TOX3

Last updated
TOX high mobility group box family member 3
Identifiers
SymbolTOX3
Alt. symbolsTNRC9, CAGF9
NCBI gene 27324
HGNC 11972
OMIM 611416
RefSeq XM_049037
UniProt O15405
Other data
Locus Chr. 16 q12.1

TOX high mobility group box family member 3, also known as TOX3, is a human gene. [1] [2]

The protein encoded by this gene is a member of a subfamily of transcription factors that also includes TOX , TOX2 , and TOX4 that share almost identical HMG-box DNA-binding domains which function to modify chromatin structure by unwinding and bending DNA. [3] The protein TOX3 has a glutamine-rich C-terminus due to CAG repeats. [4] TOX3 is located on human chromosome band 16q12.1. [5] The gene consists of seven exons and is highly expressed in both the brain and luminal epithelial breast tissue. [6] Mutations in the gene are associated with increased susceptibility to breast cancer. [2] TOX3 plays a role in regulating calcium-dependent transcription and interacts with cAMP-response-element-binding protein (CREB) and CREB-binding protein (CBP). [7] It also increases transcription via interaction with CITED1, a transcription co-regulator that increases transcription factor activity. [7]

Disease linkage

Mutations in the TOX3 gene are associated with an increased risk of breast cancer. [1] [2] [8] [9]

The risk allele rs3803662 is a low-penetrance SNP (single nucleotide polymorphism) associated with decreased expression of TOX3 and an increase in breast cancer risk. [7] The risk locus was reported to regulate affinity of FOXA1 binding to chromatin, potentially affecting TOX3 expression. [6] This locus also interacts with high-penetrance mutations BRCA1 and BRCA2 to increase risk. [10] The rs3803662 variant has a high frequency in the population, with a minor allele frequency of 0.25. [11]

Little is known of the transcriptional mechanisms and protein interactions of TOX3. However, a 2019 publication identified TOX3 as a cancer suppressor gene in clear cell renal cell carcinoma (ccRCC) and reported that downregulation of TOX3 facilitates the epithelial mesenchymal transition by decreasing repression of SNAI1 and SNAI2 , resulting in tumor growth and metastasis. [12] Like breast cancer, downregulation of TOX3 is associated with worse prognosis in ccRCC patients. [12]

Related Research Articles

<span class="mw-page-title-main">Tumor suppressor gene</span> Gene that inhibits expression of the tumorigenic phenotype

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 reduction in its function. In combination with other genetic mutations, this could allow the cell to grow abnormally. The loss of function for these genes may be even more significant in the development of human cancers, compared to the activation of oncogenes.

Penetrance in genetics is the proportion of individuals carrying a particular variant of a gene that also express an associated trait. In medical genetics, the penetrance of a disease-causing mutation is the proportion of individuals with the mutation who exhibit clinical symptoms among all individuals with such mutation. For example, if a mutation in the gene responsible for a particular autosomal dominant disorder has 95% penetrance, then 95% of those with the mutation will develop the disease, while 5% will not.

<span class="mw-page-title-main">BRCA1</span> Gene known for its role in breast cancer

Breast cancer type 1 susceptibility protein is a protein that in humans is encoded by the BRCA1 gene. Orthologs are common in other vertebrate species, whereas invertebrate genomes may encode a more distantly related gene. BRCA1 is a human tumor suppressor gene and is responsible for repairing DNA.

<span class="mw-page-title-main">BRCA2</span> Gene known for its role in breast cancer

BRCA2 and BRCA2 are a human gene and its protein product, respectively. The official symbol and the official name are maintained by the HUGO Gene Nomenclature Committee. One alternative symbol, FANCD1, recognizes its association with the FANC protein complex. Orthologs, styled Brca2 and Brca2, are common in other vertebrate species. BRCA2 is a human tumor suppressor gene, found in all humans; its protein, also called by the synonym breast cancer type 2 susceptibility protein, is responsible for repairing DNA.

<span class="mw-page-title-main">CHEK2</span>

CHEK2 is a tumor suppressor gene that encodes the protein CHK2, a serine-threonine kinase. CHK2 is involved in DNA repair, cell cycle arrest or apoptosis in response to DNA damage. Mutations to the CHEK2 gene have been linked to a wide range of cancers.

<span class="mw-page-title-main">PARP1</span>

Poly [ADP-ribose] polymerase 1 (PARP-1) also known as NAD+ ADP-ribosyltransferase 1 or poly[ADP-ribose] synthase 1 is an enzyme that in humans is encoded by the PARP1 gene. It is the most abundant of the PARP family of enzymes, accounting for 90% of the NAD+ used by the family. PARP1 is mostly present in cell nucleus, but cytosolic fraction of this protein was also reported.

<span class="mw-page-title-main">Basal-like carcinoma</span> Breast cancer subtype

The basal-like carcinoma is a recently proposed subtype of breast cancer defined by its gene expression and protein expression profile.

<span class="mw-page-title-main">SNAI1</span> Protein

Zinc finger protein SNAI1 is a protein that in humans is encoded by the SNAI1 gene. Snail is a family of transcription factors that promote the repression of the adhesion molecule E-cadherin to regulate epithelial to mesenchymal transition (EMT) during embryonic development.

<span class="mw-page-title-main">RAD52</span>

RAD52 homolog , also known as RAD52, is a protein which in humans is encoded by the RAD52 gene.

<span class="mw-page-title-main">SNAI2</span> Protein

Zinc finger protein SNAI2 is a transcription factor that in humans is encoded by the SNAI2 gene. It promotes the differentiation and migration of certain cells and has roles in initiating gastrulation.

<span class="mw-page-title-main">BRIP1</span>

Fanconi anemia group J protein is a protein that in humans is encoded by the BRCA1-interacting protein 1 (BRIP1) gene.

<span class="mw-page-title-main">ZNF350</span> Protein-coding gene in the species Homo sapiens

Zinc finger protein 350 is a protein that in humans is encoded by the ZNF350 gene.

<span class="mw-page-title-main">PALB2</span> Protein-coding gene in the species Homo sapiens

Partner and localizer of BRCA2, also known as PALB2 or FANCN, is a protein which in humans is encoded by the PALB2 gene.

<span class="mw-page-title-main">TOX</span> Protein-coding gene in the species Homo sapiens

Thymocyte selection-associated high mobility group box protein TOX is a protein that in humans is encoded by the TOX gene. TOX drives T-cell exhaustion and plays a role in innate lymphoid cell development.

Post-transcriptional regulation is the control of gene expression at the RNA level. It occurs once the RNA polymerase has been attached to the gene's promoter and is synthesizing the nucleotide sequence. Therefore, as the name indicates, it occurs between the transcription phase and the translation phase of gene expression. These controls are critical for the regulation of many genes across human tissues. It also plays a big role in cell physiology, being implicated in pathologies such as cancer and neurodegenerative diseases.

Fanconi anemia, complementation group M, also known as FANCM is a human gene. It is an emerging target in cancer therapy, in particular cancers with specific genetic deficiencies.

<span class="mw-page-title-main">Cancer epigenetics</span> Field of study in cancer research

Cancer epigenetics is the study of epigenetic modifications to the DNA of cancer cells that do not involve a change in the nucleotide sequence, but instead involve a change in the way the genetic code is expressed. Epigenetic mechanisms are necessary to maintain normal sequences of tissue specific gene expression and are crucial for normal development. They may be just as important, if not even more important, than genetic mutations in a cell's transformation to cancer. The disturbance of epigenetic processes in cancers, can lead to a loss of expression of genes that occurs about 10 times more frequently by transcription silencing than by mutations. As Vogelstein et al. points out, in a colorectal cancer there are usually about 3 to 6 driver mutations and 33 to 66 hitchhiker or passenger mutations. However, in colon tumors compared to adjacent normal-appearing colonic mucosa, there are about 600 to 800 heavily methylated CpG islands in the promoters of genes in the tumors while these CpG islands are not methylated in the adjacent mucosa. Manipulation of epigenetic alterations holds great promise for cancer prevention, detection, and therapy. In different types of cancer, a variety of epigenetic mechanisms can be perturbed, such as the silencing of tumor suppressor genes and activation of oncogenes by altered CpG island methylation patterns, histone modifications, and dysregulation of DNA binding proteins. There are several medications which have epigenetic impact, that are now used in a number of these diseases.

<span class="mw-page-title-main">Cancer syndrome</span> Genetic condition that predisposes a person to cancer

A cancer syndrome, or family cancer syndrome, is a genetic disorder in which inherited genetic mutations in one or more genes predispose the affected individuals to the development of cancers and may also cause the early onset of these cancers. Cancer syndromes often show not only a high lifetime risk of developing cancer, but also the development of multiple independent primary tumors.

<span class="mw-page-title-main">DIRAS3 (gene)</span> Mammalian protein found in Homo sapiens

GTP-binding protein Di-Ras3 (DIRAS3) also known as aplysia ras homology member I (ARHI) is a protein that in humans is encoded by the DIRAS3 gene.

<span class="mw-page-title-main">Hereditary diffuse gastric cancer</span> Medical condition

Hereditary diffuse gastric cancer (HDGC) is an inherited genetic syndrome most often caused by an inactivating mutation in the E-cadherin gene (CDH1) located on chromosome 16. Individuals who inherit an inactive copy of the CDH1 gene are at significantly elevated risk for developing stomach cancer. For this reason, individuals with these mutations will often elect to under go prophylactic gastrectomy, or a complete removal of the stomach to prevent this cancer. Mutations in CDH1 are also associated with high risk of lobular breast cancers, and may be associated with a mildly elevated risk of colon cancer.

References

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  4. "TOX3 TOX high mobility group box family member 3 [Homo sapiens (human)]". Gene - NCBI. National Center for Biotechnology Information (NCBI), U.S. National Library of Medicine.
  5. "TOX3 (TOX high mobility group box family member 3)". Atlas of Genetics and Cytogenetics in Oncology and Haematology.
  6. 1 2 Jones JO, Chin SF, Wong-Taylor LA, Leaford D, Ponder BA, Caldas C, Maia AT (2013). "TOX3 mutations in breast cancer". PLOS ONE. 8 (9): e74102. Bibcode:2013PLoSO...874102J. doi: 10.1371/journal.pone.0074102 . PMC   3777980 . PMID   24069272.
  7. 1 2 3 Gudmundsdottir ET, Barkardottir RB, Arason A, Gunnarsson H, Amundadottir LT, Agnarsson BA, et al. (December 2012). "The risk allele of SNP rs3803662 and the mRNA level of its closest genes TOX3 and LOC643714 predict adverse outcome for breast cancer patients". BMC Cancer. 12: 621. doi:10.1186/1471-2407-12-621. PMC   3553017 . PMID   23270421.
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  10. "OMIM Entry - * 611416 - TOX HIGH MOBILITY GROUP BOX FAMILY MEMBER 3; TOX3". Online Mendelian Inheritance in Man (OMIM).
  11. Mavaddat N, Antoniou AC, Easton DF, Garcia-Closas M (June 2010). "Genetic susceptibility to breast cancer". Molecular Oncology. 4 (3): 174–91. doi:10.1016/j.molonc.2010.04.011. PMC   5527934 . PMID   20542480.
  12. 1 2 Jiang B, Chen W, Qin H, Diao W, Li B, Cao W, et al. (May 2019). "TOX3 inhibits cancer cell migration and invasion via transcriptional regulation of SNAI1 and SNAI2 in clear cell renal cell carcinoma". Cancer Letters. 449: 76–86. doi:10.1016/j.canlet.2019.02.020. PMID   30772441. S2CID   73487599.