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Subnuclear distribution of SSX regulates its function

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Abstract

SSX, a family of genes clustered on the X chromosome, has been identified as a cancer–testis antigen and also forms a part of the SYT–SSX fusion gene found in synovial sarcoma, implying that it has an important role in tumorigenesis. However, knowledge of the molecular regulation of SSX is still limited. In this study, we demonstrate that SSX or its SYT fusion protein is distributed as nuclear speckles, in which it is co-localized with B cell-specific Moloney murine leukemia virus insertion site 1 (Bmi1), which is a core factor of polycomb repressor complex 1. The C-terminal residues of SSX are indispensable for the nuclear speckle distribution, while the N-terminal domain is necessary for the recruitment of Bmi1, indicating that intact SSX must be needed for interaction with Bmi1 both spatially and functionally. In addition, the N-terminus of SSX also proved to contain an intrinsic nucleolar localization signal, which mediates the nucleolar translocation of SSX in particular kinds of cell stress such as the oxidation of hydrogen peroxide or heat shock. This stress-induced translocation is reversible and accompanied by HSP 70 or p14ARF traffic, suggesting that SSX is a stress response gene. It is of note that nucleolar translocation of SSX can result in disassociation of SSX from Bmi1, with consequent down-regulation of Bmi1 activity. These novel findings regarding distinct domains of SSX and its interaction with Bmi1 may shed light on the mechanism by which synovial sarcoma develops and on the up-regulation of SSX in cancer cells.

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References

  1. Güre AO, Wei IJ, Old LJ, Chen YT (2002) The SSX gene family: characterization of 9 complete genes. Int J Cancer 101:448–453

    Article  PubMed  Google Scholar 

  2. Scanlan MJ, Gure AO, Jungbluth AA, Old LJ, Chen YT (2002) Cancer/testis antigens: an expanding family of targets for cancer immunotherapy. Immunol Rev 188:22–32

    Article  CAS  PubMed  Google Scholar 

  3. Smith HA, McNeel DG (2010) The SSX family of cancer-testis antigens as target proteins for tumor therapy. Clin Dev Immunol. doi:10.1155/2010/150591

  4. Crew A, Clark J, Fisher C, Gill S, Grimer R, Chand A, Shipley J, Gusterson B, Cooper C (1995) Fusion of SYT to two genes, SSX1 and SSX2, encoding proteins with homology to the Kruppel-associated box in human synovial sarcoma. EMBO J 14:2333–2340

    CAS  PubMed  Google Scholar 

  5. de Leeuw B, Balemans M, Olde Weghuis D, Geurts van Kessel A (1995) Identification of two alternative fusion genes, SYT-SSX1 and SYT-SSX2, in t(X;18)(p11.2;q11.2)-positive synovial sarcomas. Hum Mol Genet 4:1097–1099

    Article  PubMed  Google Scholar 

  6. Agus V, Tamborini E, Mezzelani A, Pierotti MA, Pilotti S (2001) Re: A novel fusion gene, SYT–SSX4, in Synovial Sarcoma. J Natl Cancer Inst 93:1347–1349

    Article  CAS  PubMed  Google Scholar 

  7. Lim FL, Soulez M, Koczan D, Thiesen HJ, Knight JC (1998) A KRAB-related domain and a novel transcription repression domain in proteins encoded by SSX genes that are disrupted in human sarcomas. Oncogene 17:2013–2018

    Article  CAS  PubMed  Google Scholar 

  8. Brett D, Whitehouse S, Antonson P, Shipley J, Cooper C, Goodwin G (1997) The SYT protein involved in the t(X;18) synovial sarcoma translocation is a transcriptional activator localised in nuclear bodies. Hum Mol Genet 6:1559–1564

    Article  CAS  PubMed  Google Scholar 

  9. Soulez M, Saurin AJ, Freemont PS, Knight JC (1999) SSX and the synovial-sarcoma-specific chimaeric protein SYT–SSX co-localize with the human Polycomb group complex. Oncogene 18:2739–2746

    Article  CAS  PubMed  Google Scholar 

  10. dos Santos NR, de Bruijn DRH, Kater-Baats E, Otte AP, van Kessel AG (2000) Delineation of the protein domains responsible for SYT, SSX, and SYT–SSX nuclear localization. Exp Cell Res 256:192–202

    Article  PubMed  Google Scholar 

  11. Park IK, Morrison SJ, Clarke MF (2004) Bmi1, stem cells, and senescence regulation. J Clin Invest 113:175–179

    CAS  PubMed  Google Scholar 

  12. Satijn DPE, Otte AP (1999) Polycomb group protein complexes: do different complexes regulate distinct target genes. Biochim Biophys Acta 1447:1–16

    Article  CAS  PubMed  Google Scholar 

  13. Shao Z, Raible F, Mollaaghababa R, Guyon JR, Wu C, Bender W, Kingston RE (1999) Stabilization of chromatin structure by PRC1, a Polycomb complex. Cell 98:37–46

    Article  CAS  PubMed  Google Scholar 

  14. Meng S, Luo M, Sun H, Yu X, Shen M, Zhang Q, Zhou R, Ju X, Tao W, Liu D (2010) Identification and characterization of Bmi-1-responding element within the human p16 promoter. J Biol Chem 285:33219–33229

    Article  CAS  PubMed  Google Scholar 

  15. Bracken AP, Dietrich N, Pasini D, Hansen KH, Helin K (2006) Genome-wide mapping of Polycomb target genes unravels their roles in cell fate transitions. Gene Dev 20:1123–1136

    Article  CAS  PubMed  Google Scholar 

  16. Guo WJ, Datta S, Band V, Dimri GP (2007) Mel-18, a polycomb group protein, regulates cell proliferation and senescence via transcriptional repression of Bmi1 and c-Myc oncoproteins. Mol Biol Cell 18:536–546

    Article  CAS  PubMed  Google Scholar 

  17. Yang J, Chai L, Liu F, Fink LM, Lin P, Silberstein LE, Amin HM, Ward DC, Ma Y (2007) Bmi-1 is a target gene for SALL4 in hematopoietic and leukemic cells. Proc Natl Acad Sci USA 104:10494–10499

    Article  CAS  PubMed  Google Scholar 

  18. Li SKM, Smith DK, Leung WY, Cheung A, Lam EWF, Dimri GP, Yao KM (2008) FoxM1c counteracts oxidative stress-induced senescence and stimulates Bmi1 expression. J Biol Chem 283:16545–16553

    Article  CAS  PubMed  Google Scholar 

  19. Lessard J, Sauvageau G (2003) Bmi1 determines the proliferative capacity of normal and leukaemic stem cells. Nature 423:255–260

    Article  CAS  PubMed  Google Scholar 

  20. Molofsky AV, Pardal R, Iwashita T, Park IK, Clarke MF, Morrison SJ (2003) Bmi1 dependence distinguishes neural stem cell self-renewal from progenitor proliferation. Nature 425:962–967

    Article  CAS  PubMed  Google Scholar 

  21. Raaphorst FM (2003) Self-renewal of hematopoietic and leukemic stem cells: a central role for the Polycomb-group gene Bmi1. Trends Immunol 24:522–524

    Article  CAS  PubMed  Google Scholar 

  22. Liu S, Dontu G, Mantle ID, Patel S, Ahn N, Jackson KW, Suri P, Wicha MS (2006) Hedgehog signaling and Bmi-1 regulate self-renewal of normal and malignant human mammary stem cells. Cancer Res 66:6063–6071

    Article  CAS  PubMed  Google Scholar 

  23. Barco R, Garcia CB, Eid JE (2009) The synovial sarcoma-associated SYT–SSX2 oncogene antagonizes the polycomb complex protein Bmi1. PLoS ONE 4:e5060

    Article  PubMed  Google Scholar 

  24. Groner AC, Meylan S, Ciuffi A, Zangger N, Ambrosini G, Dénervaud N, Bucher P, Trono D (2010) KRAB–zinc finger proteins and KAP1 can mediate long-range transcriptional repression through heterochromatin spreading. PLoS Genet 6:e1000869

    Article  PubMed  Google Scholar 

  25. Stoop H, van Gurp R, de Krijger R, van Kessel AG, Köberle B, Oosterhuis W, Looijenga L (2001) Reactivity of germ cell maturation stage-specific markers in spermatocytic seminoma: diagnostic and etiological implications. Lab Invest 8:919–928

    Article  Google Scholar 

  26. Gallagher SJ, Kefford RF, Rizos H (2006) The ARF tumour suppressor. Int J Biochem Cell Biol 38:1637–1641

    Article  CAS  PubMed  Google Scholar 

  27. Zeng Y, He Y, Yang F, Mooney SM, Getzenberg RH, Orban J, Kulkarni P (2011) The cancer/testis antigen prostate-associated gene 4 (PAGE4) is a highly intrinsically disordered protein. J Biol Chem 286:13985–13994

    Article  CAS  PubMed  Google Scholar 

  28. Marcar L, MacLaine NJ, Hupp TR, Meek DW (2010) Mage-A cancer/testis antigens inhibit p53 function by blocking its interaction with chromatin. Cancer Res 70:10362–10370

    Article  CAS  PubMed  Google Scholar 

  29. Gure AO, Türeci Ö, Sahin U, Tsang S, Scanlan MJ, Jäger E, Knuth A, Pfreundschuh M, Old LJ, Chen YT (1997) SSX: a multigene family with several members transcribed in normal testis and human cancer. Int J Cancer 72:965–971

    Article  CAS  PubMed  Google Scholar 

  30. Türeci Ö, Chen YT, Sahin U, Güre AO, Zwick C, Villena C, Tsang S, Seitz G, Old LJ, Pfreundschuh M (1998) Expression of SSX genes in human tumors. Int J Cancer 77:19–23

    Article  PubMed  Google Scholar 

  31. dos Santos NR, Torensma R, de Vries TJ, Schreurs MWJ, de Bruijn DRH, Kater-Baats E, Ruiter DJ, Adema GJ, van Muijen GNP, van Kessel AG (2000) Heterogeneous expression of the SSX cancer/testis antigens in human melanoma lesions and cell lines. Cancer Res 60:1654–1662

    PubMed  Google Scholar 

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Acknowledgments

This project (No. 3077830, No. 30570691, No. 81171907) supported by National Natural Science Foundation of China, and the Research Fund for the Doctoral Program of Higher Education (200800010060).

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Authors and Affiliations

  1. Department of Pathology, School of Basic Medical Sciences, Health Science Center of Peking University, 38 Xueyuan Road, Haidian District, Beijing, 100191, China

    Jiaochen Wang, Huali Wang, Wei Hou, Haijing Liu, Yongxin Zou, Hong Zhang, Lin Hou, Michael A. McNutt & Bo Zhang

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  1. Jiaochen Wang
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  2. Huali Wang
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  3. Wei Hou
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  4. Haijing Liu
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  6. Hong Zhang
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  7. Lin Hou
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  8. Michael A. McNutt
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  9. Bo Zhang
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Correspondence to Bo Zhang.

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Jiaochen Wang and Huali Wang contributed equally to this work.

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Wang, J., Wang, H., Hou, W. et al. Subnuclear distribution of SSX regulates its function. Mol Cell Biochem 381, 17–29 (2013). https://doi.org/10.1007/s11010-013-1684-9

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  • DOI: https://doi.org/10.1007/s11010-013-1684-9

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