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  • Original Paper
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The Kaposi's sarcoma-associated herpesvirus K-bZIP protein represses transforming growth factor β signaling through interaction with CREB-binding protein

Oncogene volume 23, pages 8272–8281 (2004)Cite this article

Abstract

Kaposi's sarcoma (KS)-associated herpesvirus (KSHV) is involved in the pathogenesis of KS, primary effusion lymphoma, and multicentric Castleman's disease. K-bZIP, the protein encoded by the open reading frame K8 of KSHV, is a member of the basic region-leucine zipper family of transcription factors. We studied the mechanisms that underlie KSHV-induced oncogenesis by investigating whether K-bZIP perturbs signaling through transforming growth factor β (TGF-β), which inhibits proliferation of a wide range of cell types. K-bZIP repressed TGF-β-induced, Smad-mediated transcriptional activity and antagonized the growth-inhibitory effects of TGF-β. Since both K-bZIP and Smad are known to interact with CREB-binding protein (CBP), the effect of CBP on inhibition of Smad-mediated transcriptional activation by K-bZIP was examined. K-bZIP mutants, which lacked the CBP-binding site, could not repress TGF-β-induced or Smad3-mediated transcriptional activity. Overexpression of CBP restored K-bZIP-induced inhibition of Smad3-mediated transcriptional activity. Competitive interaction studies showed that K-bZIP inhibited the interaction of Smad3 with CBP. These results suggest that K-bZIP, through its binding to CBP, disrupts TGF-β signaling by interfering with the recruitment of CBP into transcription initiation complexes on TGF-β-responsive elements. We propose a possibility that K-bZIP may contribute to oncogenesis through its ability to promote cell survival by repressing TGF-β signaling.

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Abbreviations

KSHV:

Kaposi's sarcoma-associated herpesvirus

PEL:

primary effusion lymphoma

CBP:

CREB-binding protein

NF:

nuclear factor

TGF-β:

transforming growth factor β

TβRII:

type II TGF-β receptor

TβRI:

type I TGF-β receptor

PAI:

plasminogen activator inhibitor

ARE:

activin response element

EMSA:

electrophoretic mobility shift assay

References

  • Alkan S, Karcher DS, Ortiz A, Khalil S, Akhtar M and Ali MA . (1997). Br. J. Haematol., 96, 412–414.

  • Arvanitakis L, Geras-Raaka E, Varma A, Gershengorn MC and Cesarman E . (1997). Nature (Lond.), 385, 347–350.

  • Bex F, Yin M-J, Burny A and Gaynor RB . (1998). Mol. Cell. Biol., 18, 2392–2405.

  • Blobe GC, Schiemann WP and Lodish HF . (2000). N. Engl. J. Med., 342, 1350–1358.

  • Boshoff C . (1998). Nature (Lond.), 391, 24–25.

  • Boshoff C, Endo Y, Collins PD, Takeuchi Y, Reeves JD, Schweickart VL, Siani MA, Sasaki T, Williams TJ, Gray PW, Moore PS, Chang Y and Weiss RA . (1997). Science (Wash. DC), 278, 290–294.

  • Boshoff C, Schulz TF, Kennedy MM, Graham AK, Fisher C, Thomas A, McGee JO, Weiss RA and O'Leary JJ . (1995). Nat. Med., 1, 1274–1278.

  • Cesarman E, Chang Y, Moore PS, Said JW and Knowles DM . (1995). N. Engl. J. Med., 332, 1186–1191.

  • Chan HM and La Thangue NB . (2001). J. Cell Sci., 114, 2363–2373.

  • Chang Y, Cesarman E, Pessin MS, Lee F, Culpepper J, Knowles DM and Moore PS . (1994). Science (Wash. DC), 266, 1865–1869.

  • Chen F and Weinberg R . (1995). Proc. Natl. Acad. Sci. USA, 92, 1565–1569.

  • Chen X, Rubock MJ and Whitman M . (1996). Nature (Lond.), 383, 691–696.

  • Chen X, Weisberg E, Fridmacher V, Watanabe M, Naco G and Whitman M . (1997). Nature (Lond.), 389, 85–89.

  • Datto M, Hu P, Kowalik T, Yingling J and Wang X . (1997). Mol. Cell. Biol., 17, 2030–2037.

  • Dennler S, Itoh S, Vivien D, ten Dijke P, Huet S and Gauthier JM . (1998). EMBO J., 17, 3091–3100.

  • Feng XH, Zhang Y, Wu RY and Derynck R . (1998). Genes Dev., 12, 2153–2163.

  • Harrod R, Tang Y, Nicot C, Lu HS, Vassilev A, Nakatani Y and Giam C-Z . (1998). Mol. Cell. Biol., 18, 5052–5061.

  • Horvai AE, Xu L, Korzus E, Brard G, Kalafus D, Mullen TM, Rose DW, Rosenfeld MG and Glass CK . (1997). Proc. Natl. Acad. Sci. USA, 94, 1074–1079.

  • Huang YQ, Li JJ, Kaplan MH, Poiesz B, Katabira E, Zhang WC, Feiner D and Friedman-Kien AE . (1995). Lancet, 345, 759–761.

  • Hwang S, Gwack Y, Byun H, Lim C and Choe J . (2001). J. Virol., 75, 9509–9516.

  • Janknecht R, Wells NJ and Hunter T . (1998). Genes Dev., 12, 2114–2119.

  • Kamei Y, Xu L, Heinzel T, Torchia J, Kurokawa R, Gloss B, Lin SC, Heyman RA, Rose DW, Glass CK and Rosenfeld MG . (1996). Cell, 85, 403–414.

  • Katano H, Sato Y, Kurata T, Mori S and Sata T . (2000). Virology, 269, 335–344.

  • Labbe E, Silvestri C, Hoodless PA, Wrana JL and Attisano L . (1998). Mol. Cell, 2, 109–120.

  • Lee CW, Sorensen TS, Shikama N and La Thangue NB . (1998). Oncogene, 16, 2695–2710.

  • Lin S-F, Robinson DR, Miller G and Kung H-J . (1999). J. Virol., 73, 1909–1917.

  • Massague J . (1998). Annu. Rev. Biochem., 67, 753–791.

  • Memar OM, Rady PL and Tyring SK . (1995). J. Mol. Med., 73, 603–609.

  • Miyazono K, ten Dijke P, Yamashita H and Heldin CH . (1994). Semin. Cell Biol., 5, 389–398.

  • Moore PS and Chang Y . (1995). N. Engl. J. Med., 332, 1181–1185.

  • Mori N, Fujii M, Iwai K, Ikeda S, Yamasaki Y, Hata T, Yamada Y, Tanaka Y, Tomonaga M and Yamamoto N . (2000). Blood, 95, 3915–3921.

  • Mori N, Morishita M, Tsukazaki T, Giam CZ, Kumatori A, Tanaka Y and Yamamoto N . (2001). Blood, 97, 2137–2144.

  • Mori N, Morishita M, Tsukazaki T and Yamamoto N . (2003). Int. J. Cancer, 105, 661–668.

  • Nishihara A, Hanai J, Imamura T, Miyazono K and Kawabata M . (1999). J. Biol. Chem., 274, 28716–28723.

  • Nishihara A, Hanai JI, Okamoto N, Yanagisawa J, Kato S, Miyazono K and Kawabata M . (1998). Genes Cells, 3, 613–623.

  • Park J, Seo T, Hwang S, Lee D, Gwack Y and Choe J . (2000). J. Virol., 74, 11977–11982.

  • Portes-Sentis S, Manet E, Gourru G, Sergeant A and Gruffat H . (2001). J. Gen. Virol., 82, 507–512.

  • Pouponnot C, Jayaraman L and Massague J . (1998). J. Biol. Chem., 273, 22865–22868.

  • Shen X, Hu PP, Liberati NT, Datto MB, Frederick JP and Wang XF . (1998). Mol. Biol. Cell, 9, 3309–3319.

  • Sheppard KA, Phelps KM, Williams AJ, Thanos D, Glass CK, Rosenfeld MG, Gerritsen ME and Collins T . (1998). J. Biol. Chem., 273, 29291–29294.

  • Song CZ, Siok TE and Gelehrter TD . (1998). J. Biol. Chem., 273, 29287–29290.

  • Soulier J, Grollet L, Oksenhendler E, Cacoub P, Cazals-Hatem D, Babinet P, d'Agay M-F, Clauvel J-P, Raphael M, Degos L and Sigaux F . (1995). Blood, 86, 1276–1280.

  • Sporn MB and Roberts AB . (1990). Ann. NY Acad. Sci., 593, 1–6.

  • Staskus KA, Zhong W, Gebhard K, Herndier B, Wang H, Renne R, Beneke J, Pudney J, Anderson DJ, Ganem D and Haase AT . (1997). J. Virol., 71, 715–719.

  • Sun R, Lin SF, Staskus K, Gradoville L, Grogan E, Haase A and Miller G . (1999). J. Virol., 73, 2232–2242.

  • Topper JN, DiChiara MR, Brown JD, Williams AJ, Falb D, Collins T and Gimbrone Jr MA . (1998). Proc. Natl. Acad. Sci. USA, 95, 9506–9511.

  • Tsukazaki T, Chiang TA, Davison AF, Attisano L and Wrana JL . (1998). Cell, 95, 779–791.

  • Wadgaonkar R, Phelps KM, Haque Z, Williams AJ, Silverman ES and Collins T . (1999). J. Biol. Chem., 274, 1879–1882.

  • Wrana JL, Attisano L, Wieser R, Ventura F and Massague J . (1994). Nature (Lond.), 370, 341–347.

  • Zawel L, Dai JL, Buckhaults P, Zhou S, Kinzler KW, Vogelstein B and Kern SE . (1998). Mol. Cell, 1, 611–617.

  • Zhang Y, Feng X, We R and Derynck R . (1996). Nature (Lond.), 383, 168–172.

  • Zhou S, Zawel L, Lengauer C, Kinzler KW and Vogelstein B . (1998). Mol. Cell, 2, 121–127.

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Acknowledgements

We acknowledge all of the members in the laboratory for discussions and help. We thank Drs S Tan and MP Pando for critical reading of the manuscript. We also thank Dr J Massague for p3TP-Lux; Dr M Whitman for FAST-1 expression plasmid; Dr JL Wrana for Flag-Smad2, Flag-Smad3, Smad4-HA, Myc-Smad2, Myc-Smad3, Myc-Smad4, TβRI-WT-HA, TβRI-T204D-HA, and ARE-Lux; and Dr K Miyazono for CBP expression plasmid. This work was supported by a Grant-in-Aid for Scientific Research (C) from the Japan Society for the Promotion of Science.

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Authors and Affiliations

  1. Division of Molecular Virology and Oncology, Graduate School of Medicine, University of the Ryukyus, Nishihara, 903-0215, Japan

    Mariko Tomita & Naoki Mori

  2. Department of Biological Sciences, Korea Advanced Institute of Science and Technology, Daejeon, 305-701, Korea

    Joonho Choe

  3. Division of Orthopaedic Pathomechanism, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, 852-8588, Japan

    Tomoo Tsukazaki

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  1. Mariko Tomita
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Correspondence to Naoki Mori.

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Tomita, M., Choe, J., Tsukazaki, T. et al. The Kaposi's sarcoma-associated herpesvirus K-bZIP protein represses transforming growth factor β signaling through interaction with CREB-binding protein. Oncogene 23, 8272–8281 (2004). https://doi.org/10.1038/sj.onc.1208059

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