USP6
Identifiers
AliasesUSP6, HRP1, TRE17, TRE2, TRESMCR, Tre-2, USP6-short, ubiquitin specific peptidase 6
External IDsOMIM: 604334 HomoloGene: 136783 GeneCards: USP6
Orthologs
SpeciesHumanMouse
Entrez

9098

n/a

Ensembl

ENSG00000129204

n/a

UniProt

P35125

n/a

RefSeq (mRNA)

NM_001304284
NM_004505
NM_005152

n/a

RefSeq (protein)

NP_001291213
NP_004496

n/a

Location (UCSC)Chr 17: 5.12 – 5.18 Mbn/a
PubMed search[2]n/a
Wikidata
View/Edit Human

Ubiquitin carboxyl-terminal hydrolase 6 (USB6), also termed TRE17 and Tre-2, is a deubiquitinating enzyme[3] that in humans is encoded by the hominid (i.e. found only in primates) USP6 gene[4][5][6] located at band 13.2 on the short (i.e. "p") arm of chromosome 17 (notated as 17p13.2).[7] Deubiquitinating enzymes (DUBs) are enzymes that act within cells to remove ubiquitins from various functionally important proteins. Ubiquitin enzymes add ubiquitin to these proteins and thereby regulate their cellular location, alter their activity, and/or promote their degradation. By deubiquitinating these proteins, DUBs counter the effects of the ubiquinating enzymes and contribute to regulating the actions of the targeted proteins.[8] In normal adult tissues, USP6 is highly expressed in testicle tissue, modestly expressed in ovarian tissue, and absent or minimally expressed in other tissues.[9] It is also highly expressed in fetal brain tissue. The specific functions of USP6 are poorly defined primarily because its presence is restricted to primates: there are no available animal models to determine the effects of its deletion, although some studies suggest that UPSP6 contributes to normal brain development.[7] In all events, USP6 has gained wide interest because of its abnormally increased expression by the neoplastic cells in various tumors derived from mesenchymal tissue.

The USP6 gene associated with tumors is part of a fusion gene. Fusion genes are abnormal and potentially tumor-inducing genes formed by mergers between parts of two different genes as a result of large scale gene mutations such as chromosomal translocations, interstitial deletions, or inversions. For example, the USP6-COL1A1 fusion gene is formed by a translocation between part of the USP6 gene located at band 13.2 on the p arm of chromosome 17 and the COL1A1 gene located at band 21.33 on the q arm of this same chromosome.[10] The USP6 gene has been documented to fuse with any one of scores of other genes and in doing so (as tested in many cases) create a fusion gene that is overproduced and contains high levels of deubiquitinating activity.[11] Studies suggest that USP6-containing fusion genes cause or at least contribute to tumor development by inappropriately activating multiple cell signaling pathways including the Wnt signaling pathway, one of the JAK-STAT signaling pathways (i.e. the Jak1-STAT3 pathway), the c-Jun signaling pathway,[12] and the NF-κB signaling pathway.[13] All of these pathways, when inappropriately activated, have been implicated in promoting the development of tumors and cancers.[12] The World Health Organization, 2021, classification of Tumors of Soft Tissue suggests that USP6-containing fusion protein-associated tumors are typically benign and usually self-limited in their growth.[12] Furthermore, high levels of USP6 activity may act to suppress rather than promote tumor development in Ewing sarcoma, a tumor which has USP-containing fusion genes in ~1/3 of cases.[3]

Tumor types that are associated with USP6-containing fusion genes and appear to promote their development and/or growth include:

References

  1. 1 2 3 GRCh38: Ensembl release 89: ENSG00000129204 - Ensembl, May 2017
  2. ↑ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  3. 1 2 Henrich IC, Jain K, Young R, Quick L, Lindsay JM, Park DH, Oliveira AM, Blobel GA, Chou MM (April 2021). "Ubiquitin-Specific Protease 6 Functions as a Tumor Suppressor in Ewing Sarcoma through Immune Activation". Cancer Research. 81 (8): 2171–2183. doi:10.1158/0008-5472.CAN-20-1458. PMC 8137534. PMID 33558334.
  4. ↑ Puente XS, Sanchez LM, Overall CM, Lopez-Otin C (Jul 2003). "Human and mouse proteases: a comparative genomic approach". Nat Rev Genet. 4 (7): 544–58. doi:10.1038/nrg1111. PMID 12838346. S2CID 2856065.
  5. ↑ Hoogendijk JE, Hensels GW, Gabreels-Festen AA, Gabreels FJ, Janssen EA, de Jonghe P, Martin JJ, van Broeckhoven C, Valentijn LJ, Baas F, et al. (May 1992). "De-novo mutation in hereditary motor and sensory neuropathy type I". Lancet. 339 (8801): 1081–2. doi:10.1016/0140-6736(92)90668-S. PMID 1349106. S2CID 35908066.
  6. ↑ "Entrez Gene: USP6 ubiquitin specific peptidase 6 (Tre-2 oncogene)".
  7. 1 2 Oliveira AM, Chou MM (January 2012). "The TRE17/USP6 oncogene: a riddle wrapped in a mystery inside an enigma". Frontiers in Bioscience (Scholar Edition). 4 (1): 321–34. doi:10.2741/271. PMID 22202063.
  8. ↑ Snyder NA, Silva GM (August 2021). "Deubiquitinating enzymes (DUBs): regulation, homeostasis, and oxidative stress response". The Journal of Biological Chemistry. 297 (3): 101077. doi:10.1016/j.jbc.2021.101077. PMC 8424594. PMID 34391779.
  9. ↑ "USP6 ubiquitin specific peptidase 6 [Homo sapiens (Human)] - Gene - NCBI".
  10. ↑ Stražar K, Šekoranja D, Matjašič A, Zupan A, Snoj Ž, Martinčič D, Pižem J (June 2021). "Intraarticular nodular fasciitis-detection of USP6 gene fusions in three cases by targeted RNA sequencing". Virchows Archiv. 478 (6): 1117–1124. doi:10.1007/s00428-020-02991-6. ISSN 0945-6317. PMID 33404853. S2CID 230783712.
  11. ↑ Legrand M, Jourdan ML, Tallet A, Collin C, Audard V, Larousserie F, Aubert S, Gomez-Brouchet A, Bouvier C, de Pinieux G (July 2021). "Novel partners of USP6 gene in a spectrum of bone and soft tissue lesions". Virchows Archiv. 479 (1): 147–156. doi:10.1007/s00428-021-03047-z. PMID 33558945. S2CID 231850082.
  12. 1 2 3 Nakayama S, Nishio J, Aoki M, Koga K, Nabeshima K, Yamamoto T (2021). "Ubiquitin-specific Peptidase 6 (USP6)-associated Fibroblastic/Myofibroblastic Tumors: Evolving Concepts". Cancer Genomics & Proteomics. 18 (2): 93–101. doi:10.21873/cgp.20244. PMC 7943209. PMID 33608306.
  13. ↑ Ye Y, Pringle LM, Lau AW, et al. (June 2010). "TRE17/USP6 oncogene translocated in aneurysmal bone cyst induces matrix metalloproteinase production via activation of NFκB". Oncogene. 29 (25): 3619–29. doi:10.1038/onc.2010.116. PMC 2892027. PMID 20418905.
  14. 1 2 Agaram NP, LeLoarer FV, Zhang L, Hwang S, Athanasian EA, Hameed M, Antonescu CR (June 2014). "USP6 gene rearrangements occur preferentially in giant cell reparative granulomas of the hands and feet but not in gnathic location". Human Pathology. 45 (6): 1147–52. doi:10.1016/j.humpath.2014.01.020. PMC 4225080. PMID 24742829.
  15. 1 2 Baumhoer D, Amary F, Flanagan AM (February 2019). "An update of molecular pathology of bone tumors. Lessons learned from investigating samples by next generation sequencing". Genes, Chromosomes & Cancer. 58 (2): 88–99. doi:10.1002/gcc.22699. PMID 30582658. S2CID 58637942.
  16. ↑ Hiemcke-Jiwa LS, van Gorp JM, Fisher C, Creytens D, van Diest PJ, Flucke U (December 2020). "USP6-Associated Neoplasms: A Rapidly Expanding Family of Lesions". International Journal of Surgical Pathology. 28 (8): 816–825. doi:10.1177/1066896920938878. PMID 32635781. S2CID 220413896.
  17. ↑ Sbaraglia M, Bellan E, Dei Tos AP (April 2021). "The 2020 WHO Classification of Soft Tissue Tumours: news and perspectives". Pathologica. 113 (2): 70–84. doi:10.32074/1591-951X-213. PMC 8167394. PMID 33179614.
  18. ↑ Bekers EM, Eijkelenboom A, Grünberg K, Roverts RC, de Rooy JW, van der Geest IC, van Gorp JM, Creytens D, Flucke U (June 2018). "Myositis ossificans - Another condition with USP6 rearrangement, providing evidence of a relationship with nodular fasciitis and aneurysmal bone cyst". Annals of Diagnostic Pathology. 34: 56–59. doi:10.1016/j.anndiagpath.2018.01.006. hdl:1854/LU-8559797. PMID 29661729. S2CID 4957974.

Further reading

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