In cells infected with Kaposi's sarcoma-associated herpesvirus (KSHV), the activation of mitogen-activated protein kinase (MAPK) pathways plays a crucial role early after virus infection as well as during reactivation. In order to systematically identify viral proteins activating MAPK pathways in KSHV-infected cells, a clone collection of KSHV open reading frames (ORFs) was screened for induction of the serum response element (SRE), as SRE is induced by MAPKs. The strongest induction of the SRE was found with ORF73 (latency-associated nuclear antigen 1, or Lana-1), although weaker activation was also found with the kaposin B isoform, ORF54 (dUTPase) and ORF74 (G-protein-coupled receptor). The bipartite SRE is bound by a ternary complex consisting of serum response factor (SRF) and ternary complex factor. Lana-1 bound directly to SRF, but also to the MED25 (ARC92/ACID-1), MED15 (PCQAP) and MED23 (Sur-2) subunits of the Mediator complex, a multi-subunit transcriptional co-activator complex for RNA polymerase II. Lana-1-induced SRE activation was inhibited by the dominant-negative N-terminal domain of the MED25 mediator subunit, suggesting that this subunit mediates Lana-1-induced SRE activation. In summary, these data suggest a model in which Lana-1 acts as an adaptor between the transcription factor SRF and the basal transcriptional machinery.


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  1. Angel, P. & Karin, M.(1991). The role of Jun, Fos and the AP-1 complex in cell-proliferation and transformation. Biochim Biophys Acta 1072, 129–157. [Google Scholar]
  2. Arvanitakis, L., Geras, R. E., Varma, A., Gershengorn, M. C. & Cesarman, E.(1997). Human herpesvirus KSHV encodes a constitutively active G-protein-coupled receptor linked to cell proliferation. Nature 385, 347–350.[CrossRef] [Google Scholar]
  3. Barbera, A. J., Chodaparambil, J. V., Kelley-Clarke, B., Joukov, V., Walter, J. C., Luger, K. & Kaye, K. M.(2006). The nucleosomal surface as a docking station for Kaposi's sarcoma herpesvirus LANA. Science 311, 856–861.[CrossRef] [Google Scholar]
  4. Bourbon, H. M., Aguilera, A., Ansari, A. Z., Asturias, F. J., Berk, A. J., Bjorklund, S., Blackwell, T. K., Borggrefe, T., Carey, M. & other authors(2004). A unified nomenclature for protein subunits of mediator complexes linking transcriptional regulators to RNA polymerase II. Mol Cell 14, 553–557.[CrossRef] [Google Scholar]
  5. Casamassimi, A. & Napoli, C.(2007). Mediator complexes and eukaryotic transcription regulation: an overview. Biochimie 89, 1439–1446.[CrossRef] [Google Scholar]
  6. Cesarman, E., Chang, Y., Moore, P. S., Said, J. W. & Knowles, D. M.(1995). Kaposi's sarcoma-associated herpesvirus-like DNA sequences in AIDS-related body-cavity-based lymphomas. N Engl J Med 332, 1186–1191. (see comments)[CrossRef] [Google Scholar]
  7. Chai, J. & Tarnawski, A. S.(2002). Serum response factor: discovery, biochemistry, biological roles and implications for tissue injury healing. J Physiol Pharmacol 53, 147–157. [Google Scholar]
  8. Chang, Y., Cesarman, E., Pessin, M. S., Lee, F., Culpepper, J., Knowles, D. M. & Moore, P. S.(1994). Identification of herpesvirus-like DNA sequences in AIDS-associated Kaposi's sarcoma. Science 266, 1865–1869.[CrossRef] [Google Scholar]
  9. Dupin, N., Fisher, C., Kellam, P., Ariad, S., Tulliez, M., Franck, N., van Marck, E., Salmon, D., Gorin, I. & other authors(1999). Distribution of human herpesvirus-8 latently infected cells in Kaposi's sarcoma, multicentric Castleman's disease, and primary effusion lymphoma. Proc Natl Acad Sci U S A 96, 4546–4551.[CrossRef] [Google Scholar]
  10. Ford, P. W., Bryan, B. A., Dyson, O. F., Weidner, D. A., Chintalgattu, V. & Akula, S. M.(2006). Raf/MEK/ERK signalling triggers reactivation of Kaposi's sarcoma-associated herpesvirus latency. J Gen Virol 87, 1139–1144.[CrossRef] [Google Scholar]
  11. Glaser, R., Litsky, M. L., Padgett, D. A., Baiocchi, R. A., Yang, E. V., Chen, M., Yeh, P. E., Green-Church, K. B., Caligiuri, M. A. & Williams, M. V.(2006). EBV-encoded dUTPase induces immune dysregulation: implications for the pathophysiology of EBV-associated disease. Virology 346, 205–218.[CrossRef] [Google Scholar]
  12. Hong, Y. K., Foreman, K., Shin, J. W., Hirakawa, S., Curry, C. L., Sage, D. R., Libermann, T., Dezube, B. J., Fingeroth, J. D. & Detmar, M.(2004). Lymphatic reprogramming of blood vascular endothelium by Kaposi sarcoma-associated herpesvirus. Nat Genet 36, 683–685.[CrossRef] [Google Scholar]
  13. Katano, H., Sato, Y., Kurata, T., Mori, S. & Sata, T.(2000). Expression and localization of human herpesvirus 8-encoded proteins in primary effusion lymphoma, Kaposi's sarcoma, and multicentric Castleman's disease. Virology 269, 335–344.[CrossRef] [Google Scholar]
  14. Kellam, P., Boshoff, C., Whitby, D., Matthews, S., Weiss, R. A. & Talbot, S. J.(1997). Identification of a major latent nuclear antigen, LNA-1, in the human herpesvirus 8 genome. J Hum Virol 1, 19–29. [Google Scholar]
  15. Kovary, K. & Bravo, R.(1991). The Jun and Fos protein families are both required for cell cycle progression in fibroblasts. Mol Cell Biol 11, 4466–4472. [Google Scholar]
  16. Kremmer, E., Sommer, P., Holzer, D., Galetsky, S. A., Molochkov, V. A., Gurtsevitch, V., Winkelmann, C., Lisner, R., Niedobitek, G. & Grasser, F. A.(1999). Kaposi's sarcoma-associated herpesvirus (human herpesvirus-8) ORF54 encodes a functional dUTPase expressed in the lytic replication cycle. J Gen Virol 80, 1305–1310. [Google Scholar]
  17. Krithivas, A., Young, D. B., Liao, G., Greene, D. & Hayward, S. D.(2000). Human herpesvirus 8 LANA interacts with proteins of the mSin3 corepressor complex and negatively regulates Epstein–Barr virus gene expression in dually infected PEL cells. J Virol 74, 9637–9645.[CrossRef] [Google Scholar]
  18. Lan, K., Kuppers, D. A., Verma, S. C. & Robertson, E. S.(2004). Kaposi's sarcoma-associated herpesvirus-encoded latency-associated nuclear antigen inhibits lytic replication by targeting Rta: a potential mechanism for virus-mediated control of latency. J Virol 78, 6585–6594.[CrossRef] [Google Scholar]
  19. Lazo, P. S., Dorfman, K., Noguchi, T., Mattei, M. G. & Bravo, R.(1992). Structure and mapping of the fosB gene. FosB downregulates the activity of the fosB promoter. Nucleic Acids Res 20, 343–350.[CrossRef] [Google Scholar]
  20. Liao, J., Hodge, C., Meyer, D., Ho, P. S., Rosenspire, K. & Schwartz, J.(1997). Growth hormone regulates ternary complex factors and serum response factor associated with the c-fos serum response element. J Biol Chem 272, 25951–25958.[CrossRef] [Google Scholar]
  21. Lim, C., Sohn, H., Gwack, Y. & Choe, J.(2000). Latency-associated nuclear antigen of Kaposi's sarcoma-associated herpesvirus (human herpesvirus-8) binds ATF4/CREB2 and inhibits its transcriptional activation activity. J Gen Virol 81, 2645–2652. [Google Scholar]
  22. Lim, C., Gwack, Y., Hwang, S., Kim, S. & Choe, J.(2001). The transcriptional activity of cAMP response element-binding protein-binding protein is modulated by the latency associated nuclear antigen of Kaposi's sarcoma-associated herpesvirus. J Biol Chem 276, 31016–31022.[CrossRef] [Google Scholar]
  23. Liu, J., Martin, H. J., Liao, G. & Hayward, S. D.(2007). The Kaposi's sarcoma-associated herpesvirus LANA protein stabilizes and activates c-Myc. J Virol 81, 10451–10459.[CrossRef] [Google Scholar]
  24. McCormick, C. & Ganem, D.(2005). The kaposin B protein of KSHV activates the p38/MK2 pathway and stabilizes cytokine mRNAs. Science 307, 739–741.[CrossRef] [Google Scholar]
  25. Mittler, G., Stuhler, T., Santolin, L., Uhlmann, T., Kremmer, E., Lottspeich, F., Berti, L. & Meisterernst, M.(2003). A novel docking site on Mediator is critical for activation by VP16 in mammalian cells. EMBO J 22, 6494–6504.[CrossRef] [Google Scholar]
  26. Montaner, S., Sodhi, A., Molinolo, A., Bugge, T. H., Sawai, E. T., He, Y., Li, Y., Ray, P. E. & Gutkind, J. S.(2003). Endothelial infection with KSHV genes in vivo reveals that vGPCR initiates Kaposi's sarcomagenesis and can promote the tumorigenic potential of viral latent genes. Cancer Cell 3, 23–36.[CrossRef] [Google Scholar]
  27. Naranatt, P. P., Akula, S. M., Zien, C. A., Krishnan, H. H. & Chandran, B.(2003). Kaposi's sarcoma-associated herpesvirus induces the phosphatidylinositol 3-kinase-PKC-ζ-MEK-ERK signaling pathway in target cells early during infection: implications for infectivity. J Virol 77, 1524–1539.[CrossRef] [Google Scholar]
  28. Pan, H., Xie, J., Ye, F. & Gao, S. J.(2006). Modulation of Kaposi's sarcoma-associated herpesvirus infection and replication by MEK/ERK, JNK, and p38 multiple mitogen-activated protein kinase pathways during primary infection. J Virol 80, 5371–5382.[CrossRef] [Google Scholar]
  29. Platt, G. M., Simpson, G. R., Mittnacht, S. & Schulz, T. F.(1999). Latent nuclear antigen of Kaposi's sarcoma-associated herpesvirus interacts with RING3, a homolog of the Drosophila female sterile homeotic (fsh) gene. J Virol 73, 9789–9795. [Google Scholar]
  30. Posern, G. & Treisman, R.(2006). Actin' together: serum response factor, its cofactors and the link to signal transduction. Trends Cell Biol 16, 588–596.[CrossRef] [Google Scholar]
  31. Rainbow, L., Platt, G. M., Simpson, G. R., Sarid, R., Gao, S. J., Stoiber, H., Herrington, C. S., Moore, P. S. & Schulz, T. F.(1997). The 222- to 234-kilodalton latent nuclear protein (LNA) of Kaposi's sarcoma-associated herpesvirus (human herpesvirus 8) is encoded by orf73 and is a component of the latency-associated nuclear antigen. J Virol 71, 5915–5921. [Google Scholar]
  32. Renne, R., Barry, C., Dittmer, D., Compitello, N., Brown, P. O. & Ganem, D.(2001). Modulation of cellular and viral gene expression by the latency-associated nuclear antigen of Kaposi's sarcoma-associated herpesvirus. J Virol 75, 458–468.[CrossRef] [Google Scholar]
  33. Rovnak, J. & Quackenbush, S. L.(2002). Walleye dermal sarcoma virus cyclin interacts with components of the mediator complex and the RNA polymerase II holoenzyme. J Virol 76, 8031–8039.[CrossRef] [Google Scholar]
  34. Schwarz, M. & Murphy, P. M.(2001). Kaposi's sarcoma-associated herpesvirus G protein-coupled receptor constitutively activates NF-κB and induces proinflammatory cytokine and chemokine production via a C-terminal signaling determinant. J Immunol 167, 505–513.[CrossRef] [Google Scholar]
  35. Sharma-Walia, N., Krishnan, H. H., Naranatt, P. P., Zeng, L., Smith, M. S. & Chandran, B.(2005). ERK1/2 and MEK1/2 induced by Kaposi's sarcoma-associated herpesvirus (human herpesvirus 8) early during infection of target cells are essential for expression of viral genes and for establishment of infection. J Virol 79, 10308–10329.[CrossRef] [Google Scholar]
  36. Shaw, P. E. & Saxton, J.(2003). Ternary complex factors: prime nuclear targets for mitogen-activated protein kinases. Int J Biochem Cell Biol 35, 1210–1226.[CrossRef] [Google Scholar]
  37. Smit, M. J., Verzijl, D., Casarosa, P., Navis, M., Timmerman, H. & Leurs, R.(2002). Kaposi's sarcoma-associated herpesvirus-encoded G protein-coupled receptor ORF74 constitutively activates p44/p42 MAPK and Akt via Gi and phospholipase C-dependent signaling pathways. J Virol 76, 1744–1752.[CrossRef] [Google Scholar]
  38. Soulier, J., Grollet, L., Oksenhendler, E., Cacoub, P., Cazals-Hatem, D., Babinet, P., d'Agay, M. F., Clauvel, J. P., Raphael, M. & other authors(1995). Kaposi's sarcoma-associated herpesvirus-like DNA sequences in multicentric Castleman's disease. Blood 86, 1276–1280. [Google Scholar]
  39. Stevens, J. L., Cantin, G. T., Wang, G., Shevchenko, A., Shevchenko, A. & Berk, A. J.(2002). Transcription control by E1A and MAP kinase pathway via Sur2 mediator subunit. Science 296, 755–758.[CrossRef] [Google Scholar]
  40. Subramani, S., Mulligan, R. & Berg, P.(1981). Expression of the mouse dihydrofolate reductase complementary deoxyribonucleic acid in simian virus 40 vectors. Mol Cell Biol 1, 854–864. [Google Scholar]
  41. Treisman, R.(1986). Identification of a protein-binding site that mediates transcriptional response of the c-fos gene to serum factors. Cell 46, 567–574.[CrossRef] [Google Scholar]
  42. Uetz, P., Dong, Y. A., Zeretzke, C., Atzler, C., Baiker, A., Berger, B., Rajagopala, S. V., Roupelieva, M., Rose, D. & other authors(2006). Herpesviral protein networks and their interaction with the human proteome. Science 311, 239–242.[CrossRef] [Google Scholar]
  43. Viejo-Borbolla, A., Kati, E., Sheldon, J. A., Nathan, K., Mattsson, K., Szekely, L. & Schulz, T. F.(2003). A domain in the C-terminal region of latency-associated nuclear antigen 1 of Kaposi's sarcoma-associated herpesvirus affects transcriptional activation and binding to nuclear heterochromatin. J Virol 77, 7093–7100.[CrossRef] [Google Scholar]
  44. Wang, G. & Berk, A. J.(2002). In vivo association of adenovirus large E1A protein with the human mediator complex in adenovirus-infected and -transformed cells. J Virol 76, 9186–9193.[CrossRef] [Google Scholar]
  45. Wang, H. W., Trotter, M. W., Lagos, D., Bourboulia, D., Henderson, S., Makinen, T., Elliman, S., Flanagan, A. M., Alitalo, K. & Boshoff, C.(2004). Kaposi sarcoma herpesvirus-induced cellular reprogramming contributes to the lymphatic endothelial gene expression in Kaposi sarcoma. Nat Genet 36, 687–693.[CrossRef] [Google Scholar]
  46. Winter, H. Y. & Marriott, S. J.(2007). Human T-cell leukemia virus type 1 Tax enhances serum response factor DNA binding and alters site selection. J Virol 81, 6089–6098.[CrossRef] [Google Scholar]
  47. Xie, J., Ajibade, A. O., Ye, F., Kuhne, K. & Gao, S. J.(2008). Reactivation of Kaposi's sarcoma-associated herpesvirus from latency requires MEK/ERK, JNK and p38 multiple mitogen-activated protein kinase pathways. Virology 371, 139–154.[CrossRef] [Google Scholar]
  48. Yang, M., Hay, J. & Ruyechan, W. T.(2008). Varicella-zoster virus IE62 protein utilizes the human mediator complex in promoter activation. J Virol 82, 12154–12163.[CrossRef] [Google Scholar]
  49. Yu, F., Harada, J. N., Brown, H. J., Deng, H., Song, M. J., Wu, T. T., Kato-Stankiewicz, J., Nelson, C. G., Vieira, J. & other authors(2007). Systematic identification of cellular signals reactivating Kaposi sarcoma-associated herpesvirus. PLoS Pathog 3, e44[CrossRef] [Google Scholar]

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