T-box transcription factor T
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T-box transcription factor T, also known as Brachyury protein, is encoded for in humans by the ''TBXT''
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 b ...
. Brachyury functions 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 f ...
within the T-box family of genes. Brachyury
homologs A couple of homologous chromosomes, or homologs, are a set of one maternal and one paternal chromosome that pair up with each other inside a cell during fertilization. Homologs have the same genes in the same loci where they provide points alon ...
have been found in all bilaterian animals that have been screened, as well as the freshwater
cnidaria Cnidaria () is a phylum under kingdom Animalia containing over 11,000 species of aquatic animals found both in freshwater and marine environments, predominantly the latter. Their distinguishing feature is cnidocytes, specialized cells that ...
n ''Hydra''.


History

The ''brachyury'' mutation was first described in mice by Nadezhda Alexandrovna Dobrovolskaya-Zavadskaya in 1927 as a mutation that affected tail length and sacral vertebrae in heterozygous animals. In homozygous animals the brachyury mutation is lethal at around embryonic day 10 due to defects in mesoderm formation, notochord differentiation and the absence of structures posterior to the forelimb bud (Dobrovolskaïa-Zavadskaïa, 1927). The name brachyury comes from the Greek ''brakhus'' meaning short and ''oura'' meaning tail. In 2018 HGNC updated the human gene name from ''T'' to ''TBXT'', presumably to overcome difficulties associated with searching for a single letter gene symbol. The mouse gene has been changed to ''Tbxt''. ''Tbxt'' was cloned by Bernhard Herrmann and colleagues and proved to encode a 436 amino acid embryonic nuclear
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 f ...
. Tbxt binds to a specific DNA element, a near palindromic sequence TCACACCT through a region in its N-terminus, called the T-box. ''Tbxt'' is the founding member of the
T-box T-box refers to a group of transcription factors involved in embryonic limb and heart development. Every T-box protein has a relatively large DNA-binding domain, generally comprising about a third of the entire protein that is both necessary a ...
family which in mammals currently consists of 18 T-box genes. The crystal structure of the human brachyury protein was solved in 2017 by Opher Gileadi and colleagues at the Structural Genomics Consortium in Oxford.


Role in development

The gene ''brachyury'' appears to have a conserved role in defining the midline of a bilaterian organism, and thus the establishment of the anterior-posterior axis; this function is apparent in chordates and molluscs. Its ancestral role, or at least the role it plays in the Cnidaria, appears to be in defining the blastopore. It also defines the mesoderm during gastrulation. Tissue-culture based techniques have demonstrated one of its roles may be in controlling the velocity of cells as they leave the primitive streak. It effects transcription of genes required for mesoderm formation and cellular differentiation. ''Brachyury'' has also been shown to help establish the cervical vertebral blueprint during fetal development. The number of cervical vertebrae is highly conserved among all mammals; however a spontaneous vertebral and spinal
dysplasia Dysplasia is any of various types of abnormal growth or development of cells (microscopic scale) or organs ( macroscopic scale), and the abnormal histology or anatomical structure(s) resulting from such growth. Dysplasias on a mainly microscopi ...
(VSD) mutation in this gene has been associated with the development of six or fewer cervical vertebrae instead of the usual seven.


Expression

In mice ''T'' is expressed in the inner cell mass of the blastocyst stage embryo (but not in the majority of mouse
embryonic stem cells Embryonic stem cells (ESCs) are pluripotent stem cells derived from the inner cell mass of a blastocyst, an early-stage pre- implantation embryo. Human embryos reach the blastocyst stage 4–5 days post fertilization, at which time they consist ...
) followed by the primitive streak (see image). In later development expression is localised to the node and notochord. In ''
Xenopus laevis The African clawed frog (''Xenopus laevis'', also known as the xenopus, African clawed toad, African claw-toed frog or the ''platanna'') is a species of African aquatic frog of the family Pipidae. Its name is derived from the three short claws ...
'' ''Xbra'' (the ''Xenopus'' ''T'' homologue, also recently renamed ''t'') is expressed in the mesodermal marginal zone of the pre-gastrula embryo followed by localisation to the blastopore and notochord at the mid-gastrula stage.


Orthologs

The ''
Danio rerio The zebrafish (''Danio rerio'') is a freshwater fish belonging to the minnow family (Cyprinidae) of the order Cypriniformes. Native to South Asia, it is a popular aquarium fish, frequently sold under the trade name zebra danio (and thus often ca ...
'' ortholog is known as ''ntl'' (no tail)


Role in disease


Cancer

Brachyury is implicated in the initiation and/or progression of a number of tumor types including chordoma, germ cell tumors,
hemangioblastoma Hemangioblastomas, or haemangioblastomas, are vascular tumors of the central nervous system that originate from the vascular system, usually during middle age. Sometimes, these tumors occur in other sites such as the spinal cord and retina. They ma ...
, GIST,
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 tissues of the lung. Lung carcinomas derive from transformed, malign ...
,
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 ...
of the lung,
breast cancer Breast cancer is cancer that develops from breast tissue. Signs of breast cancer may include a lump in the breast, a change in breast shape, dimpling of the skin, milk rejection, fluid coming from the nipple, a newly inverted nipple, or a r ...
, colon cancer, hepatocellular carcinoma, prostate cancer, and oral squamous carcinoma. In breast cancer brachyury expression is associated with recurrence, metastasis and reduced survival. It is also associated with resistance to tamoxifen and to cytotoxic chemotherapy. In lung cancer brachyury expression is associated with recurrence and decreased survival. It is also associated with resistance to cytotoxic chemotherapy, radiation, and EGFR kinase inhibitors. In prostate cancer brachyury expression is associated with Gleason score, perineural, invasion and capsular invasion. In addition to its role in common cancers, brachyury has been identified as a definitive diagnostic marker, key driver and therapeutic target for
chordoma Chordoma is a rare slow-growing neoplasm thought to arise from cellular remnants of the notochord. The evidence for this is the location of the tumors (along the neuraxis), the similar immunohistochemical staining patterns, and the demonstration ...
, a rare malignant tumor that arises from remnant notochordal cells lodged in the vertebrae. The evidence regarding brachyury's role in chordoma includes: * Brachyury is highly expressed in all chordomas except for the dedifferentiated subtype, which accounts for less than 5% of cases * Germ line duplication of the brachyury gene is responsible for familial chordoma. * A germline SNP in brachyury is present in 97% of chordoma patients. * Somatic amplifications of brachyury are seen in a subset of sporadic chordomas either by aneuploidy or focal duplication. * Brachyury is the most selectively essential gene in chordoma relative to other cancer types. * Brachyury is associated with a large superenhancer in chordoma tumors and cell lines, and is the most highly expressed superenhancer-associated transcription factor. ''Brachyury'' is an important factor in promoting the
epithelial–mesenchymal transition The epithelial–mesenchymal transition (EMT) is a process by which epithelial cells lose their cell polarity and cell–cell adhesion, and gain migratory and invasive properties to become mesenchymal stem cells; these are multipotent stromal ...
(EMT). Cells that over-express ''brachyury'' have down-regulated expression of the adhesion molecule
E-cadherin Cadherin-1 or Epithelial cadherin (E-cadherin), (not to be confused with the APC/C activator protein CDH1) is a protein that in humans is encoded by the ''CDH1'' gene. Mutations are correlated with gastric, breast, colorectal, thyroid, and ovarian ...
, which allows them to undergo EMT. This process is at least partially mediated by the transcription factors
AKT Protein kinase B (PKB), also known as Akt, is the collective name of a set of three serine/threonine-specific protein kinases that play key roles in multiple cellular processes such as glucose metabolism, apoptosis, cell proliferation, tran ...
and Snail. Overexpression of ''brachyury'' has been linked to hepatocellular carcinoma (HCC, also called malignant hepatoma), a common type of liver cancer. While ''brachyury'' is promoting EMT, it can also induce
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 ...
of HCC cells. ''Brachyury'' expression is a prognostic biomarker for HCC, and the gene may be a target for cancer treatments in the future.


Other diseases

Overexpression of ''brachyury'' may play a part in EMT associated with benign disease such as renal
fibrosis Fibrosis, also known as fibrotic scarring, is a pathological wound healing in which connective tissue replaces normal parenchymal tissue to the extent that it goes unchecked, leading to considerable tissue remodelling and the formation of perma ...
.


Role as a therapeutic target

Because brachyury is expressed in tumors but not in normal adult tissues it has been proposed as a potential drug target with applicability across tumor types. In particular, brachyury-specific peptides are presented on HLA receptors of cells in which it is expressed, representing a tumor specific antigen. Various therapeutic vaccines have been developed which are intended to stimulate an immune response to brachyury expressing cells.


See also

*
Homeobox protein NANOG Homeobox protein NANOG (hNanog) is a transcriptional factor that helps embryonic stem cells (ESCs) maintain pluripotency by suppressing cell determination factors. hNanog is encoded in humans by the ''NANOG'' gene. Several types of cancer are as ...
*
POU5F1 Oct-4 (octamer-binding transcription factor 4), also known as POU5F1 (POU domain, class 5, transcription factor 1), is a protein that in humans is encoded by the ''POU5F1'' gene. Oct-4 is a homeodomain transcription factor of the POU family. I ...
* SOX2 *
MIXL1 Mixl1 is a paired-type homeobox transcription factor weighing 27 kDa with 232 amino acids. Mixl1 transcription factor preferentially binds to the DNA sequence TAAT on the Mix gene. Mixl1 is part of the Mix/Bix family of transcription factors, wit ...
* GSC *
Transcription factors 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 fun ...
* Gene regulatory network * Bioinformatics *
Chordoma Chordoma is a rare slow-growing neoplasm thought to arise from cellular remnants of the notochord. The evidence for this is the location of the tumors (along the neuraxis), the similar immunohistochemical staining patterns, and the demonstration ...


References


Further reading

* *


External links


Protein Atlas entry for Brachyury

Mouse Genome Informatics entry for Brachyury

European Bioinformatics Institute InterPro entry for Brachyury


*
Xenbase Xenbase is a Model Organism Database (MOD), providing informatics resources, as well as genomic and biological data on Xenopus frogs.K. Karimi et al. (2017Xenbase: a genomic, epigenomic and transcriptomic model organism database Nucleic Acids Re ...
br>Gene entry for Brachyury
* {{Transcription factors, g4 Transcription factors Embryology