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  • Original Article
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Downregulation of ZEB1 and overexpression of Smad7 contribute to resistance to TGF-β1-mediated growth suppression in adult T-cell leukemia/lymphoma

Oncogene volume 29, pages 4157–4169 (2010)Cite this article

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A Corrigendum to this article was published on 23 June 2011

Abstract

Zinc-finger E-box binding homeobox 1 (ZEB1) is a candidate tumor-suppressor gene in adult T-cell leukemia/lymphoma (ATLL). ZEB1 binds phosphorylated Smad2/3 to enhance transforming growth factor-β1 (TGF-β1) signaling. In addition to downregulation of ZEB1 mRNA, we found overexpression of inhibitory Smad, Smad7, in resistance of ATLL cells to growth suppression by TGF-β1. A protein complex of Smad7 and histone deacetylase constantly bound to the promoter region of TGF-β1 responsive genes with the Smad-responsive element (SRE) to inhibit TGF-β1 signaling; however, ectopic expression of ZEB1 reactivated TGF-β1 signaling by binding to Smad7 and recruiting the Smad3/p300 histone acetyltransferase complex to the promoter after TGF-β1 stimulation in ATLL. Conversely, because ZEB1 mRNA was detected in the late stages of T-cell development, we used CTLL2 cells with ZEB1 expression, a murine peripheral T-cell lymphoma, and found that a complex of Smad3, Smad7 and ZEB1 was bound to the SRE of the p21CDKN1A promoter after the induction of Smad7 by TGF-β1 treatment. Because the duration of TGF-β1-induced transcriptional activation of PAI-1 and p21 was shortened in shZEB1-expressing CTLL2 cells, ZEB1 may have a role in enhancing TGF-β1 signaling by binding not only to Smad3 but also to Smad7 in the nucleus. Altogether, these results suggest that both ZEB1 downregulation and Smad7 overexpression contribute to resistance to TGF-β1-mediated growth suppression in ATLL.

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References

  • Arnulf B, Villemain A, Nicot C, Mordelet E, Charneau P, Kersual J et al. (2002). Human T-cell lymphotropic virus oncoprotein Tax represses TGF-beta 1 signaling in human T cells via c-Jun activation: a potential mechanism of HTLV-I leukemogenesis. Blood 100: 4129–4138.

    Article  CAS  Google Scholar 

  • Bai S, Shi X, Yang X, Cao X . (2000). Smad6 as a transcriptional corepressor. J Biol Chem 275: 8267–8270.

    Article  CAS  Google Scholar 

  • Blobe GC, Schiemann WP, Lodish HF . (2000). Role of transforming growth factor β in human disease. N Engl J Med 342: 1350–1358.

    Article  CAS  Google Scholar 

  • Derynck R, Akhurst RJ, Balmain A . (2001). TGF-beta signaling in tumor suppression and cancer progression. Nat Genet 29: 117–129.

    Article  CAS  Google Scholar 

  • Ebisawa T, Fukuchi M, Murakami G, Chiba T, Tanaka K, Imamura T et al. (2001). Smurf1 interacts with transforming growth factor-beta type I receptor through Smad7 and induces receptor degradation. J Biol Chem 276: 12477–12480.

    Article  CAS  Google Scholar 

  • Gillis S, Smith KA . (1977). Long term culture of tumour-specific cytotoxic T cells. Nature 268: 154–156.

    Article  CAS  Google Scholar 

  • Hata A, Lagna G, Massagué J, Hemmati-Brivanlou A . (1998). Smad6 inhibits BMP/Smad1 signaling by specifically competing with the Smad4 tumor suppressor. Genes Dev 12: 186–197.

    Article  CAS  Google Scholar 

  • Hidaka T, Nakahata S, Hatakeyama K, Hamasaki M, Yamashita K, Kohno T et al. (2008). Down-regulation of TCF8 is involved in the leukemogenesis of adult-T cell leukemia/lymphoma. Blood 112: 383–393.

    Article  CAS  Google Scholar 

  • Inge TH, McCoy KM, Susskind BM, Barrett SK, Zhao G, Bear HD . (1992). Immunomodulatory effects of transforming growth factor-beta on T lymphocytes. Induction of CD8 expression in the CTLL-2 cell line and in normal thymocytes. J Immunol 148: 3847–3856.

    CAS  PubMed  Google Scholar 

  • Kavsak P, Rasmussen RK, Causing CG, Bonni S, Zhu H, Thomsen GH et al. (2000). Smad7 binds to Smurf2 to form an E3 ubiquitin ligase that targets the TGF beta receptor for degradation. Mol Cell 6: 1365–1375.

    Article  CAS  Google Scholar 

  • Kim SJ, Kehrl JH, Burton J, Tendler CL, Jeang KT, Danielpour D et al. (1990). Transactivation of the transforming growth factor beta 1 (TGF-beta 1) gene by human T lymphotropic virus type 1 tax: a potential mechanism for the increased production of TGF-beta 1 in adult T cell leukemia. J Exp Med 172: 121–129.

    Article  CAS  Google Scholar 

  • Kingsley DM . (1994). The TGF-beta superfamily: new members, new receptors, and new genetic tests of function in different organisms. Genes Dev 8: 133–146.

    Article  CAS  Google Scholar 

  • Lin X, Duan X, Liang YY, Su Y, Wrighton KH, Long J et al. (2006). PPM1A functions as a Smad phosphatase to terminate TGFbeta signaling. Cell 125: 915–928.

    Article  CAS  Google Scholar 

  • Lin X, Liang YY, Sun B, Liang M, Shi Y, Brunicardi FC et al. (2003). Smad6 recruits transcription corepressor CtBP to repress bone morphogenetic protein-induced transcription. Mol Cell Biol 23: 9081–9093.

    Article  CAS  Google Scholar 

  • Miyoshi I, Kubonishi I, Yoshimoto S, Akagi T, Ohtsuki Y, Shiraishi Y et al. (1981). Type C virus particles in a cord T-cell line derived by co-cultivating normal human cord leukocytes and human leukaemic T cells. Nature 294: 770–771.

    Article  CAS  Google Scholar 

  • Mochizuki N, Shimizu S, Nagasawa T, Tanaka H, Taniwaki M, Yokota J et al. (2000). A novel gene, MEL1, mapped to 1p36.3 is highly homologous to the MDS1/EVI1 gene and is transcriptionally activated in t(1;3)(p36;q21)-positive leukemia cells. Blood 96: 3209–3214.

    CAS  Google Scholar 

  • Mori N, Morishita M, Tsukazaki T, Giam CZ, Kumatori A, Tanaka Y et al. (2001). Human T-cell leukemia virus type I oncoprotein Tax represses Smad-dependent transforming growth factor beta signaling through interaction with CREB-binding protein/p300. Blood 97: 2137–2144.

    Article  CAS  Google Scholar 

  • Okada M, Maeda M, Tagaya Y, Taniguchi Y, Teshigawara K, Yoshiki T et al. (1985). TCGF (IL 2)-receptor induction Factor (S). II. Possible role of ATL-derived factor (ADF) on constitutive IL 2 receptor expression of HTLV-1(+) T cell lines. J Immunol 135: 3995–4003.

    CAS  PubMed  Google Scholar 

  • Postigo AA . (2003). Opposing functions of ZEB proteins in the regulation of the TGFbeta/BMP signaling pathway. EMBO J 22: 2443–2452.

    Article  CAS  Google Scholar 

  • Schneider U, Schwenk HU, Bornkamm G . (1977). Characterization of EBV-genome negative ‘null’ and ‘T’ cell lines derived from children with acute lymphoblastic leukemia and leukemic transformed non-Hodgkin lymphoma. Int J Cancer 19: 621–626.

    Article  CAS  Google Scholar 

  • Shi Y, Massagué J . (2003). Mechanisms of TGF-beta signaling from cell membrane to the nucleus. Cell 113: 685–700.

    Article  CAS  Google Scholar 

  • Seoane J, Le HV, Shen L, Anderson SA, Massagué J . (2004). Integration of Smad and forkhead pathways in the control of neuroepithelial and glioblastoma cell proliferation. Cell 117: 211–223.

    Article  CAS  Google Scholar 

  • Souchelnytskyi S, Nakayama T, Nakao A, Morén A, Heldin CH, Christian JL et al. (1998). Physical and functional interaction of murine and Xenopus Smad7 with bone morphogenetic protein receptors and transforming growth factor-beta receptors. J Biol Chem 273: 25364–25370.

    Article  CAS  Google Scholar 

  • Suzuki C, Murakami G, Fukuchi M, Shimanuki T, Shikauchi Y, Imamura T et al. (2002). Smurf1 regulates the inhibitory activity of Smad7 by targeting Smad7 to the plasma membrane. J Biol Chem 277: 39919–39925.

    Article  CAS  Google Scholar 

  • Tsukasaki K, Krebs J, Nagai K, Tomonaga M, Koeffler HP, Bartram CR et al. (2001). Comparative genomic hybridization analysis in adult T-cell leukemia/lymphoma: correlation with clinical course. Blood 97: 3875–3881.

    Article  CAS  Google Scholar 

  • van Grunsven LA, Schellens A, Huylebroeck D, Verschueren K . (2001). SIP1 (Smad interacting protein 1) and deltaEF1 (delta-crystallin enhancer binding factor) are structurally similar transcriptional repressors. J Bone Joint Surg Am 83-A: Suppl 1 (Part 1): S40–S47.

    Google Scholar 

  • Vermeer MH, van Doorn R, Dijkman R, Mao X, Whittaker S, van Voorst Vader PC et al. (2008). Novel and highly recurrent chromosomal alterations in Sézary syndrome. Cancer Res 68: 2689–2698.

    Article  CAS  Google Scholar 

  • Yamada Y, Ohmoto Y, Hata T, Yamamura M, Murata K, Tsukasaki K et al. (1996). Features of the cytokines secreted by adult T cell leukemia (ATL) cells. Leuk Lymphoma 21: 443–447.

    Article  CAS  Google Scholar 

  • Yasunaga J, Matsuoka M . (2003). Leukemogenesis of adult T-cell leukemia. Int J Hematol 78: 312–320.

    Article  Google Scholar 

  • Yoshida M, Nosaka K, Yasunaga J, Nishikata I, Morishita K, Matsuoka M . (2004). Aberrant expression of the MEL1S gene identified in association with hypomethylation in adult T-cell leukemia cells. Blood 103: 2753–2760.

    Article  CAS  Google Scholar 

  • Zhang S, Fei T, Zhang L, Zhang R, Chen F, Ning Y et al. (2007). Smad7 antagonizes transforming growth factor beta signaling in the nucleus by interfering with functional Smad-DNA complex formation. Mol Cell Biol 27: 4488–4499.

    Article  CAS  Google Scholar 

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Acknowledgements

This work was supported by Grants-in-Aid for Scientific Research of Priority Area from the Ministry of Education, Culture, Sports, Science and Technology, Japan; Leukemia Research fund; Research fund from Miyazaki Prefecture Collaboration of Regional Entities for the Advancement of Technological Excellence, JST (KM) and Young Scientists (B) (19790344) of Japan Society for the Promotion of Science (SN).

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Authors and Affiliations

  1. Division of Tumor and Cellular Biochemistry, Department of Medical Sciences, Faculty of Medicine, University of Miyazaki, Miyazaki, Japan

    S Nakahata & K Morishita

  2. Laboratory of Stem Cell Therapy, Center for Experimental Medicine, The Institute of Medical Science, University of Tokyo, Tokyo, Japan

    S Yamazaki & H Nakauchi

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  1. S Nakahata
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  2. S Yamazaki
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  3. H Nakauchi
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Correspondence to K Morishita.

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Nakahata, S., Yamazaki, S., Nakauchi, H. et al. Downregulation of ZEB1 and overexpression of Smad7 contribute to resistance to TGF-β1-mediated growth suppression in adult T-cell leukemia/lymphoma. Oncogene 29, 4157–4169 (2010). https://doi.org/10.1038/onc.2010.172

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