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Protein TOX PDB 2co9.png
AliasesTOX, TOX1, thymocyte selection associated high mobility group box
External IDsOMIM: 606863 MGI: 2181659 HomoloGene: 8822 GeneCards: TOX
Gene location (Human)
Chromosome 8 (human)
Chr.Chromosome 8 (human)[1]
Chromosome 8 (human)
Genomic location for TOX
Genomic location for TOX
Band8q12.1Start58,805,412 bp[1]
End59,119,147 bp[1]
RNA expression pattern
PBB GE TOX 204529 s at fs.png

PBB GE TOX 204530 s at fs.png
More reference expression data
RefSeq (mRNA)



RefSeq (protein)



Location (UCSC)Chr 8: 58.81 – 59.12 MbChr 4: 6.69 – 6.99 Mb
PubMed search[3][4]
View/Edit HumanView/Edit Mouse

Thymocyte selection-associated high mobility group box protein TOX is a protein that in humans is encoded by the TOX gene.[5][6][7]

Structure and function[edit]

The TOX gene encodes a protein that belongs to a large superfamily of chromatin associated proteins that share an approximately 75 amino acid DNA binding motif, the HMG (high mobility group)-box (named after that found in the canonical member of the family, high mobility group protein 1). Some high mobility group (HMG) box proteins (e.g., LEF1) contain a single HMG box motif and bind DNA in a sequence-specific manner, while other members of this family (e.g., HMGB1) have multiple HMG boxes and bind DNA in a sequence-independent but structure-dependent manner. While TOX has a single HMG-box motif,[7] it is predicted to bind DNA in a sequence-independent manner.[8] TOX is also a member of a small subfamily of proteins (TOX2, TOX3, and TOX4) that share almost identical HMG-box sequences.[8] TOX3 has been identified as a breast cancer susceptibility locus.[9][10] TOX is highly expressed in the thymus, the site of development of T lymphocytes. Knockout mice that lack TOX have a severe defect in development of certain subsets of T lymphocytes[11].

Role in diseases[edit]

In cancer or during chronic viral infection, TOX is necessary for T cell persistence but also drives T-cell "exhaustion" thus contributing to diminished anti-tumor or anti-viral function in these cells[12][13][14].


  1. ^ a b c GRCh38: Ensembl release 89: ENSG00000198846 - Ensembl, May 2017
  2. ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000041272 - Ensembl, May 2017
  3. ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. ^ Nagase T, Ishikawa K, Suyama M, Kikuno R, Miyajima N, Tanaka A, Kotani H, Nomura N, Ohara O (Apr 1999). "Prediction of the coding sequences of unidentified human genes. XI. The complete sequences of 100 new cDNA clones from brain which code for large proteins in vitro". DNA Res. 5 (5): 277–86. doi:10.1093/dnares/5.5.277. PMID 9872452.
  6. ^ Wilkinson B, Chen JY, Han P, Rufner KM, Goularte OD, Kaye J (Mar 2002). "TOX: an HMG box protein implicated in the regulation of thymocyte selection". Nat Immunol. 3 (3): 272–80. doi:10.1038/ni767. PMID 11850626.
  7. ^ a b "Entrez Gene: thymocyte selection-associated high mobility group box gene TOX".
  8. ^ a b O'Flaherty E, Kaye J (April 2003). "TOX defines a conserved subfamily of HMG-box proteins". BMC Genomics. 4 (1): 13. doi:10.1186/1471-2164-4-13. PMC 155677. PMID 12697058.
  9. ^ Easton DF, Pooley KA, Dunning AM, et al. (June 2007). "Genome-wide association study identifies novel breast cancer susceptibility loci". Nature. 447 (7148): 1087–93. doi:10.1038/nature05887. PMC 2714974. PMID 17529967.
  10. ^ Stacey SN, Manolescu A, Sulem P, et al. (July 2007). "Common variants on chromosomes 2q35 and 16q12 confer susceptibility to estrogen receptor-positive breast cancer". Nat. Genet. 39 (7): 865–9. doi:10.1038/ng2064. PMID 17529974.
  11. ^ Aliahmad, Parinaz; Kaye, Jonathan (2008-01-21). "Development of all CD4 T lineages requires nuclear factor TOX". The Journal of Experimental Medicine. 205 (1): 245–256. doi:10.1084/jem.20071944. ISSN 1540-9538. PMC 2234360. PMID 18195075.
  12. ^ Alfei, Francesca; Kanev, Kristiyan; Hofmann, Maike; Wu, Ming; Ghoneim, Hazem E.; Roelli, Patrick; Utzschneider, Daniel T.; von Hoesslin, Madlaina; Cullen, Jolie G. (2019). "TOX reinforces the phenotype and longevity of exhausted T cells in chronic viral infection". Nature. 571 (7764): 265–269. doi:10.1038/s41586-019-1326-9. ISSN 1476-4687. PMID 31207605.
  13. ^ Khan, Omar; Giles, Josephine R.; McDonald, Sierra; Manne, Sasikanth; Ngiow, Shin Foong; Patel, Kunal P.; Werner, Michael T.; Huang, Alexander C.; Alexander, Katherine A. (2019). "TOX transcriptionally and epigenetically programs CD8+ T cell exhaustion". Nature. 571 (7764): 211–218. doi:10.1038/s41586-019-1325-x. ISSN 1476-4687. PMID 31207603.
  14. ^ Scott, Andrew C.; Dündar, Friederike; Zumbo, Paul; Chandran, Smita S.; Klebanoff, Christopher A.; Shakiba, Mojdeh; Trivedi, Prerak; Menocal, Laura; Appleby, Heather (2019). "TOX is a critical regulator of tumour-specific T cell differentiation". Nature. 571 (7764): 270–274. doi:10.1038/s41586-019-1324-y. ISSN 1476-4687. PMID 31207604.

Further reading[edit]