at birth and formation of lamellar bodies. NKX2-1 also plays an important role in the endocrine system: it regulates the expression of the thyroid-specific genes thyroglobulin, thyroid peroxidase, thyrotropin receptor and sodium-iodide-symporter, therefore being crucial for proper thyroid hormone synthesis. In accordance with the findings concerning the role of NKX2-1 in the development of the above-mentioned organs, NKX2-1-defective mice die at birth due to a characteristic set of malformations and functional impairments: hypoplastic lungs and insufficient surfactant production, defective hypothalamus, absence of thyroid and pituitary gland, delayed development of dopaminergic, GABAergic and cholinergic neurons. |
Mutations |
Note |
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Germinal | Mutations in NKX2-1 (for details see table 1) can cause benign hereditary chorea (BHC, a dyskinesia, i.e. a neurological disorder characterized by abnormal involuntary movements) and brain-lung-thyroid syndrome (in addition to BHC, patients suffer from congenital hypothyroidism and infant respiratory distress syndrome). A heterozygous substitution at position 1016 in the coding sequence (C → T) leads to a mutant NKX2-1 protein (A339V) and can contribute to a predisposition for multinodular goiter and papillary thyroid carcinoma. For other heterozygous NKX2-1 mutations in humans, phenotypes vary widely. Homozygous NKX2-1 mutations in humans are probably not viable. |
Implicated in |
Note | |||||||||||||||||||||||||||||||||||||||||
Entity | Various cancers | ||||||||||||||||||||||||||||||||||||||||
Note | NKX2-1 expression has been found in a variety of tumor entities, especially lung and thyroid tumors (for details see table 2). | ||||||||||||||||||||||||||||||||||||||||
Disease |
Table 2. Expression of NKX2-1 in different tumor entities. | ||||||||||||||||||||||||||||||||||||||||
Entity | Lung neoplasms | ||||||||||||||||||||||||||||||||||||||||
Disease | NKX2-1 is strongly expressed in 75-90% of primary lung adenocarcinomas, whereas only 1/4 of bronchioloalveolar carcinomas show NKX2-1 positivity. Among non-small cell lung cancers, NKX2-1 is not expressed in squamous cell lung cancer. Small cell lung cancer, as well as pulmonary carcinoids and non-neuroendocrine large-cell carcinomas partly exhibit NKX2-1 protein expression. | ||||||||||||||||||||||||||||||||||||||||
Prognosis | Overall, NKX2-1 expression is a predictor for better survival in adenocarcinomas of the lung (just one smaller study suggested that NKX2-1 expression is associated with poor prognosis). Controversially, NKX2-1 pathway activation in lung cancers is associated with poor survival and cisplatin resistance if PAX9 or Nkx2-8 pathways are activated at the same time. | ||||||||||||||||||||||||||||||||||||||||
Oncogenesis | NKX2-1 is highly amplified in 5-15% of primary lung adenocarcinomas. In cells harbouring NKX2-1 amplification, this recurrent gene amplification seems to be a mechanism of high-level NKX2-1 expression. For a subset of lung adenocarcinomas (especially those which are derived from the terminal respiratory unit) sustained expression of NKX2-1 has been shown to be crucial for the survival of tumor cells. In these tumors RNAi inhibition of NKX2-1 induces proliferation inhibition, growth inhibition and apoptosis (lineage-specific dependency model). Interestingly, NKX2-1 is also an activator of HOP (Hsp70/Hsp90 Organizing Protein), a potential tumor suppressor gene in lung cancer, and it inhibits EMT (epithelial to mesenchymal transition). NKX2-1 restores epithelial phenotypes in lung adenocarcinomas, acting as an adversary of the EMT-stimulating TGF-beta and a suppressor of tumor progression and invasiveness. TGF-beta inhibits the expression of NKX2-1 and thus lung morphogenesis. Moreover, NKX2-1 is expressed in most metastatic lung adenocarcinomas. | ||||||||||||||||||||||||||||||||||||||||
Entity | Thyroid neoplasms | ||||||||||||||||||||||||||||||||||||||||
Disease | Well-differentiated thyroid follicular cell tumors, such as follicular adenomas, follicular carcinomas and papillary carcinomas exhibit strong nuclear positivity for NKX2-1 staining. In contrast, undifferentiated thyroid carcinomas show low or no immunoreaction. Concerning parafollicular cells, NKX2-1 expression can be found in normal and hyperplastic c-cells, as well as in medullary thyroid carcinomas. However, the signal intensity is much weaker and less homogenous than observed in tumors originating from follicular thyroid cells. Non-malignant branchiogenic cysts can easily be confounded with papillary thyroid carcinomas. Since positive immunostaining for NKX2-1 has been found in a subset of these non-malignant cervical cysts, NKX2-1 cannot serve to distinguish between both entities. | ||||||||||||||||||||||||||||||||||||||||
Oncogenesis | NKX2-1 is expressed in most differentiated thyroid neoplasms, but not in undifferentiated tumors of thyroid origin. On DNA-level, normal thyroids and papillary carcinomas do not exhibit DNA methylation in the CpG of NKX2-1 promoter, whereas undifferenciated thyroid carcinomas show DNA methylation in this region in about 60%. Most metastases of thyroid origin are positive for NKX2-1 expression. A heterozygous germline mutation, which leads to a mutant NKX2-1 protein has been shown to be associated with increased cell proliferation. Consequently, it might contribute to a predisposition for multinodular goiter and papillary thyroid carcinoma (for details see section mutations). | ||||||||||||||||||||||||||||||||||||||||
Entity | Neoplasms of the gastrointestinal tract | ||||||||||||||||||||||||||||||||||||||||
Disease | Small cell esophageal cancers exhibit NKX2-1 expression in the majority of cases. In contrast, carcinoids originating from the gastrointestinal tract, such as ileal, appendical, duodenal, ampullary, rectal, pancreatic and gastric carcinoids are negative for NKX2-1 immunohistochemical staining. | ||||||||||||||||||||||||||||||||||||||||
Entity | Neoplasms of the genitourinary tract | ||||||||||||||||||||||||||||||||||||||||
Disease | NKX2-1 seems to be implicated in neoplasms arising from the urinary system. Small cell carcinomas of the urinary bladder are positive for NKX2-1 staining in 25-40% of cases. Likewise, large cell neuroendocrine bladder carcinomas exhibit NKX2-1 expression. In one study, 1/6 of a set of nephroblastomas showed nuclear positivity for NKX2-1, whereas metanephric adenomas and cystic nephromas were NKX2-1 negative. NKX2-1 expression can be found in benign tubal and endometrial epithelia, as well as in benign tumors originating from these tissues. In addition, malignant tumors of the female genital tract, such as endocervical adenocarcinomas, small cell carcinomas of the uterine cervix, endometrioid adenocarcinomas, serous carcinomas, clear cell carcinomas, and uterine malignant mixed Mullerian tumors show positivity for NKX2-1. Staining morphology in these tumors differs from rare positive cells to a diffusely positive staining pattern. | ||||||||||||||||||||||||||||||||||||||||
Prognosis | No correlation could be detected between positive NKX2-1 immunostaining in small cell carcinomas of the urinary bladder and clinicopathologic features (including outcome, age, sex, smoking history, stage and metastatic status). | ||||||||||||||||||||||||||||||||||||||||
Entity | Neuroendocrine neoplasms | ||||||||||||||||||||||||||||||||||||||||
Disease | Among well-differentiated neuroendocrine tumors, only those tumors originating from the lung or thyroid are positive for NKX2-1 expression. Neither gastrointestinal typical or atypical carcinoids, nor neuroendocrine tumors from other sites (e.g. Merkel cell carcinomas, thymic carcinoids, ovarian large cell neuroendocrine carcinomas) show NKX2-1 expression. Concerning small cell carcinomas, NKX2-1 expression is not specific for small cell lung cancer, as NKX2-1 expression can also be found in small cell carcinomas originating from the esophagus, prostate, bladder or uterine cervix. | ||||||||||||||||||||||||||||||||||||||||
Entity | Neoplasms of neuroectodermal origin | ||||||||||||||||||||||||||||||||||||||||
Disease | NKX2-1 occasionally has been detected in glioblastoma multiforme and in ependymomas of the third ventricle. Other primary brain tumors, such as astrocytomas, oligodendrogliomas, medulloblastomas and gangliomas from various sites do not exhibit NKX2-1 expression. Sellar tumors, including pituicytomas, atypical pituicytomas, granular cell tumors and spindle cell oncocytomas can show positive immunostaining for NKX2-1. | ||||||||||||||||||||||||||||||||||||||||
To be noted |
NKX2-1 has been well studied in neoplasms of the lung and thyroid, but lacks a sufficient level of evidence in other tumor entities. |
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Citation |
This paper should be referenced as such : |
Wilbertz, Theresia ; Maier, Sebastian ; Perner, Sven |
NKX2-1 (NK2 homeobox 1) |
Atlas Genet Cytogenet Oncol Haematol. 2011;15(1):19-28. |
Free journal version : [ pdf ] [ DOI ] |
Other Leukemias implicated (Data extracted from papers in the Atlas) [ 6 ] |
Pediatric T-Cell Acute Lymphoblastic Leukemia
t(7;14)(q21;q13) CDK6/NKX2-1 t(14;14)(q11;q13) NKX2-1/TRA t(14;14)(q11;q13) TRA/NKX2-1 t(14;14)(q13;q31) NKX2-1/DIO2 t(14;14)(q13;q32) NKX2-1/BCL11B |
Other Solid tumors implicated (Data extracted from papers in the Atlas) [ 7 ] |
External links |
REVIEW articles | automatic search in PubMed |
Last year publications | automatic search in PubMed |
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