TOX high mobility group box family member 3 | |||||||
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Identifiers | |||||||
Symbol | TOX3 | ||||||
Alt. symbols | TNRC9, CAGF9 | ||||||
NCBI gene | 27324 | ||||||
HGNC | 11972 | ||||||
OMIM | 611416 | ||||||
RefSeq | XM_049037 | ||||||
UniProt | O15405 | ||||||
Other data | |||||||
Locus | Chr. 16 q12.1 | ||||||
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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]
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]