Abstract
The Kaposi's sarcoma-associated herpesvirus (KSHV) encodes a FADD-like interferon converting enzyme or caspase 8 (FLICE) inhibitory protein (vFLIP) that prevents death receptor-mediated apoptosis by inhibiting the recruitment and activation of FLICE. Since vFLIP physically interacts with tumor necrosis factor receptor associated factor 2 (TRAF2) and TRAF2 mediates activation of the jun NH2-terminal kinase (JNK)/activation protein 1 (AP1) pathway, we hypothesized that vFLIP might also activate this pathway. To evaluate this hypothesis, we transiently and stably transfected a vFLIP expression construct and performed several complementary assays to document that vFLIP activates the JNK/AP1 pathway and does so in a TRAF-dependent fashion. As vFLIP also activates the nuclear factor κB (NF-κB) signaling pathway and the NF-κB and JNK/AP1 pathways both modulate cellular interleukin-6 (cIL-6) expression, we postulated that vFLIP induces expression of this cytokine. We show that vFLIP induces cIL-6 expression and activates the cIL-6 promoter, and maximal activation of the cIL-6 promoter by vFLIP requires NF-κB and AP1 activation. In addition, vFLIP and latency-associated nuclear antigen (LANA), another KSHV-encoded latent protein, potentiate each other's ability to activate the cIL-6 promoter. Gene silencing experiments by RNA interference demonstrate that vFLIP in BCBL-1 endogenously infected primary effusion lymphoma (PEL) cells mediates JNK/AP1 activation and cIL-6 expression. Thus, we conclude that vFLIP, in addition to its known effects on NF-κB activation, also modulates the JNK/AP1 pathway and induces gene expression from the cIL-6 promoter in a JNK/AP1-dependent fashion.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 50 print issues and online access
$259.00 per year
only $5.18 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
An J, Lichtenstein AK, Brent G and Rettig MB . (2002). Blood, 99, 649–654.
Asou H, Said JW, Yang R, Munker R, Park DJ, Kamada N and Koeffler HP . (1998). Blood, 91, 2475–2481.
Baud V, Liu ZG, Bennett B, Suzuki N, Xia Y and Karin M . (1999). Genes Dev., 13, 1297–1308.
Black EJ, Street AJ and Gillespie DA . (1991). Oncogene, 6, 1949–1958.
Butterfield L, Storey B, Maas L and Heasley LE . (1997). J. Biol. Chem., 272, 10110–10116.
Cesarman E, Chang Y, Moore PS, Said JW and Knowles DM . (1995). N. Engl. J. Med., 332, 1186–1191.
Chang Y, Cesarman E, Pessin MS, Lee F, Culpepper J, Knowles DM and Moore PS . (1994). Science, 266, 1865–1869.
Chaudhary PM, Jasmin A, Eby MT and Hood L . (1999). Oncogene, 18, 5738–5746.
Dadgostar H and Cheng G . (1998). J. Biol. Chem., 273, 24775–24780.
Dendorfer U, Oettgen P and Libermann TA . (1994). Mol. Cell. Biol., 14, 4443–4454.
Diaz BV, Lenoir MC, Ladoux A, Frelin C, Demarchez M and Michel S . (2000). J. Biol. Chem., 275, 642–650.
Dittmer D, Lagunoff M, Renne R, Staskus K, Haase A and Ganem D . (1998). J. Virol., 72, 8309–8315.
Djerbi M. Screpanti V, Catrina AI, Bogen B, Biberfeld P and Grandien A . (1999). J. Exp. Med., 190, 1025–1032.
Ensoli B, Nakamura S, Salahuddin SZ, Biberfeld P, Larsson L, Beaver B, Wong-Staal F and Gallo RC . (1989). Science, 243, 223–226.
Foreman KE, Friborg J, Kong WP, Woffendin C, Polverini PJ . Nickoloff BJ and Nabel GJ . (1997). N. Engl. J. Med., 336, 163–171.
Foussat A, Wijdenes J, Bouchet L, Gaidano G, Neipel F, Balabanian K, Galanaud P, Couderc J and Emilie D . (1999). Eur. Cytokine Netw., 10, 501–508.
Gao SJ, Kingsley L, Hoover DR, Spira TJ, Rinaldo CR, Saah A, Phair J, Detels R, Parry P, Chang Y and Moore PS . (1996). N. Engl. J. Med., 335, 233–241.
Glykofrydes D, Niphuis H, Kuhn EM, Rosenwirth B, Heeney JL, Bruder J, Niedobitek G, Muller-Fleckenstein I, Fleckenstein B and Ensser A . (2000). J. Virol., 74, 11919–11927.
Grandadam M, Dupin N, Calvez V, Gorin I, Blum L, Kernbaum S, Sicard D, Buisson Y, Agut H, Escande JP and Huraux JM . (1997). J. Infect. Dis., 175, 1198–1201.
Grundhoff A and Ganem D . (2001). J. Virol., 75, 1857–1863.
Hu S, Vincenz C, Buller M and Dixit VM . (1997). J. Biol. Chem., 272, 9621–9624.
Karin M . (1994). Curr. Opin. Cell Biol., 6, 415–424.
Keller SA, Schattner EJ and Cesarman E . (2000). Blood, 96, 2537–2542.
Lee HH, Dadgostar H, Cheng Q, Shu J and Cheng G . (1999). Proc. Natl. Acad. Sci. USA, 96, 9136–9141.
Leger-Ravet MB, Peuchmaur M, Devergne O, Audouin J. Raphael M, Van Damme J, Galanaud P, Diebold J and Emilie D . (1991). Blood, 78, 2923–2930.
Libermann TA and Baltimore D . (1990). Mol. Cell. Biol., 10, 2327–2334.
Liu B and Shuai K . (2001). J. Biol. Chem., 276, 36624–36631.
Low W, Harries M, Ye H, Du MQ, Boshoff C and Collins M . (2001). J. Virol., 75, 2938–2945.
Miles SA, Rezai AR, Salazar-Gonzalez JF, Vander MM . Stevens RH, Logan DM, Mitsuyasu RT, Taga T, Hirano T, Kishimoto T and Martinez-Maza O . (1990). Proc. Natl. Acad. Sci. USA, 87, 4068–4072.
Moore PS and Chang Y . (1995). N. Engl. J. Med., 332, 1181–1185.
Panyutich EA, Said JW and Miles SA . (1998). AIDS, 12, 467–472.
Radkov SA, Kellam P and Boshoff C . (2000). Nat. Med., 6, 1121–1127.
Rainbow L, Platt GM, Simpson GR, Sarid R, Gao SJ, Stoiber H, Herrington CS, Moore PS and Schulz TF . (1997). J. Virol., 71, 5915–5921.
Raitano AB, Halpern JR, Hambuch TM, and Sawyers CL . (1995). Proc. Natl. Acad. Sci. USA, 92, 11746–11750.
Ray A, Ratter SB, May LT and Sehgal PB . (1988). Proc. Natl. Acad. Sci. USA, 85, 6701–6705.
Reinhard C, Shamoon B, Shyamala V and Williams LT . (1997). EMBO J., 16, 1080–1092.
Sarid R, Flore O, Bohenzky RA, Chang Y and Moore PS . (1998). J. Virol., 72, 1005–1012.
Sarid R, Wiezorek JS, Moore PS and Chang Y . (1999). J. Virol., 73, 1438–1446.
Screpanti I, Musiani P, Bellavia D, Cappelletti M, Aiello FB. Maroder M, Frati L, Modesti A, Gulino A and Poli V . (1996). J. Exp. Med., 184, 1561–1566.
Siegmund D, Mauri D, Peters N, Juo P, Thome M, Reichwein M, Blenis J, Scheurich P, Tschopp J and Wajant H . (2001). J. Biol. Chem., 276, 32585–32590.
Smeal T, Binetruy B, Mercola D, Grover-Bardwick A, Heidecker G, Rapp UR and Karin M . (1992). Mol. Cell. Biol., 12, 3507–3513.
Smeal T, Binetruy B, Mercola DA, Birrer M and Karin M . (1991). Nature, 354, 494–496.
Song HY, Regnier CH, Kirschning CJ, Goeddel DV and Rothe M . (1997). Proc. Natl. Acad. Sci. USA, 94, 9792–9796.
Soulier J, Grollet L, Oksenhendler E, Cacoub P, Cazals-Hatem D, Babinet P, d'Agay MF, Clauvel JP, Raphael M and Degos L . (1995). Blood, 86, 1276–1280.
Talbot SJ, Weiss RA, Kellam P and Boshoff C . (1999). Virology, 257, 84–94.
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 and Tschopp J . (1997). Nature, 386, 517–521.
Acknowledgements
We thank Drs Alan K Lichtenstein and Gregory Brent for their critical review of the manuscript and helpful discussions. Supported by research funds of the Veterans Administration, including a Career Development Award and the VA Research Enhancement Award Program (REAP) (both to MBR), the Jonsson Comprehensive Cancer Center at UCLA (to MBR and RS), the American Cancer Society (Grant # RPG-00-305-01-MBC to MBR), the Public Health Service (Grant # 1R01CA80004-01A1 to MBR), and the American Society of Hematology (Junior Faculty Scholar Award to MBR).
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
An, J., Sun, Y., Sun, R. et al. Kaposi's sarcoma-associated herpesvirus encoded vFLIP induces cellular IL-6 expression: the role of the NF-κB and JNK/AP1 pathways. Oncogene 22, 3371–3385 (2003). https://doi.org/10.1038/sj.onc.1206407
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/sj.onc.1206407
Keywords
This article is cited by
-
Nm23-H1 induces apoptosis in primary effusion lymphoma cells via inhibition of NF-κB signaling through interaction with oncogenic latent protein vFLIP K13 of Kaposi’s sarcoma-associated herpes virus
Cellular Oncology (2022)
-
Castleman disease
Nature Reviews Disease Primers (2021)
-
The anti-malaria agent artesunate exhibits cytotoxic effects in primary effusion lymphoma
Investigational New Drugs (2021)
-
Modulation of the extrinsic cell death signaling pathway by viral Flip induces acute-death mediated liver failure
Cell Death & Disease (2019)
-
Cellular and viral oncogenes: the key to unlocking unknowns of Kaposi’s sarcoma-associated herpesvirus pathogenesis
Archives of Virology (2018)