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:

Human T-cell leukemia virus type 1 Tax interacts with Chk1 and attenuates DNA-damage induced G2 arrest mediated by Chk1

Oncogene volume 23, pages 4966–4974 (2004)Cite this article

Abstract

Checkpoint kinase 1 (Chk1) mediates diverse cellular responses to genotoxic stress, regulating the network of genome-surveillance pathways that coordinate cell cycle progression with DNA repair. Chk1 is essential for mammalian development and viability, and has been shown to be important for both S and G2 checkpoints. We now present evidence that the HTLV-1 Tax protein interacts directly with Chk1 and impairs its kinase activities in vitro and in vivo. The direct and physical interaction of Chk1 and Tax was observed in HTLV-1-infected T cells (C81, HuT 102 and MT-2) and transfected fibroblasts (293 T) by coimmunoprecipitation and by in vitro GST pull-down assays. Interestingly, Tax inhibited the kinase activity of Chk1 protein in in vitro and in vivo kinase assays. Consistent with these results, Tax inhibited the phosphorylation-dependent degradation of Cdc25A and G2 arrest in response to γ-irradiation (IR) in a dose-dependent manner in vivo. The G2 arrest did not require Chk2 or p53. These studies provide the first example of a viral transforming protein targeting Chk1 and provide important insights into checkpoint pathway regulation.

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
Figure 7

Similar content being viewed by others

References

  • Abraham RT . (2001). Genes Dev., 15, 2177–2196.

  • Akagi T, Ono H, Tsuchida N and Shimotohno K . (1997). FEBS Lett., 406, 263–266.

  • Anderson CW, Appella E and Sakaguchi K . (1998). J. Protein Chem., 17, 527.

  • Ariumi Y, Ego T, Kaida A, Matsumoto M, Pandolfi PP and Shimotohno K . (2003). Oncogene, 22, 1611–1619.

  • Ariumi Y, Kaida A, Lin JY, Hirota M, Masui O, Yamaoka S, Taya Y and Shimotohno K . (2000). Oncogene, 19, 1491–1499.

  • Bartek J and Lukas J . (2003). Cancer Cell, 3, 421–429.

  • Bex F and Gaynor RB . (1998). Methods, 16, 83–94.

  • Brown AL, Lee CH, Schwarz JK, Mitiku N, Piwnica-Worms H and Chung JH . (1999). Proc. Natl. Acad. Sci. USA, 96, 3745–3750.

  • Bunz F, Dutriaux A, Lengauer C, Waldman T, Zhou S, Brown JP, Sedivy JM, Kinzler KW and Vogelstein B . (1998). Science, 282, 1497–1501.

  • Burton M, Upadhyaya CD, Maier B, Hope TJ and Semmes OJ . (2000). J. Virol., 74, 2351–2364.

  • Canman CE, Lim DS, Cimprich KA, Taya Y, Tamai K, Sakaguchi K, Appella E, Kastan MB and Siliciano JD . (1998). Science, 281, 1677–1679.

  • Cereseto A, Diella F, Mulloy JC, Cara A, Michieli P, Grassmann R, Franchini G and Klotman ME . (1996). Blood, 88, 1551–1560.

  • Chen Z, Xiao Z, Chen J, Ng SC, Sowin T, Sham H, Rosenberg S, Fesik S and Zhang H . (2003). Mol. Cancer Ther., 2, 543–548.

  • Clifford B, Beljin M, Stark GR and Taylor WR . (2003). Cancer Res., 63, 4074–4081.

  • Coscoy L, Gonzalez-Dunia D, Tangy F, Syan S, Brahic M and Ozden S . (1998). Virology, 248, 332–341.

  • Feijoo C, Hall-Jackson C, Wu R, Jenkins D, Leitch J, Gilbert DM and Smythe C . (2001). J. Cell Biol., 154, 913–924.

  • Franchini G . (1995). Blood, 86, 3619–3639.

  • Gartenhaus RB and Wang P . (1995). Leukemia, 9, 2082–2086.

  • Gatei M, Sloper K, Sorensen C, Syljuasen R, Falck J, Hobson K, Savage K, Lukas J, Zhou BB, Bartek J and Khanna KK . (2003). J. Biol. Chem., 278, 14806–14811.

  • Gatei M, Zhou BB, Hobson K, Scott S, Young D and Khanna KK . (2001). J. Biol. Chem., 276, 17276–17280.

  • 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.

  • Grossman WJ, Kimata JT, Wong F, Zutter M, Ley TJ and Ratner L . (1995). Proc. Natl. Acad. Sci. USA, 92, 1057–1061.

  • Guerra B, Issinger OG and Wang JY . (2003). Oncogene, 22, 4933–4942.

  • Haoudi A, Daniels RC, Wong E, Kupfer G and Semmes OJ . (2003). J. Biol. Chem., 278, 37736–37744.

  • Haoudi A and Semmes OJ . (2003). Virology, 305, 229–239.

  • Heffernan TP, Simpson DA, Frank AR, Heinloth AN, Paules RS, Cordeiro-Stone M and Kaufmann WK . (2002). Mol. Cell. Biol., 22, 8552–8561.

  • Hirao A, Kong YY, Matsuoka S, Wakeham A, Ruland J, Yoshida H, Liu D, Elledge SJ and Mak TW . (2000). Science, 287, 1824–1827.

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

  • Jallepalli PV, Lengauer C, Vogelstein B and Bunz F . (2003). J. Biol. Chem., 278, 20475–20479.

  • Jeang KT, Derse D, Matocha M and Sharma O . (1997). J. Virol., 71, 6277–6278.

  • Jeang KT, Widen SG, Semmes OJ and Wilson SH . (1990). Science, 247, 1082–1084.

  • Johnson JM, Harrod R and Franchini G . (2001). Int. J. Exp. Pathol., 82, 135–147.

  • Kaneko YS, Watanabe N, Morisaki H, Akita H, Fujimoto A, Tominaga K, Terasawa M, Tachibana A, Ikeda K, Nakanishi M and Kaneko Y . (1999). Oncogene, 18, 3673–3681.

  • Kao SY and Marriott SJ . (1999). J. Virol., 73, 4299–4304.

  • Kasai T, Iwanaga Y, Iha H and Jeang KT . (2002). J. Biol. Chem., 277, 5187–5193.

  • Lemoine FJ, Kao SY and Marriott SJ . (2000). AIDS Res Hum. Retroviruses, 16, 1623–1627.

  • Lemoine FJ and Marriott SJ . (2001). J. Biol. Chem., 276, 31851–31857.

  • Liu Q, Guntuku S, Cui XS, Matsuoka S, Cortez D, Tamai K, Luo G, Carattini-Rivera S, DeMayo F, Bradley A, Donehower LA and Elledge SJ . (2000). Genes Dev., 14, 1448–1459.

  • Marriott SJ, Lemoine FJ and Jeang KT . (2002). J. Biomed. Sci., 9, 292–298.

  • Matsuoka S, Huang M and Elledge SJ . (1998). Science, 282, 1893–1897.

  • Matsuoka S, Rotman G, Ogawa A, Shiloh Y, Tamai K and Elledge SJ . (2000). Proc. Natl. Acad. Sci. USA, 97, 10389–10394.

  • McGowan CH . (2002). Bioessays, 24, 502–511.

  • Melchionna R, Chen XB, Blasina A and McGowan CH . (2000). Nat. Cell Biol., 2, 762–765.

  • Miwa M, Shimotohno K, Hoshino H, Fujino M and Sugimura T . (1984). Gann, 75, 752–755.

  • Mulloy JC, Kislyakova T, Cereseto A, Casareto L, LoMonico A, Fullen J, Lorenzi MV, Cara A, Nicot C, Giam CZ and Franchini G . (1998). J. Virol., 72, 8852–8860.

  • Philpott SM and Buehring GC . (1999). J. Natl. Cancer Inst., 91, 933–942.

  • Pise-Masison CA, Choi KS, Radonovich M, Dittmer J, Kim SJ and Brady JN . (1998a). J. Virol., 72, 1165–1170.

  • Pise-Masison CA, Mahieux R, Jiang H, Ashcroft M, Radonovich M, Duvall J, Guillerm C and Brady JN . (2000). Mol. Cell. Biol., 20, 3377–3386.

  • Pise-Masison CA, Mahieux R, Radonovich M, Jiang H and Brady JN . (2001). J. Biol. Chem., 276, 200–205.

  • Pise-Masison CA, Radonovich M, Sakaguchi K, Appella E and Brady JN . (1998b). J. Virol., 72, 6348–6355.

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

  • Robek MD and Ratner L . (1999). J. Virol., 73, 4856–4865.

  • Saka Y, Esashi F, Matsusaka T, Mochida S and Yanagida M . (1997). Genes Dev., 11, 3387–3400.

  • Semmes OJ and Jeang KT . (1996). J. Virol., 70, 6347–6357.

  • Shieh SY, Ahn J, Tamai K, Taya Y and Prives C . (2000). Genes Dev., 14, 289–300.

  • Shiloh Y . (2003). Nat. Rev. Cancer, 3, 155–168.

  • Sorensen CS, Syljuasen RG, Falck J, Schroeder T, Ronnstrand L, Khanna KK, Zhou BB, Bartek J and Lukas J . (2003). Cancer Cell, 3, 247–258.

  • Sugiyama K, Shimizu M, Akiyama T, Tamaoki T, Yamaguchi K, Takahashi R, Eastman A and Akinaga S . (2000). Int. J. Cancer, 85, 703–709.

  • Tanaka A, Takahashi G, Yamaoka S, Nosaka T, Maki M and Hatanaka M . (1990). Proc. Natl. Acad. Sci. USA, 87, 1071–1075.

  • Taylor WR, DePrimo SE, Agarwal A, Agarwal ML, Schonthal AH, Katula KS and Stark GR . (1999). Mol. Biol. Cell, 10, 3607–3622.

  • Van Orden K, Giebler HA, Lemasson I, Gonzales M and Nyborg JK . (1999). J. Biol. Chem., 274, 26321–26328.

  • Walworth NC . (2000). Curr. Opin. Cell Biol., 12, 697–704.

  • Wang Q, Fan S, Eastman A, Worland PJ, Sausville EA and O'Connor PM . (1996). J. Natl. Cancer Inst., 88, 956–965.

  • Xiao Z, Chen Z, Gunasekera AH, Sowin TJ, Rosenberg SH, Fesik S and Zhang H . (2003). J. Biol. Chem., 278, 21767–21773.

  • Xu B, Kim St and Kastan MB . (2001). Mol. Cell. Biol., 21, 3445–3450.

  • Xu B, Kim St, Lim DS and Kastan MB . (2002). Mol. Cell. Biol., 22, 1049–1059.

  • Yu Q, La Rose J, Zhang H, Takemura H, Kohn KW and Pommier Y . (2002). Cancer Res., 62, 5743–5748.

  • Zachos G, Rainey MD and Gillespie DAF . (2003). EMBO J., 22, 713–723.

  • Zhao B, Bower MJ, McDevitt PJ, Zhao H, Davis ST, Johanson KO, Green SM, Concha NO and Zhou BB . (2002a). J. Biol. Chem., 277, 46609–46615.

  • Zhao H and Piwnica-Worms H . (2001). Mol. Cell. Biol., 21, 4129–4139.

  • Zhao H, Watkins JL and Piwnica-Worms H . (2002b). Proc. Natl. Acad. Sci. USA, 99, 14795–14800.

  • Zhou BB and Elledge SJ . (2000). Nature, 408, 433–439.

Download references

Acknowledgements

We thank Dr Cynthia Pise-Masison and members of Dr Brady's laboratory for helpful discussion, and the FACS core facility of CCR, NCI, NIH for flow cytometry analysis. We also thank Drs Bert Vogelstein and Fred Bunz for providing HCT116p21+/+, p53−/−, and Chk2−/− cell lines.

Author information

Authors and Affiliations

  1. Virus Tumor Biology Section, Laboratory of Cellular Oncology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, 20892, MD, USA

    Hyeon Ung Park & John N Brady

  2. Laboratory of Biochemical Genetics, National Heart Lung and Blood Institute, National Institutes of Health, Bethesda, 20892, MD, USA

    Jae-Hoon Jeong & Jay H Chung

Authors
  1. Hyeon Ung Park
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Jae-Hoon Jeong
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Jay H Chung
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. John N Brady
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to John N Brady.

Additional information

Supplementary Information accompanies the paper on Oncogene website: (http://www.nature.com/onc).

Supplementary information

Figure S1

Western blot of immunoprecipitates from HTLV-1-transformed C81cell lysates using a polyclonal anti-Chk1 antibody or control IgG antibody for 2-h or overnight incubation. The upper panel shows the coprecipitated Tax level. The lower panel indicates the amount of Chk1 precipitated. IP, immunoprecipitation; o/n, overnight (JPG 87 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Park, H., Jeong, JH., Chung, J. et al. Human T-cell leukemia virus type 1 Tax interacts with Chk1 and attenuates DNA-damage induced G2 arrest mediated by Chk1. Oncogene 23, 4966–4974 (2004). https://doi.org/10.1038/sj.onc.1207644

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.onc.1207644

Keywords

This article is cited by

Search

Advanced search

Quick links