Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Original Article
  • Published:

HTLV-1 bZIP factor protein targets the Rb/E2F-1 pathway to promote proliferation and apoptosis of primary CD4+ T cells

Oncogene volume 35, pages 4509–4517 (2016)Cite this article

Subjects

Abstract

Human T-cell leukemia virus type 1 (HTLV-1) is an oncogenic retrovirus that induces a fatal T-cell malignancy, adult T-cell leukemia (ATL). Among several regulatory/accessory genes in HTLV-1, HTLV-1 bZIP factor (HBZ) is the only viral gene constitutively expressed in infected cells. Our previous study showed that HBZ functions in two different molecular forms, HBZ protein and HBZ RNA. In this study, we show that HBZ protein targets retinoblastoma protein (Rb), which is a critical tumor suppressor in many types of cancers. HBZ protein interacts with the Rb/E2F-1 complex and activates the transcription of E2F-target genes associated with cell cycle progression and apoptosis. Mouse primary CD4+ T cells transduced with HBZ show accelerated G1/S transition and apoptosis, and importantly, T cells from HBZ transgenic (HBZ-Tg) mice also demonstrate enhanced cell proliferation and apoptosis. To evaluate the functions of HBZ protein alone in vivo, we generated a new transgenic mouse strain that expresses HBZ mRNA altered by silent mutations but encoding intact protein. In these mice, the numbers of effector/memory and Foxp3+ T cells were increased, and genes associated with proliferation and apoptosis were upregulated. This study shows that HBZ protein promotes cell proliferation and apoptosis in primary CD4+ T cells through activation of the Rb/E2F pathway, and that HBZ protein also confers onto CD4+ T-cell immunophenotype similar to those of ATL cells, suggesting that HBZ protein has important roles in dysregulation of CD4+ T cells infected with HTLV-1.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2
Figure 3
Figure 4
Figure 5
Figure 6

Similar content being viewed by others

References

  1. Matsuoka M, Jeang KT . Human T-cell leukaemia virus type 1 (HTLV-1) infectivity and cellular transformation. Nat Rev Cancer 2007; 7: 270–280.

    CAS  PubMed  Google Scholar 

  2. Matsuoka M, Yasunaga JI . Human T-cell leukemia virus type 1: replication, proliferation and propagation by Tax and HTLV-1 bZIP factor. Curr Opin Virol 2013; 3: 684–691.

    CAS  PubMed  Google Scholar 

  3. Gillet NA, Malani N, Melamed A, Gormley N, Carter R, Bentley D et al. The host genomic environment of the provirus determines the abundance of HTLV-1-infected T-cell clones. Blood 2011; 117: 3113–3122.

    CAS  PubMed  PubMed Central  Google Scholar 

  4. Melamed A, Laydon DJ, Gillet NA, Tanaka Y, Taylor GP, Bangham CR . Genome-wide determinants of proviral targeting, clonal abundance and expression in natural HTLV-1 infection. PLoS Pathog 2013; 9: e1003271.

    CAS  PubMed  PubMed Central  Google Scholar 

  5. Philip S, Zahoor MA, Zhi H, Ho YK, Giam CZ . Regulation of human T-lymphotropic virus type I latency and reactivation by HBZ and Rex. PLoS Pathog 2014; 10: e1004040.

    PubMed  PubMed Central  Google Scholar 

  6. Yasunaga J, Matsuoka M . Molecular mechanisms of HTLV-1 infection and pathogenesis. Int J Hematol 2011; 94: 435–442.

    CAS  PubMed  Google Scholar 

  7. Gaudray G, Gachon F, Basbous J, Biard-Piechaczyk M, Devaux C, Mesnard JM . The complementary strand of the human T-cell leukemia virus type 1 RNA genome encodes a bZIP transcription factor that down-regulates viral transcription. J Virol 2002; 76: 12813–12822.

    CAS  PubMed  PubMed Central  Google Scholar 

  8. Satou Y, Yasunaga J, Yoshida M, Matsuoka M . HTLV-I basic leucine zipper factor gene mRNA supports proliferation of adult T cell leukemia cells. Proc Natl Acad Sci USA 2006; 103: 720–725.

    CAS  PubMed  PubMed Central  Google Scholar 

  9. Fan J, Ma G, Nosaka K, Tanabe J, Satou Y, Koito A et al. APOBEC3G generates nonsense mutations in human T-cell leukemia virus type 1 proviral genomes in vivo. J Virol 2010; 84: 7278–7287.

    CAS  PubMed  PubMed Central  Google Scholar 

  10. Mitobe Y, Yasunaga J, Furuta R, Matsuoka M . HTLV-1 bZIP Factor RNA and Protein Impart Distinct Functions on T-cell Proliferation and Survival. Cancer Res 2015; 75: 4143–4152.

    CAS  PubMed  Google Scholar 

  11. Satou Y, Matsuoka M . Molecular and cellular mechanism of leukemogenesis of ATL: emergent evidence of a significant role for HBZ in HTLV-1-induced pathogenesis. Leuk Res Treat 2012; 2012: 213653.

    Google Scholar 

  12. Classon M, Harlow E . The retinoblastoma tumour suppressor in development and cancer. Nat Rev Cancer 2002; 2: 910–917.

    CAS  PubMed  Google Scholar 

  13. Dyson N . The regulation of E2F by pRB-family proteins. Genes Dev 1998; 12: 2245–2262.

    CAS  PubMed  Google Scholar 

  14. Satou Y, Yasunaga J, Zhao T, Yoshida M, Miyazato P, Takai K et al. HTLV-1 bZIP factor induces T-cell lymphoma and systemic inflammation in vivo. PLoS Pathog 2011; 7: e1001274.

    CAS  PubMed  PubMed Central  Google Scholar 

  15. Dick FA, Rubin SM . Molecular mechanisms underlying RB protein function. Nat Rev Mol Cell Biol 2013; 14: 297–306.

    CAS  PubMed  PubMed Central  Google Scholar 

  16. Kehn K, Fuente Cde L, Strouss K, Berro R, Jiang H, Brady J et al. The HTLV-I Tax oncoprotein targets the retinoblastoma protein for proteasomal degradation. Oncogene 2005; 24: 525–540.

    CAS  PubMed  Google Scholar 

  17. Trimarchi JM, Lees JA . Sibling rivalry in the E2F family. Nat Rev Mol Cell Biol 2002; 3: 11–20.

    CAS  PubMed  Google Scholar 

  18. Polager S, Ginsberg D . p53 and E2f: partners in life and death. Nat Rev Cancer 2009; 9: 738–748.

    CAS  PubMed  Google Scholar 

  19. Komarov PG, Komarova EA, Kondratov RV, Christov-Tselkov K, Coon JS, Chernov MV et al. A chemical inhibitor of p53 that protects mice from the side effects of cancer therapy. Science 1999; 285: 1733–1737.

    CAS  PubMed  Google Scholar 

  20. Davidson W, Ren Q, Kari G, Kashi O, Dicker AP, Rodeck U . Inhibition of p73 function by Pifithrin-alpha as revealed by studies in zebrafish embryos. Cell Cycle 2008; 7: 1224–1230.

    CAS  PubMed  Google Scholar 

  21. Boyer SN, Wazer DE, Band V . E7 protein of human papilloma virus-16 induces degradation of retinoblastoma protein through the ubiquitin-proteasome pathway. Cancer Res 1996; 56: 4620–4624.

    CAS  PubMed  Google Scholar 

  22. Munakata T, Liang Y, Kim S, McGivern DR, Huibregtse J, Nomoto A et al. Hepatitis C virus induces E6AP-dependent degradation of the retinoblastoma protein. PLoS Pathog 2007; 3: 1335–1347.

    CAS  PubMed  Google Scholar 

  23. Knight JS, Sharma N, Robertson ES . Epstein-Barr virus latent antigen 3C can mediate the degradation of the retinoblastoma protein through an SCF cellular ubiquitin ligase. Proc Natl Acad Sci USA 2005; 102: 18562–18566.

    CAS  PubMed  PubMed Central  Google Scholar 

  24. Borchert S, Czech-Sioli M, Neumann F, Schmidt C, Wimmer P, Dobner T et al. High-affinity Rb binding, p53 inhibition, subcellular localization, and transformation by wild-type or tumor-derived shortened Merkel cell polyomavirus large T antigens. J Virol 2014; 88: 3144–3160.

    PubMed  PubMed Central  Google Scholar 

  25. Swaims AY, Khani F, Zhang Y, Roberts AI, Devadas S, Shi Y et al. Immune activation induces immortalization of HTLV-1 LTR-Tax transgenic CD4+ T cells. Blood 2010; 116: 2994–3003.

    CAS  PubMed  PubMed Central  Google Scholar 

  26. Arpin-Andre C, Laverdure S, Barbeau B, Gross A, Mesnard JM . Construction of a reporter vector for analysis of bidirectional transcriptional activity of retrovirus LTR. Plasmid 2014; 74: 45–51.

    CAS  PubMed  Google Scholar 

  27. Yoshida M, Satou Y, Yasunaga J, Fujisawa J, Matsuoka M . Transcriptional control of spliced and unspliced human T-cell leukemia virus type 1 bZIP factor (HBZ) gene. J Virol 2008; 82: 9359–9368.

    CAS  PubMed  PubMed Central  Google Scholar 

  28. Wu X, Levine AJ . p53 and E2F-1 cooperate to mediate apoptosis. Proc Natl Acad Sci USA 1994; 91: 3602–3606.

    CAS  PubMed  PubMed Central  Google Scholar 

  29. Irwin M, Marin MC, Phillips AC, Seelan RS, Smith DI, Liu W et al. Role for the p53 homologue p73 in E2F-1-induced apoptosis. Nature 2000; 407: 645–648.

    CAS  PubMed  Google Scholar 

  30. Bosco EE, Mayhew CN, Hennigan RF, Sage J, Jacks T, Knudsen ES . RB signaling prevents replication-dependent DNA double-strand breaks following genotoxic insult. Nucleic Acids Res 2004; 32: 25–34.

    CAS  PubMed  PubMed Central  Google Scholar 

  31. Lowe SW, Cepero E, Evan G . Intrinsic tumour suppression. Nature 2004; 432: 307–315.

    CAS  PubMed  Google Scholar 

  32. Vernin C, Thenoz M, Pinatel C, Gessain A, Gout O, Delfau-Larue MH et al. HTLV-1 bZIP factor HBZ promotes cell proliferation and genetic instability by activating OncomiRs. Cancer Res 2014; 74: 6082–6093.

    CAS  PubMed  Google Scholar 

  33. Zhao T, Satou Y, Sugata K, Miyazato P, Green PL, Imamura T et al. HTLV-1 bZIP factor enhances TGF-beta signaling through p300 coactivator. Blood 2011; 118: 1865–1876.

    CAS  PubMed  PubMed Central  Google Scholar 

  34. Yamamoto-Taguchi N, Satou Y, Miyazato P, Ohshima K, Nakagawa M, Katagiri K et al. HTLV-1 bZIP factor induces inflammation through labile Foxp3 expression. PLoS Pathog 2013; 9: e1003630.

    CAS  PubMed  PubMed Central  Google Scholar 

  35. Takeda S, Maeda M, Morikawa S, Taniguchi Y, Yasunaga J, Nosaka K et al. Genetic and epigenetic inactivation of tax gene in adult T-cell leukemia cells. Int J Cancer 2004; 109: 559–567.

    CAS  PubMed  Google Scholar 

  36. Katoh T, Harada T, Morikawa S, Wakutani T . IL-2- and IL-2-R- independent proliferation of T-cell lines from adult T-cell leukemia/lymphoma patients. Int J Cancer 1986; 38: 265–274.

    CAS  PubMed  Google Scholar 

  37. Zhao T, Yasunaga J, Satou Y, Nakao M, Takahashi M, Fujii M et al. Human T-cell leukemia virus type 1 bZIP factor selectively suppresses the classical pathway of NF-kappaB. Blood 2009; 113: 2755–2764.

    CAS  PubMed  Google Scholar 

  38. Peloponese Jr JM, Yasunaga J, Kinjo T, Watashi K, Jeang KT . Peptidylproline cis-trans-isomerase Pin1 interacts with human T-cell leukemia virus type 1 tax and modulates its activation of NF-kappaB. J Virol 2009; 83: 3238–3248.

    CAS  PubMed  PubMed Central  Google Scholar 

  39. Sawada S, Gowrishankar K, Kitamura R, Suzuki M, Suzuki G, Tahara S et al. Disturbed CD4+ T cell homeostasis and in vitro HIV-1 susceptibility in transgenic mice expressing T cell line-tropic HIV-1 receptors. J Exp Med 1998; 187: 1439–1449.

    CAS  PubMed  PubMed Central  Google Scholar 

  40. Arnold J, Zimmerman B, Li M, Lairmore MD, Green PL . Human T-cell leukemia virus type-1 antisense-encoded gene, Hbz, promotes T-lymphocyte proliferation. Blood 2008; 112: 3788–3797.

    CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

We thank Linda Kingsbury and Kathleen Hayes-Ozello for editorial comments and proofreading. This study was supported by grants from the Ministry of Education, Science, Sports and Culture of Japan to MM (22114003) and JY (26460554) and a grant from the Takeda Science Foundation (JY) and a grant from the National Institutes of Health (CA100730) to PLG. This study was performed as a research program of the Platform for Dynamic Approaches to Living System from the Ministry of Education, Culture, Sports, Science and Technology, Japan (AK), and also supported in part by the JSPS Core-to-Core Program A, Advanced Research Networks.

Author information

Authors and Affiliations

  1. Laboratory of Virus Control, Institute for Virus Research, Kyoto University, Sakyo-ku, Kyoto, Japan

    A Kawatsuki, J-i Yasunaga, Y Mitobe & M Matsuoka

  2. Center for Retrovirus Research and Departments of Veterinary Biosciences and Molecular Virology, Immunology and Medical Genetics, The Ohio State University, Columbus, OH, USA

    P L Green

Authors
  1. A Kawatsuki
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. J-i Yasunaga
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Y Mitobe
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. P L Green
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. M Matsuoka
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to J-i Yasunaga.

Ethics declarations

Competing interests

The authors declare no conflict of interest.

Additional information

Supplementary Information accompanies this paper on the Oncogene website

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Kawatsuki, A., Yasunaga, Ji., Mitobe, Y. et al. HTLV-1 bZIP factor protein targets the Rb/E2F-1 pathway to promote proliferation and apoptosis of primary CD4+ T cells. Oncogene 35, 4509–4517 (2016). https://doi.org/10.1038/onc.2015.510

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/onc.2015.510

This article is cited by

Search

Advanced search

Quick links