NK2 homeobox 1 (NKX2-1), also known as thyroid transcription factor 1 (TTF-1), is a
protein
Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residues. Proteins perform a vast array of functions within organisms, including catalysing metabolic reactions, DNA replication, respo ...
which in humans is encoded by the ''NKX2-1''
gene
In biology, the word gene (from , ; "...Wilhelm Johannsen coined the word gene to describe the Mendelian units of heredity..." meaning ''generation'' or ''birth'' or ''gender'') can have several different meanings. The Mendelian gene is a ba ...
.
Function
Thyroid transcription factor-1 (TTF-1) is a
protein
Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residues. Proteins perform a vast array of functions within organisms, including catalysing metabolic reactions, DNA replication, respo ...
that regulates
transcription
Transcription refers to the process of converting sounds (voice, music etc.) into letters or musical notes, or producing a copy of something in another medium, including:
Genetics
* Transcription (biology), the copying of DNA into RNA, the fir ...
of
gene
In biology, the word gene (from , ; "...Wilhelm Johannsen coined the word gene to describe the Mendelian units of heredity..." meaning ''generation'' or ''birth'' or ''gender'') can have several different meanings. The Mendelian gene is a ba ...
s specific for the
thyroid
The thyroid, or thyroid gland, is an endocrine gland in vertebrates. In humans it is in the neck and consists of two connected lobes. The lower two thirds of the lobes are connected by a thin band of tissue called the thyroid isthmus. The thy ...
,
lung
The lungs are the primary organs of the respiratory system in humans and most other animals, including some snails and a small number of fish. In mammals and most other vertebrates, two lungs are located near the backbone on either side of t ...
, and
diencephalon. It is also known as thyroid specific enhancer binding protein. It is used in
anatomic pathology
Anatomical pathology (''Commonwealth'') or Anatomic pathology (''U.S.'') is a medical specialty that is concerned with the diagnosis of disease based on the gross examination, macroscopic, Histopathology, microscopic, biochemical, immu ...
as a marker to determine if a
tumor
A neoplasm () is a type of abnormal and excessive growth of tissue. The process that occurs to form or produce a neoplasm is called neoplasia. The growth of a neoplasm is uncoordinated with that of the normal surrounding tissue, and persists ...
arises from the lung or thyroid. NKX2.1 can be induced by
activin A
Activin and inhibin are two closely related protein complexes that have almost directly opposite biological effects. Identified in 1986, activin enhances FSH biosynthesis and secretion, and participates in the regulation of the menstrual c ...
via
SMAD2
Mothers against decapentaplegic homolog 2 also known as SMAD family member 2 or SMAD2 is a protein that in humans is encoded by the ''SMAD2'' gene. MAD homolog 2 belongs to the SMAD, a family of proteins similar to the gene products of the ''Dros ...
signaling in a human embryonic stem cell differentiation model.
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
The esophagus ( American English) or oesophagus (British English; both ), non-technically known also as the food pipe or gullet, is an organ in vertebrates through which food passes, aided by peristaltic contractions, from the pharynx to ...
will emerge from. NKX2.1
knockout in mice results in the development of a shortened
trachea
The trachea, also known as the windpipe, is a Cartilage, cartilaginous tube that connects the larynx to the bronchi of the lungs, allowing the passage of air, and so is present in almost all air-breathing animals with lungs. The trachea extends ...
which is fused to the esophagus, with the
bronchi
A bronchus is a passage or airway in the lower respiratory tract that conducts air into the lungs. The first or primary bronchi pronounced (BRAN-KAI) to branch from the trachea at the carina are the right main bronchus and the left main bronchus. ...
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
The wild type (WT) is the phenotype of the typical form of a species as it occurs in nature. Originally, the wild type was conceptualized as a product of the standard "normal" allele at a locus, in contrast to that produced by a non-standard, "m ...
mice. The
epithelial
Epithelium or epithelial tissue is one of the four basic types of animal tissue, along with connective tissue, muscle tissue and nervous tissue. It is a thin, continuous, protective layer of compactly packed cells with a little intercell ...
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. 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.
Clinical significance
![Immunohistochemistry of adenocarcinoma with cytoplasmic versus nuclear staining for TTF-1](https://upload.wikimedia.org/wikipedia/commons/b/bc/Immunohistochemistry_of_adenocarcinoma_with_cytoplasmic_versus_nuclear_staining_for_TTF-1.jpg)
TTF-1 positive cells are found in the lung as
type II pneumocyte
A pulmonary alveolus (plural: alveoli, from Latin ''alveolus'', "little cavity"), also known as an air sac or air space, is one of millions of hollow, distensible cup-shaped cavities in the lungs where oxygen is exchanged for carbon dioxide. A ...
s and
club cell
Club cells, also known as bronchiolar exocrine cells, and formerly known as Clara cells, are low columnar/cuboidal cells with short microvilli, found in the small airways (bronchioles) of the lungs.
Club cells are found in the ciliated simple epit ...
s. In the thyroid,
follicular and
parafollicular cell
Parafollicular cells, also called C cells, are neuroendocrine cells in the thyroid. The primary function of these cells is to secrete calcitonin. They are located adjacent to the thyroid follicles and reside in the connective tissue. These cells a ...
s are also positive for TTF-1.
For
lung cancer
Lung cancer, also known as lung carcinoma (since about 98–99% of all lung cancers are carcinomas), is a malignant lung tumor characterized by uncontrolled cell growth in tissue (biology), tissues of the lung. Lung carcinomas derive from tran ...
s,
adenocarcinoma
Adenocarcinoma (; plural adenocarcinomas or adenocarcinomata ) (AC) is a type of cancerous tumor that can occur in several parts of the body. It is defined as neoplasia of epithelial tissue that has glandular origin, glandular characteristics, or ...
s are usually positive, while
squamous cell carcinomas and
large cell carcinoma
Large-cell carcinoma (LCC, LCLC) is a heterogeneous group of undifferentiated malignant neoplasms that lack the cytologic and architectural features of small cell carcinoma and glandular or squamous differentiation. LCC is categorized as a type of ...
s are rarely positive.
Small cell carcinoma
Small-cell carcinoma is a type of highly malignant cancer that most commonly arises within the lung, although it can occasionally arise in other body sites, such as the cervix, prostate, and gastrointestinal tract. Compared to non-small cell c ...
s (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.
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.
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.
It is also positive in
thyroid cancer
Thyroid cancer is cancer that develops from the tissues of the thyroid gland. It is a disease in which cells grow abnormally and have the potential to spread to other parts of the body. Symptoms can include swelling or a lump in the neck. C ...
s and is used for monitoring for
metastasis
Metastasis is a pathogenic agent's spread from an initial or primary site to a different or secondary site within the host's body; the term is typically used when referring to metastasis by a cancerous tumor. The newly pathological sites, then, ...
and recurrence.
Interactions
NK2 homeobox 1 has been shown to
interact
Advocates for Informed Choice, dba interACT or interACT Advocates for Intersex Youth, is a 501(c)(3) nonprofit organization using innovative strategies to advocate for the legal and human rights of children with intersex traits. The organizati ...
with
Calreticulin
Calreticulin also known as calregulin, CRP55, CaBP3, calsequestrin-like protein, and endoplasmic reticulum resident protein 60 (ERp60) is a protein that in humans is encoded by the ''CALR'' gene.
Calreticulin is a multifunctional soluble prote ...
and
PAX8
Paired box gene 8, also known as PAX8, is a protein which in humans is encoded by the ''PAX8'' gene.
Function
This gene is a member of the paired box ( PAX) family of transcription factors. Members of this gene family typically encode proteins ...
.
References
Further reading
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External links
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{{NLM content
Transcription factors
Anatomical pathology
Proteins