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 Paper
  • Published:

IL-2- and STAT5-regulated cytokine gene expression in cells expressing the Tax protein of HTLV-1

Oncogene volume 24, pages 4624–4633 (2005)Cite this article

Abstract

Interleukin-2 (IL-2) mediates cell cycle progression and antiapoptosis in human T cells via several signal transduction pathways. The Tax protein of the human T-cell leukemia virus type I (HTLV-1) deregulates cell growth and alters the role of IL-2 in infected cells. However, Tax-immortalized cells stay dependent on IL-2, suggesting that events besides HTLV-1 gene expression are required for leukemia to develop. Here, IL-2-dependent and -independent events were analysed in a human T cell line immortalized by Tax. These studies show that, of the signaling pathways evaluated, only STAT5 remains dependent. Microarray analyses revealed several genes, including il-5, il-9 and il-13, are uniquely upregulated by IL-2 in the presence of Tax. Bioinformatics and supporting molecular biology show that some of these genes are STAT5 targets, explaining their IL-2 upregulation. These results suggest that IL-2 and viral proteins work together to induce gene expression, promoting the hypothesis that deregulation via the constitutive activation of STAT5 may lead to the IL-2-independent phenotype of HTLV-1-transformed cells.

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

Similar content being viewed by others

References

  • Akagi T and Shimotohno K . (1993). J. Virol., 67, 1211–1217.

  • Albrecht B and Lairmore MD . (2002). Microbiol. Mol. Biol. Rev., 66, 396–406.

  • Blumenthal SG, Aichele G, Wirth T, Czernilofsky AP, Nordheim A and Dittmer J . (1999). J. Biol. Chem., 274, 12910–12916.

  • Boer AK, Drayer AL, Rui H and Vellenga E . (2002). Blood, 100, 467–473.

  • Chung HK, Young HA, Goon PK, Heidecker G, Princler GL, Shimozato O, Taylor GP, Bangham CR and Derse D . (2003). Blood, 102, 4130–4136.

  • Darnell Jr JE . (1997). Science, 277, 1630–1635.

  • Decker T and Kovarik P . (2000). Oncogene, 19, 2628–2637.

  • Fung MM, Rohwer F and McGuire KL . (2003). Cell. Signal, 15, 625–636.

  • Gaffen SL . (2001). Cytokine, 14, 63–77.

  • Gatza ML, Watt JC and Marriott SJ . (2003). Oncogene, 22, 5141–5149.

  • Grassmann R, Berchtold S, Radant I, Alt M, Fleckenstein B, Sodroski JG, Haseltine WA and Ramstedt U . (1992). J. Virol., 66, 4570–4575.

  • Grassmann R, Dengler C, Muller-Fleckenstein I, Fleckenstein B, McGuire K, Dokhelar MC, Sodroski JG and Haseltine WA . (1989). Proc. Natl. Acad. Sci. USA, 86, 3351–3355.

  • Hertz GZ, Hartzell III GW and Stormo GD . (1990). Comput. Appl. Biosci., 6, 81–92.

  • Hertz GZ and Stormo GD . (1999). Bioinformatics, 15, 563–577.

  • Hollsberg P . (1999). Microbiol. Mol. Biol. Rev., 63, 308–333.

  • Hollsberg P and Hafler DA . (1993). New Engl. J. Med., 328, 1173–1182.

  • Houssiau FA, Renauld JC, Stevens M, Lehmann F, Lethe B, Coulie PG and Van Snick J . (1993). J. Immunol., 150, 2634–2640.

  • Iacobelli M, Rohwer F, Shanahan P, Quiroz JA and McGuire KL . (1999). J. Immunol., 162, 3308–3315.

  • Jin DY, Teramoto H, Giam CZ, Chum RF, Gutkind JS and Jeang KT . (1997). J. Biol. Chem., 272, 25816–25823.

  • Karnitz LM, Burns LA, Sutor SL, Blenis J and Abraham RT . (1995). Mol. Cell. Biol., 15, 3049–3057.

  • Kelleher K, Bean K, Clark SC, Leung WY, Yang-Feng TL, Chen JW, Lin PF, Luo W and Yang YC . (1991). Blood, 77, 1436–1441.

  • Kim HP, Kelly J and Leonard WJ . (2001). Immunity, 15, 159–172.

  • Kirken RA, Rui H, Evans GA and Farrar WL . (1993). J. Biol. Chem., 268, 22765–22770.

  • Kirken RA, Rui H, Malabarba MG and Farrar WL . (1994). J. Biol. Chem., 269, 19136–19141.

  • Li C and Wong WH . (2001a). Genome Biol., 2, RESEARCH0032.

  • Li C and Wong WH . (2001b). Proc. Natl. Acad. Sci. USA., 98, 31–36.

  • Lin JX and Leonard WJ . (2000). Oncogene, 19, 2566–2576.

  • Li-Weber M, Giaisi M and Krammer PH . (2001). Eur. J. Immunol., 31, 3694–3703.

  • Lord JD, McIntosh BC, Greenberg PD and Nelson BH . (2000). J. Immunol., 164, 2533–2541.

  • Lu L, Zhu J, Zheng Z, Yan M, Xu W, Sun L, Theze J and Liu X . (1998). Eur. J. Immunol., 28, 805–810.

  • Martino A, Holmes JHT, Lord JD, Moon JJ and Nelson BH . (2001). J. Immunol., 166, 1723–1729.

  • Matsushita K, Arima N, Ohtsubo H, Fujiwara H, Hidaka S, Fukumori J and Tanaka H . (1997). Leuk. Res., 21, 211–216.

  • McGuire KL and Iacobelli M . (1997). J. Immunol., 159, 1319–1327.

  • McGuire KL, Rohwer F, Sabzevari H, Theofilopoulous AN, Fung MM and Bower K . (1999). Recent Res. Devel. Immunol., 1, 149.

  • Migone TS, Lin JX, Cereseto A, Mulloy JC, O'Shea JJ, Franchini G and Leonard WJ . (1995). Science, 269, 79–81.

  • Miyazaki T, Kawahara A, Fujii H, Nakagawa Y, Minami Y, Liu Z-J, Oishi I, Silvennoinen O, Witthuhn BA, Ihle JN and Taniguchi T . (1994). Science, 266, 1045–1047.

  • Murata K, Yamada Y, Kamihira S, Atogami S, Tsukasaki K, Momita S, Amagasaki T, Sadamiri N, Tomonaga M, Kinoshita K and Ichimaru M . (1992). Cancer, 69, 966–971.

  • Ng J and Cantrell D . (1997). J. Biol. Chem., 272, 24542–24549.

  • Ogata M, Ogata Y, Kohno K, Uno N, Ohno E, Ohtsuka E, Saburi Y, Kamberi P, Nasu M and Kikuchi H . (1998). Am. J. Hematol., 59, 242–245.

  • O'Shea JJ . (1997). Immunity, 7, 1–11.

  • Pfaffl MW . (2001). Nucleic Acids Res., 29, e45.

  • Poiesz BJ, Ruscetti FW, Gazdar AF, Bunn PA, Minna JD and Gallo RC . (1980). Proc. Natl. Acad. Sci. USA, 77, 7415–7419.

  • Robb RJ . (1984). Immunol. Today, 5, 203–209.

  • Robek MD, Wong FH and Ratner L . (1998). J. Virol., 72, 4458–4462.

  • Rohwer F, Todd S and McGuire KL . (1996). J. Immunol., 157, 643–649.

  • Ruckes T, Saul D, Van Snick J, Hermine O and Grassmann R . (2001). Blood, 98, 1150–1159.

  • Russell SM, Johnston JA, Noguchi M, Kawamura M, Bacon CM, Friedmann M, Berg M, McVicar DW, Witthuhn BA, Silvennoinen O, Goldman AS, Schmalsteig FC, Ihle JN, O'Shea JJ and Leonard WJ . (1994). Science, 266, 1042–1045.

  • Skinnider BF, Kapp U and Mak TW . (2001). Int. Arch. Allergy. Immunol., 126, 267–276.

  • Skinnider BF, Kapp U and Mak TW . (2002). Leuk. Lymphoma, 43, 1203–1210.

  • Smith KA . (1984). Annu. Rev. Immunol., 2, 319–333.

  • Sodroski JG . (1992). Biochem. Biophys. Acta, 1114, 19–29.

  • Soldaini E, John S, Moro S, Bollenbacher J, Schindler U and Leonard WJ . (2000). Mol. Cell. Biol., 20, 389–401.

  • Takemoto S, Mulloy JC, Cereseto A, Migone TS, Patel BK, Matsuoka M, Yamaguchi K, Takatsuki K, Kamihira S, White JD, Leonard WJ, Waldmann T and Franchini G . (1997). Proc. Natl. Acad. Sci. USA, 94, 13897–13902.

  • Uyttenhove C, Simpson RJ and Van Snick J . (1988). Proc. Natl. Acad. Sci. USA, 85, 6934–6938.

  • Waldele K, Schneider G, Ruckes T and Grassmann R . (2004). J. Virol., 78, 6081–6090.

  • Weinmann AS, Bartley SM, Zhang T, Zhang MQ and Farnham PJ . (2001). Mol. Cell. Biol., 21, 6820–6832.

  • Witthuhn BA, Silvennoinen O, Miura O, Lai KS, Cwik C, Liu ET and Ihle JN . (1994). Nature, 370, 153–157.

  • Xu X, Kang S-H, Heidenreich O, Okerholm M, O'Shea JJ and Nerenberg MI . (1995). J. Clin. Investig., 96, 1548–1555.

  • Yamagata T, Mitani K, Ueno H, Kanda Y, Yazaki Y and Hirai H . (1997). Mol. Cell. Biol., 17, 4272–4281.

  • Ye J, Silverman L, Lairmore MD and Green PL . (2003). Blood, 102, 3963–3969.

  • Yoshida M . (1994). AIDS Res. Hum. Retrov., 10, 1193–1197.

Download references

Acknowledgements

We thank Paul Shanahan and Lisa Becker for technical contributions and Robert Stewart and Michael David for helpful discussion. We also thank William Wachsman and staff of the UCSD Gene Chip Core Facility for the microarray analyses, the operating room at Children's Hospital of San Diego for thymus specimens, Dennis J Young at the UCSD Cancer Center for assistance with FACS analysis, Robert Kirken for phosphoserine-specific STAT5a/b antisera, and Peggy Farnham for assistance with ChIP assays. This work was supported by ACS grant #RPG-96-077-03-CNE and an SDSU Research and Creative Activity Award (to KLM). Computational facilities and support for JLF were provided by the National Biomedical Computation Resource, an NIH Research Resource (P41 RR08605-08).

Author information

Authors and Affiliations

  1. Department of Biology, San Diego State University, 5500 Campanile Drive, San Diego, CA, 92182-4614, USA

    Michelle M Fung, Yen-Lin Chu & Kathleen L McGuire

  2. San Diego Supercomputer Center, University of California, San Diego, La Jolla, CA, 92093, USA

    J Lynn Fink

  3. Institute for Childhood and Neglected Diseases, The Scripps Research Institute, La Jolla, CA, 92037, USA

    Anne Wallace

Authors
  1. Michelle M Fung
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Yen-Lin Chu
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. J Lynn Fink
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Anne Wallace
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Kathleen L McGuire
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Kathleen L McGuire.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Fung, M., Chu, YL., Fink, J. et al. IL-2- and STAT5-regulated cytokine gene expression in cells expressing the Tax protein of HTLV-1. Oncogene 24, 4624–4633 (2005). https://doi.org/10.1038/sj.onc.1208507

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.onc.1208507

Keywords

This article is cited by

Search

Advanced search

Quick links