NKX3-1
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Homeobox protein Nkx-3.1, also known as NKX3-1, NKX3, BAPX2, NKX3A and NKX3.1 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 in humans is encoded by the ''NKX3-1''
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 ...
located on chromosome 8p. ''NKX3-1'' is a prostatic
tumor suppressor A tumor suppressor gene (TSG), or anti-oncogene, is a gene that regulates a cell during cell division and replication. If the cell grows uncontrollably, it will result in cancer. When a tumor suppressor gene is mutated, it results in a loss or re ...
gene. ''NKX3-1'' is an
androgen An androgen (from Greek ''andr-'', the stem of the word meaning "man") is any natural or synthetic steroid hormone that regulates the development and maintenance of male characteristics in vertebrates by binding to androgen receptors. This in ...
-regulated, prostate-specific
homeobox A homeobox is a DNA sequence, around 180 base pairs long, that regulates large-scale anatomical features in the early stages of embryonic development. For instance, mutations in a homeobox may change large-scale anatomical features of the full- ...
gene whose expression is predominantly localized to prostate epithelium. It acts as a
transcription factor In molecular biology, a transcription factor (TF) (or sequence-specific DNA-binding factor) is a protein that controls the rate of transcription of genetic information from DNA to messenger RNA, by binding to a specific DNA sequence. The fu ...
that has critical function in prostate development and tumor suppression. It is a negative regulator of epithelial cell growth in prostate tissue. The NKX3-1 homeobox
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 ...
is encoded by the ''NKX3-1''
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

The homeodomain-containing transcription factor NKX3A is a putative prostate tumor suppressor that is expressed in a largely prostate-specific and androgen-regulated manner. Loss of NKX3A protein expression is a common finding in human prostate carcinomas and prostatic intraepithelial neoplasia.


Gene

In humans, the ''NKX3-1'' gene is located on chromosome 8p21.2 with 4 exons. The 8p chromosome is a region that is frequently reported to undergo a
loss of heterozygosity Loss of heterozygosity (LOH) is a type of genetic abnormality in diploid organisms in which one copy of an entire gene and its surrounding chromosomal region are lost. Since diploid cells have two copies of their genes, one from each parent, a sing ...
(LOH) associated with tissue dedifferentiation and loss of androgen responsiveness during the progression of prostate cancer. LOH has been reported to be observed in 12-89% of high-grade prostatic intraepithelial neoplasia (PIN) and 35-86% of prostatic adenocarcinomas. The frequency of loss of heterozygosity on chromosome 8p is seen to increase with advanced prostate cancer grade and stage.


Structure

NKX3-1 contains two exons encoding a 234 amino acid protein including a homeodomain. The 234 amino acids are 35-38 kDa. One N-terminal domain one homeodomain and one C-terminal domain are present. The observed interaction between NKX3-1 and Serum Response Factor (SRF)indicate that amino-terminal domains participate in the interaction. The synergistic transcriptional activation requires both interactions at multiple protein-protein interfaces and protein-DNA interactions. This indicates that one mechanism of NKX3-1 dependent transcriptional activation in prostate epithelia requires combinatorial interactions with other factors expressed within those cells In 2000, full length NKX3-1 cDNA was obtained from a human prostate cDNA library. Korkmaz et al. identified 3 splice variants with deletions in the N-terminal region as well as a variant at position 137 within the homeobox domain. NKX3-1 expression was visualized using Fluorescence microscopy, utilizing GFP-NKX3-1 in the nucleus.


Function

NKX3-1 expression acts as a transcription factor that has been found to play a main role in prostate development and tumor suppression. The loss of NKX3-1 expression is frequently observed in prostate
tumorigenesis Carcinogenesis, also called oncogenesis or tumorigenesis, is the formation of a cancer, whereby normal cells are transformed into cancer cells. The process is characterized by changes at the cellular, genetic, and epigenetic levels and abnor ...
and has been seen to be a result of allelic loss, methylation, and post transcriptional silencing. NKX3-1 expression is seen in prostate epithelium, testis, ureter, and pulmonary bronchial mucous glands. NKX3-1 binds to DNA to suppress transcription as well as interacts with transcription factors such as serum response factor, to enhance transcriptional activation. Wang et al. demonstrated that NKX3-1 marks a stem cell population that functions during prostate regeneration. Genetic lineage marking demonstrated that rare luminal cells that express NKX3-1 in the absence of testicular androgens are bipotential and can self-renew in vivo. Single-cell transplantation assays showed that castration-resistant NKX3-1 expressing cells (CARNs) can reconstitute prostate ducts in renal grafts. Functional assays of NKX3-1 mutant mice in serial prostate regeneration suggested that NKX3-1 is required for stem cell maintenance. Furthermore, targeted deletion of PTEN gene in CARNs resulted in rapid carcinoma formation after androgen-mediated regeneration. This indicates that CARNs represent a new luminal stem cell population that is an efficient target for oncogenic transformation in prostate cancer. It has also been found to be essential in
pluripotency Pluripotency: These are the cells that can generate into any of the three Germ layers which imply Endodermal, Mesodermal, and Ectodermal cells except tissues like the placenta. According to Latin terms, Pluripotentia means the ability for many thin ...
of
stem cells In multicellular organisms, stem cells are undifferentiated or partially differentiated cells that can differentiate into various types of cells and proliferate indefinitely to produce more of the same stem cell. They are the earliest type of ...
using
Yamanaka factors is a Japanese stem cell researcher and a Nobel Prize laureate. He serves as the director of Center for iPS Cell (induced Pluripotent Stem Cell) Research and Application and a professor at the Institute for Frontier Medical Sciences at Kyo ...
.


Regulation

In 2010 it was shown that NKX3-1 was controlled by ERG and ESE3 both directly and through induction of EZH2 (Polycomb group pcg).


Discovery

Using a random cDNA sequencing approach, He et al. cloned a novel prostate-specific gene that encoded a homeobox-containing protein. The gene which they symbolized NKX3-1 encoded a 234-amino acid polypeptide with greatest homology to the Drosophila NK3 gene. Northern blot analysis showed that NKX3.1 had a uniquely restricted tissue expression pattern with mRNA being abundant in the prostate, lower levels in the testis and absent from all other tissues tested. The NKX3-1 protein expression was detected a hormone-responsive, androgen receptor-positive prostate cancer cell line, but was absent from androgen receptor-negative prostate cancer cell lines as well as other cell lines of varied origins. The link between androgen stimulation and NKX3-1 was discovered through the use of an androgen-dependent carcinoma line. The researchers suggested that the ''NKX3-1'' gene plays a role in androgen-driven differentiation of prostatic tissue as well as in loss of differentiation during the progression of prostate cancer.


Role in disease

Prostate cancer is the most commonly diagnosed cancer in American men and the second leading cause of cancer related deaths. Prostate cancer predominantly occurs in the peripheral zone of the human prostate, with fewer than 10% of cases found in the central zone. The disease develops as a result of the temporal and spatial loss of the basal epithelial compartment as well as increased proliferation and dedifferentiation of the luminal (secretory) epithelial cells. Prostate cancer is typically found in men of ages older than 60 and its incidence increases with increasing age. NKX3-1 plays an essential role in normal murine prostate development. Loss of function of ''NKX3-1'' leads to defects in prostatic protein secretions as well as ductal morphogenesis. Loss of function also contributes to prostate carcinogenesis. Furthermore,
immunohistochemistry Immunohistochemistry (IHC) is the most common application of immunostaining. It involves the process of selectively identifying antigens (proteins) in cells of a tissue section by exploiting the principle of antibodies binding specifically to an ...
using anti-NKX3-1 antibodies provides a sensitive and specific method for diagnosing metastatic prostatic adenocarcinomas in distant sites.


Interactions

NKX3-1 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
SPDEF SAM pointed domain-containing Ets transcription factor is a protein that in humans is encoded by the ''SPDEF'' gene. PDEF is an ETS transcription factor expressed in prostate epithelial cells. It acts as an androgen-independent transactivator of P ...
. The stability of NKX3-1 protein has been shown to be regulated by phosphorylation.


References


Further reading

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External links

* {{DEFAULTSORT:Nkx3-1 Transcription factors