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Human herpesvirus 8 viral FLICE-inhibitory protein retards cell proliferation via downregulation of Id2 and Id3 expression

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Abstract

Death receptor-mediated apoptosis is potently inhibited by viral FLIP (FLICE/caspase 8 inhibitory protein) through reduced activation of procaspase 8. In this study, we show that the human herpesvirus 8-encoded vFLIP retards cell proliferation. Overexpression of vFLIP caused cell cycle arrest, with an apparent decrease of cells in the S phase. The Id (inhibitor of DNA binding) proteins are considered as dominant negative regulators of differentiation pathways, but positive regulators of cellular proliferation. The mechanisms by which Id proteins promote the cell cycle are diverse, but appear to involve affecting the expression of cell cycle regulators. RT-PCR results demonstrated that the expression of vFLIP decreased the expression levels of Id2 and Id3 as well as cyclin E and cyclin A compared with the vFLIP-null cells. These indicate that vFLIP affects cell proliferation by decreasing the expression levels of cell cycle regulatory proteins.

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References

  1. Chang Y, Cesarman E, Pessin MS, Lee F, Culpepper J, Knowles DM, Moore PS (1994) Identification of herpesvirus-like DNA sequences in AIDS-associated Kaposi’s sarcoma. Science 266:1865–1869

    Article  CAS  PubMed  Google Scholar 

  2. Jenner RG, Alba MM, Boshoff C, Kellam P (2001) Kaposi’s sarcoma-associated herpesvirus latent and lytic gene expression as revealed by DNA arrays. J Virol 75:891–902

    Article  CAS  PubMed  Google Scholar 

  3. Boshoff C, Chang Y (2001) Kaposi’s sarcoma-associated herpesvirus: a new DNA tumor virus. Annu Rev Med 52:453–470

    Article  CAS  PubMed  Google Scholar 

  4. Thome M, Schneider P, Hofmann K, Fickenscher H, Meinl E, Neipel F, Mattmann C, Burns K, Bodmer JL, Schroter M, Scaffidi C, Krammer PH, Peter ME, Tschopp J (1997) Viral FLICE-inhibitory proteins (FLIPs) prevent apoptosis induced by death receptors. Nature 386:517–521

    Article  CAS  PubMed  Google Scholar 

  5. Bertin J, Armstrong RC, Ottilie S, Martin DA, Wang Y, Banks S, Wang GH, Senkevich TG, Alnemri ES, Moss B, Lenardo MJ, Tomaselli KJ, Cohen JI (1997) Death effector domain-containing herpesvirus and poxvirus proteins inhibit both Fas- and TNFR1-induced apoptosis. Proc Natl Acad Sci USA 94:1172–1176

    Article  CAS  PubMed  Google Scholar 

  6. Hu S, Vincenz C, Buller M, Dixit VM (1997) A novel family of viral death effector domain-containing molecules that inhibit both CD-95- and tumor necrosis factor receptor-1-induced apoptosis. J Biol Chem 272:9621–9624

    Article  CAS  PubMed  Google Scholar 

  7. Dittmer D, Lagunoff M, Renne R, Staskus K, Haase A, Ganem D (1998) A cluster of latently expressed genes in Kaposi’s sarcoma-associated herpesvirus. J Virol 72:8309–8315

    CAS  PubMed  Google Scholar 

  8. Fakhari FD, Dittmer DP (2002) Charting latency transcripts in Kaposi’s sarcoma-associated herpesvirus by whole-genome real-time quantitative PCR. J Virol 76:6213–6223

    Article  CAS  PubMed  Google Scholar 

  9. Talbot SJ, Weiss RA, Kellam P, Boshoff C (1999) Transcriptional analysis of human herpesvirus-8 open reading frames 71, 72, 73, K14, and 74 in a primary effusion lymphoma cell line. Virology 257:84–94

    Article  CAS  PubMed  Google Scholar 

  10. Chaudhary PM, Jasmin A, Eby MT, Hood L (1999) Modulation of the NF-kappa B pathway by virally encoded death effector domains-containing proteins. Oncogene 18:5738–5746

    Article  CAS  PubMed  Google Scholar 

  11. Matta H, Mazzacurati L, Schamus S, Yang T, Sun Q, Chaudhary PM (2007) Kaposi’s sarcoma-associated herpesvirus (KSHV) oncoprotein K13 bypasses TRAFs and directly interacts with the IkappaB kinase complex to selectively activate NF-kappaB without JNK activation. J Biol Chem 282:24858–24865

    Article  CAS  PubMed  Google Scholar 

  12. Guasparri I, Keller SA, Cesarman E (2004) KSHV vFLIP is essential for the survival of infected lymphoma cells. J Exp Med 199:993–1003

    Article  CAS  PubMed  Google Scholar 

  13. Lacoste V, Nicot C, Gessain A, Valensi F, Gabarre J, Matta H, Chaudhary PM, Mahieux R (2007) In primary effusion lymphoma cells, MYB transcriptional repression is associated with v-FLIP expression during latent KSHV infection while both v-FLIP and v-GPCR become involved during the lytic cycle. Br J Haematol 138:487–501

    Article  CAS  PubMed  Google Scholar 

  14. Sturzl M, Hohenadl C, Zietz C, Castanos-Velez E, Wunderlich A, Ascherl G, Biberfeld P, Monini P, Browning PJ, Ensoli B (1999) Expression of K13/v-FLIP gene of human herpesvirus 8 and apoptosis in Kaposi’s sarcoma spindle cells. J Natl Cancer Inst 91:1725–1733

    Article  CAS  PubMed  Google Scholar 

  15. Tzeng SF (2003) Inhibitors of DNA binding in neural cell proliferation and differentiation. Neurochem Res 28:45–52

    Article  CAS  PubMed  Google Scholar 

  16. Norton JD, Deed RW, Craggs G, Sablitzky F (1998) Id helix-loop-helix proteins in cell growth and differentiation. Trends Cell Biol 8:58–65

    Article  CAS  PubMed  Google Scholar 

  17. Norton JD (2000) ID helix-loop-helix proteins in cell growth, differentiation and tumorigenesis. J Cell Sci 113(Pt 22):3897–3905

    CAS  PubMed  Google Scholar 

  18. Yokota Y (2001) Id and development. Oncogene 20:8290–8298

    Article  CAS  PubMed  Google Scholar 

  19. Lasorella A, Uo T, Iavarone A (2001) Id proteins at the cross-road of development and cancer. Oncogene 20:8326–8333

    Article  CAS  PubMed  Google Scholar 

  20. Irmler M, Thome M, Hahne M, Schneider P, Hofmann K, Steiner V, Bodmer JL, Schroter M, Burns K, Mattmann C, Rimoldi D, French LE, Tschopp J (1997) Inhibition of death receptor signals by cellular FLIP. Nature 388:190–195

    Article  CAS  PubMed  Google Scholar 

  21. Budd RC, Yeh WC, Tschopp J (2006) cFLIP regulation of lymphocyte activation and development. Nat Rev Immunol 6:196–204

    Article  CAS  PubMed  Google Scholar 

  22. Glykofrydes D, Niphuis H, Kuhn EM, Rosenwirth B, Heeney JL, Bruder J, Niedobitek G, Muller-Fleckenstein I, Fleckenstein B, Ensser A (2000) Herpesvirus saimiri vFLIP provides an antiapoptotic function but is not essential for viral replication, transformation, or pathogenicity. J Virol 74:11919–11927

    Article  CAS  PubMed  Google Scholar 

  23. OhYama T, Tsukumo S, Yajima N, Sakamaki K, Yonehara S (2000) Reduction of thymocyte numbers in transgenic mice expressing viral FLICE-inhibitory protein in a Fas-independent manner. Microbiol Immunol 44:289–297

    CAS  PubMed  Google Scholar 

  24. Nakagiri S, Murakami A, Takada S, Akiyama T, Yonehara S (2005) Viral FLIP enhances Wnt signaling downstream of stabilized beta-catenin, leading to control of cell growth. Mol Cell Biol 25:9249–9258

    Article  CAS  PubMed  Google Scholar 

  25. De Thier F, Simonart T, Hermans P, Andre J, Van Vooren JP, Noel JC (1999) Early- and late-stage Kaposi’s sarcoma lesions exhibit similar proliferation fraction. Am J Dermatopathol 21:25–27

    Article  PubMed  Google Scholar 

  26. Simonart T, Degraef C, Mosselmans R, Hermans P, Lunardi-Iskandar Y, Noel JC, Van Vooren JP, Parent D, Heenen M, Galand P (2001) Early- and late-stage Kaposi’s sarcoma-derived cells but not activated endothelial cells can invade de-epidermized dermis. J Invest Dermatol 116:679–685

    Article  CAS  PubMed  Google Scholar 

  27. Tsukumo SI, Yonehara S (1999) Requirement of cooperative functions of two repeated death effector domains in caspase-8 and in MC159 for induction and inhibition of apoptosis, respectively. Genes Cells 4:541–549

    Article  CAS  PubMed  Google Scholar 

  28. Thurau M, Marquardt G, Gonin-Laurent N, Weinlander K, Naschberger E, Jochmann R, Alkharsah KR, Schulz TF, Thome M, Neipel F, Sturzl M (2009) Viral inhibitor of apoptosis vFLIP/K13 protects endothelial cells against superoxide-induced cell death. J Virol 83:598–611

    Article  CAS  PubMed  Google Scholar 

  29. Ngo C, Chereau C, Nicco C, Weill B, Chapron C, Batteux F (2009) Reactive oxygen species controls endometriosis progression. Am J Pathol 175:225–234

    Article  CAS  PubMed  Google Scholar 

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Acknowledgments

We thank Dr. Su Ih-Jen and Dr. Lin Su-Fang for providing cell lines, Dr. Gary R. Whittaker (Department of Microbiology and Immunology, Cornell University, USA) for critically reading the manuscript. This work was supported by Grant NSC97-2320-B-242-003-MY3 from the National Science Council, Taiwan.

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Authors and Affiliations

  1. Department of Medical Technology, Fooyin University, 151 Chien-Hsuen Road, Ta-Liao, Kaohsiung Hsien, 83102, Taiwan, ROC

    Yi-Fen Wang, Lin-Yu Wang, Yi-Ling Li, Huey-Wen Shyu, Miao-Chen Chou, Kuan-Hua Lin & Chang-Yu Chen

  2. Department of Pediatrics, Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan, ROC

    Yee-Hsuan Chiou

  3. Institute of Biomedical Sciences, National Sun Yat-Sen University, Kaohsiung, Taiwan, ROC

    Ming-Hong Tai

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  1. Yi-Fen Wang
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Correspondence to Yi-Fen Wang.

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Wang, YF., Wang, LY., Li, YL. et al. Human herpesvirus 8 viral FLICE-inhibitory protein retards cell proliferation via downregulation of Id2 and Id3 expression. Mol Cell Biochem 343, 83–89 (2010). https://doi.org/10.1007/s11010-010-0501-y

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  • DOI: https://doi.org/10.1007/s11010-010-0501-y

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