1887

Abstract

More than 2000 human endogenous retrovirus (HERV) sequences are present in the human genome, yet only a few are intact and able to produce proteins. The normal functions of these, if any, are unknown, but some HERV proteins have been implicated in cancers, in particular germ-cell cancers. For instance, it has been documented that (i) patients with germ-cell tumours frequently produce antibodies against HERV proteins; (ii) transgenic mice expressing HERV-K (HML-2) are prone to testicular carcinoma ; and (iii) Rec can bind and suppress a guardian of germline stem-cell pluripotency, the promyelocytic leukaemia zinc-finger protein (PLZF). This study identified the PLZF-related testicular zinc-finger protein (TZFP) as a binding partner of HERV-K (HML-2) Rec. Interactions occurred via the N- and C-terminal domains of Rec and the C-terminal DNA-binding zinc-finger domain of TZFP (aa 375–450). Not much is known about the function of TZFP. The protein is expressed predominantly in the testis, where it functions as a transcriptional repressor that is active during specific stages of spermatogenesis. The most intensely studied function of TZFP is that of a co-repressor of the activated androgen receptor (AR). Here, it was shown that Rec can form a trimeric complex with TZFP and AR, and can relieve the TZFP-mediated repression of AR-induced transactivation. In addition, Rec was able to overcome the direct transcriptional repression by TZFP of the c- gene promoter in reporter assays. Thus, HERV-K (HML-2) Rec may function as an oncoprotein by de-repressing oncogenic transcription factors such as AR.

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2010-06-01
2021-10-28
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References

  1. Armbruester, V., Sauter, M., Krautkraemer, E., Meese, E., Kleiman, A., Best, B., Roemer, K. & Mueller-Lantzsch, N.(2002). A novel gene from the human endogenous retrovirus K expressed in transformed cells. Clin Cancer Res 8, 1800–1807. [Google Scholar]
  2. Armbruester, V., Sauter, M., Roemer, K., Best, B., Hahn, S., Nty, A., Schmid, A., Philipp, S., Mueller, A. & other authors(2004). Np9 protein of human endogenous retrovirus K interacts with ligand of Numb protein X. J Virol 78, 10310–10319.[CrossRef] [Google Scholar]
  3. Balk, S. P. & Knudsen, K. E.(2008). AR, the cell cycle, and prostate cancer. Nucl Recept Signal 6, e001 [Google Scholar]
  4. Barbulescu, M., Turner, G., Seaman, M. I., Deinard, A. S., Kidd, K. K. & Lenz, J.(1999). Many human endogenous retrovirus K (HERV-K) proviruses are unique to humans. Curr Biol 9, 861–868.[CrossRef] [Google Scholar]
  5. Barna, M., Hawe, N., Niswander, L. & Pandolfi, P. P.(2000). Plzf regulates limb and axial skeletal patterning. Nat Genet 25, 166–172.[CrossRef] [Google Scholar]
  6. Blond, J. L., Lavillette, D., Cheynet, V., Bouton, O., Oriol, G., Chapel-Fernandes, S., Mandrand, B., Mallet, F. & Cosset, F. L.(2000). An envelope glycoprotein of the human endogenous retrovirus HERV-W is expressed in the human placenta and fuses cells expressing the type D mammalian retrovirus receptor. J Virol 74, 3321–3329.[CrossRef] [Google Scholar]
  7. Boese, A., Sauter, M., Galli, U., Best, B., Herbst, H., Mayer, J., Kremmer, E., Roemer, K. & Mueller-Lantzsch, N.(2000). Human endogenous retrovirus protein cORF supports cell transformation and associates with the promyelocytic leukemia zinc finger protein. Oncogene 19, 4328–4336.[CrossRef] [Google Scholar]
  8. Buaas, F. W., Kirsh, A. L., Sharma, M., McLean, D. J., Morris, J. L., Griswold, M. D., de Rooij, D. G. & Braun, R. E.(2004). Plzf is required in adult male germ cells for stem cell self-renewal. Nat Genet 36, 647–652.[CrossRef] [Google Scholar]
  9. Cheng, S., Brzostek, S., Lee, S. R., Hollenberg, A. N. & Balk, S. P.(2002). Inhibition of the dihydrotestosterone-activated androgen receptor by nuclear receptor corepressor. Mol Endocrinol 16, 1492–1501.[CrossRef] [Google Scholar]
  10. Costoya, J. A., Hobbs, R. M., Barna, M., Cattoretti, G., Manova, K., Sukhwani, M., Orwig, K. E., Wolgemuth, D. J. & Pandolfi, P. P.(2004). Essential role of Plzf in maintenance of spermatogonial stem cells. Nat Genet 36, 653–659.[CrossRef] [Google Scholar]
  11. Denne, M., Sauter, M., Armbruester, V., Licht, J. D., Roemer, K. & Mueller-Lantzsch, N.(2007). Physical and functional interactions of human endogenous retrovirus proteins Np9 and Rec with the promyelocytic leukemia zinc finger protein. J Virol 81, 5607–5616.[CrossRef] [Google Scholar]
  12. de Ruiter, P. E., Teuwen, R., Trapman, J., Dijkema, R. & Brinkmann, A. O.(1995). Synergism between androgens and protein kinase-C on androgen-regulated gene expression. Mol Cell Endocrinol 110, R1–R6.[CrossRef] [Google Scholar]
  13. Galli, U. M., Sauter, M., Lecher, B., Maurer, S., Herbst, H., Roemer, K. & Mueller-Lantzsch, N.(2005). Human endogenous retrovirus rec interferes with germ cell development in mice and may cause carcinoma in situ, the predecessor lesion of germ cell tumours. Oncogene 24, 3223–3228.[CrossRef] [Google Scholar]
  14. Hayashi, T., Kageyama, Y., Ishizaka, K., Xia, G., Kihara, K. & Oshima, H.(2001). Requirement of Notch 1 and its ligand Jagged 2 expressions for spermatogenesis in rat and human testes. J Androl 22, 999–1011. [Google Scholar]
  15. Hsu, K. W., Hsieh, R. H., Lee, Y. H., Chao, C. H., Wu, K. J., Tseng, M. J. & Yeh, T. S.(2008). The activated Notch1 receptor cooperates with α-enolase and MBP-1 in modulating c-myc activity. Mol Cell Biol 28, 4829–4842.[CrossRef] [Google Scholar]
  16. Inoue, A., Ishiji, A., Kasagi, S., Ishizuka, M., Hirose, S., Baba, T. & Hagiwara, H.(2000). The transcript for a novel protein with a zinc finger motif is expressed at specific stages of mouse spermatogenesis. Biochem Biophys Res Commun 273, 398–403.[CrossRef] [Google Scholar]
  17. Ishizuka, M., Ohshima, H., Tamura, N., Nakada, T., Inoue, A., Hirose, S. & Hagiwara, H.(2003). Molecular cloning and characteristics of a novel zinc finger protein and its splice variant whose transcripts are expressed during spermatogenesis. Biochem Biophys Res Commun 301, 1079–1085.[CrossRef] [Google Scholar]
  18. Ishizuka, M., Kawate, H., Takayanagi, R., Ohshima, H., Tao, R. H. & Hagiwara, H.(2005). A zinc finger protein TZF is a novel corepressor of androgen receptor. Biochem Biophys Res Commun 331, 1025–1031.[CrossRef] [Google Scholar]
  19. Lander, E. S., Linton, L. M., Birren, B., Nusbaum, C., Zody, M. C., Baldwin, J., Devon, K., Dewar, K., Doyle, M. & other authors(2001). Initial sequencing and analysis of the human genome. Nature 409, 860–921.[CrossRef] [Google Scholar]
  20. Liao, W. R., Hsieh, R. H., Hsu, K. W., Wu, M. Z., Tseng, M. J., Mai, R. T., Wu Lee, Y. H. & Yeh, T. S.(2007). The CBF1-independent Notch1 signal pathway activates human c-myc expression partially via transcription factor YY1. Carcinogenesis 28, 1867–1876.[CrossRef] [Google Scholar]
  21. Lin, W., Lai, C. H., Tang, C. J., Huang, C. J. & Tang, T. K.(1999). Identification and gene structure of a novel human PLZF-related transcription factor gene, TZFP. Biochem Biophys Res Commun 264, 789–795.[CrossRef] [Google Scholar]
  22. Mallet, F., Bouton, O., Prudhomme, S., Cheynet, V., Oriol, G., Bonnaud, B., Lucotte, G., Duret, L. & Mandrand, B.(2004). The endogenous retroviral locus ERVWE1 is a bona fide gene involved in hominoid placental physiology. Proc Natl Acad Sci U S A 101, 1731–1736.[CrossRef] [Google Scholar]
  23. Mangelsdorf, D. J., Thummel, C., Beato, M., Herrlich, P., Schutz, G., Umesono, K., Blumberg, B., Kastner, P., Mark, M. & other authors(1995). The nuclear receptor superfamily: the second decade. Cell 83, 835–839.[CrossRef] [Google Scholar]
  24. Mayer, J., Sauter, M., Racz, A., Scherer, D., Mueller-Lantzsch, N. & Meese, E.(1999). An almost intact human endogenous retrovirus K on human chromosome 7. Nat Genet 21, 257–258.[CrossRef] [Google Scholar]
  25. McConnell, M. J., Chevallier, N., Berkofsky-Fessler, W., Giltnane, J. M., Malani, R. B., Staudt, L. M. & Licht, J. D.(2003). Growth suppression by acute promyelocytic leukemia-associated protein PLZF is mediated by repression of c-myc expression. Mol Cell Biol 23, 9375–9388.[CrossRef] [Google Scholar]
  26. Ruprecht, K., Mayer, J., Sauter, M., Roemer, K. & Mueller-Lantzsch, N.(2008). Endogenous retroviruses and cancer. Cell Mol Life Sci 65, 3366–3382.[CrossRef] [Google Scholar]
  27. Sauter, M., Schommer, S., Kremmer, E., Remberger, K., Dolken, G., Lemm, I., Buck, M., Best, B., Neumann-Haefelin, D. & Mueller-Lantzsch, N.(1995). Human endogenous retrovirus K10: expression of Gag protein and detection of antibodies in patients with seminomas. J Virol 69, 414–421. [Google Scholar]
  28. Sauter, M., Roemer, K., Best, B., Afting, M., Schommer, S., Seitz, G., Hartmann, M. & Mueller-Lantzsch, N.(1996). Specificity of antibodies directed against Env protein of human endogenous retroviruses in patients with germ cell tumours. Cancer Res 56, 4362–4365. [Google Scholar]
  29. Tang, C. J., Chuang, C. K., Hu, H. M. & Tang, T. K.(2001). The zinc finger domain of Tzfp binds to the tbs motif located at the upstream flanking region of the Aie1 (aurora-C) kinase gene. J Biol Chem 276, 19631–19639.[CrossRef] [Google Scholar]
  30. Tao, R. H., Kawate, H., Wu, Y., Ohnaka, K., Ishizuka, M., Inoue, A., Hagiwara, H. & Takayanagi, R.(2006). Testicular zinc finger protein recruits histone deacetylase 2 and suppresses the transactivation function and intranuclear foci formation of agonist-bound androgen receptor competitively with TIF2. Mol Cell Endocrinol 247, 150–165.[CrossRef] [Google Scholar]
  31. Wang, R. S., Yeh, S., Tzeng, C. R. & Chang, C.(2009). Androgen receptor roles in spermatogenesis and fertility: lessons from testicular cell-specific androgen receptor knockout mice. Endocr Rev 30, 119–132.[CrossRef] [Google Scholar]
  32. Wang-Johanning, F., Frost, A. R., Jian, B., Epp, L., Lu, D. W., Johanning, G. L., Khazaeli, M. B., LoBuglio, A. F., Shaw, D. R. & Strong, T. V.(2003). Quantitation of HERV-K env gene expression and splicing in human breast cancer. Oncogene 22, 1528–1535.[CrossRef] [Google Scholar]
  33. Weijzen, S., Rizzo, P., Braid, M., Vaishnav, R., Jonkheer, S. M., Zlobin, A., Osborne, B. A., Gottipati, S., Aster, J. C. & other authors(2002). Activation of Notch-1 signaling maintains the neoplastic phenotype in human Ras-transformed cells. Nat Med 8, 979–986.[CrossRef] [Google Scholar]
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