Kaposi's sarcoma-associated herpesvirus (KSHV) is the etiologic agent associated with Kaposi's sarcoma (KS), primary effusion lymphoma (PEL), and multicentric Castleman disease (MCD). Similar to other herpesviruses, KSHV has two life cycles, latency and lytic replication. In latency, the KSHV genome persists as a circular episome in the nucleus of the host cell and only a few viral genes are expressed. In this review, we focus on oncogenic, antiapoptotic, and immunomodulating properties of KSHV-encoded homologues of cellular interferon regulatory factors (IRFs)--viral IRF1 (vIRF1) to vIRF4--and their possible role in the KSHV-mediated antiviral response, apoptosis, and oncogenicity.

Institute of Immunology and Microbiology 1st Faculty of Medicine Charles University Prague Czech Republic

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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 PubMed

Cesarman E, Chang Y, Moore PS, Said JW, Knowles DM. 1995. Kaposi's sarcoma-associated herpesvirus-like DNA sequences in AIDS-related body-cavity-based lymphomas. N. Engl. J. Med. 332:1186–1191 PubMed

Soulier J, Grollet L, Oksenhendler E, Cacoub P, Cazals-Hatem D, Babinet P, d'Agay M-F, Clauvel J-P, Raphael M, Degos L, Sigaux F. 1995. Kaposi's sarcoma-associated herpesvirus-like DNA sequences in multicentric Castleman's disease. Blood 86:1276–1280 PubMed

Wen KW, Damania B. 2010. Kaposi sarcoma-associated herpesvirus (KSHV): molecular biology and oncogenesis. Cancer Lett. 289:140–150 PubMed PMC

Boshoff C, Endo Y, Collins PD, Takeuchi Y, Reeves JD, Schweickart VL, Siani MA, Sasaki T, Williams TJ, Gray PW, Moore PS, Chang Y, Weiss RA. 1997. Angiogenic and HIV-inhibitory functions of KSHV-encoded chemokines. Science 278:290–294 PubMed

Molden J, Chang Y, You Y, Moore PS, Goldsmith MA. 1997. A Kaposi's sarcoma-associated herpesvirus-encoded cytokine homolog (vIL-6) activates signaling through the shared gp130 receptor subunit. J. Biol. Chem. 272:19625–19631 PubMed

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 PubMed

Bais C, Santomasso B, Coso O, Arvanitakis L, Raaka EG, Gutkind JS, Asch AS, Cesarman E, Gershengorn MC, Mesri EA. 1998. G-protein-coupled receptor of Kaposi's sarcoma-associated herpesvirus is a viral oncogene and angiogenesis activator. Nature 391:86–89 PubMed

Moore PS, Chang Y. 1998. Kaposi's sarcoma-associated herpesvirus-encoded oncogenes and oncogenesis. J. Natl. Cancer Inst. Monogr. 1998:65–71 PubMed

Burýsek L, Yeow WS, Lubyová B, Kellum M, Schafer SL, Huang YQ, Pitha PM. 1999. Functional analysis of human herpesvirus 8-encoded viral interferon regulatory factor 1 and its association with cellular interferon regulatory factors and p300. J. Virol. 73:7334–7342 PubMed PMC

Lubyova B, Pitha PM. 2000. Characterization of a novel human herpesvirus 8-encoded protein, vIRF-3, that shows homology to viral and cellular interferon regulatory factors. J. Virol. 74:8194–8201 PubMed PMC

Hayward GS. 1999. KSHV strains: the origins and global spread of the virus. Semin. Cancer Biol. 9:187–199 PubMed

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 PubMed PMC

Sarid R, Flore O, Bohenzky RA, Chang Y, Moore PS. 1998. Transcription mapping of the Kaposi's sarcoma-associated herpesvirus (human herpesvirus 8) genome in a body cavity-based lymphoma cell line (BC-1). J. Virol. 72:1005–1012 PubMed PMC

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 PubMed

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 PubMed PMC

Lu M, Suen J, Frias C, Pfeiffer R, Tsai MH, Chuang E, Zeichner SL. 2004. Dissection of the Kaposi's sarcoma-associated herpesvirus gene expression program by using the viral DNA replication inhibitor cidofovir. J. Virol. 78:13637–13652 PubMed PMC

Chandriani S, Ganem D. 2010. Array-based transcript profiling and limiting-dilution reverse transcription-PCR analysis identify additional latent genes in Kaposi's sarcoma-associated herpesvirus. J. Virol. 84:5565–5573 PubMed PMC

West JA, Damania B. 2010. Kaposi's sarcoma-associated herpesvirus and innate immunity. Future Virol. 5:185–196 PubMed PMC

Tamura T, Yanai H, Savitsky D, Taniguchi T. 2008. The IRF family transcription factors in immunity and oncogenesis. Annu. Rev. Immunol. 26:535–584 PubMed

Paun A, Pitha PM. 2007. The IRF family, revisited. Biochimie 89:744–753 PubMed PMC

Takeuchi O, Hemmi H, Akira S. 2004. Interferon response induced by Toll-like receptor signaling. J. Endotoxin Res. 10:252–256 PubMed

Au WC, Moore PA, Lowther W, Juang YT, Pitha PM. 1995. Identification of a member of the interferon regulatory factor family that binds to the interferon-stimulated response element and activates expression of interferon-induced genes. Proc. Natl. Acad. Sci. U. S. A. 92:11657–11661 PubMed PMC

Au WC, Yeow WS, Pitha PM. 2001. Analysis of functional domains of interferon regulatory factor 7 and its association with IRF-3. Virology 280:273–282 PubMed

Zhang L, Pagano JS. 2002. Structure and function of IRF-7. J. Interferon Cytokine Res. 22:95–101 PubMed

Solis M, Goubau D, Romieu-Mourez R, Genin P, Civas A, Hiscott J. 2006. Distinct functions of IRF-3 and IRF-7 in IFN-alpha gene regulation and control of anti-tumor activity in primary macrophages. Biochem. Pharmacol. 72:1469–1476 PubMed

Barnes BJ, Kellum MJ, Pinder KE, Frisancho JA, Pitha PM. 2003. Interferon regulatory factor 5, a novel mediator of cell cycle arrest and cell death. Cancer Res. 63:6424–6431 PubMed

Savitsky D, Tamura T, Yanai H, Taniguchi T. 2010. Regulation of immunity and oncogenesis by the IRF transcription factor family. Cancer Immunol. Immunother. 59:489–510 PubMed PMC

Harada H, Kitagawa M, Tanaka N, Yamamoto H, Harada K, Ishihara M, Taniguchi T. 1993. Anti-oncogenic and oncogenic potentials of interferon regulatory factors-1 and -2. Science 259:971–974 PubMed

Takaoka A, Tamura T, Taniguchi T. 2008. Interferon regulatory factor family of transcription factors and regulation of oncogenesis. Cancer Sci. 99:467–478 PubMed PMC

Offermann MK. 2007. Kaposi sarcoma herpesvirus-encoded interferon regulator factors. Curr. Top. Microbiol. Immunol. 312:185–209 PubMed

Russo JJ, Bohenzky RA, Chien MC, Chen J, Yan M, Maddalena D, Parry JP, Peruzzi D, Edelman IS, Chang Y, Moore PS. 1996. Nucleotide sequence of the Kaposi sarcoma-associated herpesvirus (HHV8). Proc. Natl. Acad. Sci. U. S. A. 93:14862–14867 PubMed PMC

Zimring JC, Goodbourn S, Offermann MK. 1998. Human herpesvirus 8 encodes an interferon regulatory factor (IRF) homolog that represses IRF-1-mediated transcription. J. Virol. 72:701–707 PubMed PMC

Inagi R, Okuno T, Ito M, Chen J, Mori Y, Haque M, Zou P, Yagi H, Kiniwa S, Saida T, Ueyama Y, Hayashi K, Yamanishi K. 1999. Identification and characterization of human herpesvirus 8 open reading frame K9 viral interferon regulatory factor by a monoclonal antibody. J. Hum. Virol. 2:63–71 PubMed

Pozharskaya VP, Weakland LL, Zimring JC, Krug LT, Unger ER, Neisch A, Joshi H, Inoue N, Offermann MK. 2004. Short duration of elevated vIRF-1 expression during lytic replication of human herpesvirus 8 limits its ability to block antiviral responses induced by alpha interferon in BCBL-1 cells. J. Virol. 78:6621–6635 PubMed PMC

Dittmer DP. 2003. Transcription profile of Kaposi's sarcoma-associated herpesvirus in primary Kaposi's sarcoma lesions as determined by real-time PCR arrays. Cancer Res. 63:2010–2015 PubMed

Chen J, Ueda K, Sakakibara S, Okuno T, Yamanishi K. 2000. Transcriptional regulation of the Kaposi's sarcoma-associated herpesvirus viral interferon regulatory factor gene. J. Virol. 74:8623–8634 PubMed PMC

Ueda K, Ishikawa K, Nishimura K, Sakakibara S, Do E, Yamanishi K. 2002. Kaposi's sarcoma-associated herpesvirus (human herpesvirus 8) replication and transcription factor activates the K9 (vIRF) gene through two distinct cis elements by a non-DNA-binding mechanism. J. Virol. 76:12044–12054 PubMed PMC

Park J, Lee MS, Yoo SM, Jeong KW, Lee D, Choe J, Seo T. 2007. Identification of the DNA sequence interacting with Kaposi's sarcoma-associated herpesvirus viral interferon regulatory factor 1. J. Virol. 81:12680–12684 PubMed PMC

Li M, Lee H, Guo J, Neipel F, Fleckenstein B, Ozato K, Jung JU. 1998. Kaposi's sarcoma-associated herpesvirus viral interferon regulatory factor. J. Virol. 72:5433–5440 PubMed PMC

Hew K, Dahlroth SL, Venkatachalam R, Nasertorabi F, Lim BT, Cornvik T, Nordlund P. 2013. The crystal structure of the DNA-binding domain of vIRF-1 from the oncogenic KSHV reveals a conserved fold for DNA binding and reinforces its role as a transcription factor. Nucleic Acids Res. 41:4295–4306 PubMed PMC

Gao SJ, Boshoff C, Jayachandra S, Weiss RA, Chang Y, Moore PS. 1997. KSHV ORF K9 (vIRF) is an oncogene which inhibits the interferon signaling pathway. Oncogene 15:1979–1985 PubMed

Lin R, Genin P, Mamane Y, Sgarbanti M, Battistini A, Harrington WJ, Jr, Barber GN, Hiscott J. 2001. HHV-8 encoded vIRF-1 represses the interferon antiviral response by blocking IRF-3 recruitment of the CBP/p300 coactivators. Oncogene 20:800–811 PubMed

Lagos D, Trotter MW, Vart RJ, Wang HW, Matthews NC, Hansen A, Flore O, Gotch F, Boshoff C. 2007. Kaposi sarcoma herpesvirus-encoded vFLIP and vIRF1 regulate antigen presentation in lymphatic endothelial cells. Blood 109:1550–1558 PubMed

Vogelstein B, Lane D, Levine AJ. 2000. Surfing the p53 network. Nature 408:307–310 PubMed

Gu B, Zhu WG. 2012. Surf the post-translational modification network of p53 regulation. Int. J. Biol. Sci. 8:672–684 PubMed PMC

Dai C, Gu W. 2010. p53 post-translational modification: deregulated in tumorigenesis. Trends Mol. Med. 16:528–536 PubMed PMC

Caspari T. 2000. How to activate p53. Curr. Biol. 10:R315–R317 PubMed

Brooks CL, Gu W. 2006. p53 ubiquitination: Mdm2 and beyond. Mol. Cell 21:307–315 PubMed PMC

Shin YC, Nakamura H, Liang X, Feng P, Chang H, Kowalik TF, Jung JU. 2006. Inhibition of the ATM/p53 signal transduction pathway by Kaposi's sarcoma-associated herpesvirus interferon regulatory factor 1. J. Virol. 80:2257–2266 PubMed PMC

Nakamura H, Li M, Zarycki J, Jung JU. 2001. Inhibition of p53 tumor suppressor by viral interferon regulatory factor. J. Virol. 75:7572–7582 PubMed PMC

Seo T, Park J, Lee D, Hwang SG, Choe J. 2001. Viral interferon regulatory factor 1 of Kaposi's sarcoma-associated herpesvirus binds to p53 and represses p53-dependent transcription and apoptosis. J. Virol. 75:6193–6198 PubMed PMC

Massagué J, Blain SW, Lo RS. 2000. TGFbeta signaling in growth control, cancer, and heritable disorders. Cell 103:295–309 PubMed

Kim SJ, Im YH, Markowitz SD, Bang YJ. 2000. Molecular mechanisms of inactivation of TGF-beta receptors during carcinogenesis. Cytokine Growth Factor Rev. 11:159–168 PubMed

Moustakas A, Pardali K, Gaal A, Heldin CH. 2002. Mechanisms of TGF-beta signaling in regulation of cell growth and differentiation. Immunol. Lett. 82:85–91 PubMed

Heldin CH, Miyazono K, ten Dijke P. 1997. TGF-beta signalling from cell membrane to nucleus through SMAD proteins. Nature 390:465–471 PubMed

Moustakas A, Souchelnytskyi S, Heldin CH. 2001. Smad regulation in TGF-beta signal transduction. J. Cell Sci. 114:4359–4369 PubMed

Moustakas A. 2002. Smad signalling network. J. Cell Sci. 115:3355–3356 PubMed

Datto MB, Li Y, Panus JF, Howe DJ, Xiong Y, Wang XF. 1995. Transforming growth factor beta induces the cyclin-dependent kinase inhibitor p21 through a p53-independent mechanism. Proc. Natl. Acad. Sci. U. S. A. 92:5545–5549 PubMed PMC

Hannon GJ, Beach D. 1994. p15INK4B is a potential effector of TGF-beta-induced cell cycle arrest. Nature 371:257–261 PubMed

Iavarone A, Massague J. 1997. Repression of the CDK activator Cdc25A and cell-cycle arrest by cytokine TGF-beta in cells lacking the CDK inhibitor p15. Nature 387:417–422 PubMed

Seo T, Park J, Choe J. 2005. Kaposi's sarcoma-associated herpesvirus viral IFN regulatory factor 1 inhibits transforming growth factor-beta signaling. Cancer Res. 65:1738–1747 PubMed

Choi YB, Nicholas J. 2008. Autocrine and paracrine promotion of cell survival and virus replication by human herpesvirus 8 chemokines. J. Virol. 82:6501–6513 PubMed PMC

Adams JM, Cory S. 2007. The Bcl-2 apoptotic switch in cancer development and therapy. Oncogene 26:1324–1337 PubMed PMC

Ewings KE, Wiggins CM, Cook SJ. 2007. Bim and the pro-survival Bcl-2 proteins: opposites attract, ERK repels. Cell Cycle 6:2236–2240 PubMed

Kim H, Tu HC, Ren D, Takeuchi O, Jeffers JR, Zambetti GP, Hsieh JJ, Cheng EH. 2009. Stepwise activation of BAX and BAK by tBID, BIM, and PUMA initiates mitochondrial apoptosis. Mol. Cell 36:487–499 PubMed PMC

Kuwana T, Bouchier-Hayes L, Chipuk JE, Bonzon C, Sullivan BA, Green DR, Newmeyer DD. 2005. BH3 domains of BH3-only proteins differentially regulate Bax-mediated mitochondrial membrane permeabilization both directly and indirectly. Mol. Cell 17:525–535 PubMed

Choi YB, Nicholas J. 2010. Bim nuclear translocation and inactivation by viral interferon regulatory factor. PLoS Pathog. 6:e1001031.10.1371/journal.ppat.1001031 PubMed DOI PMC

Choi YB, Sandford G, Nicholas J. 2012. Human herpesvirus 8 interferon regulatory factor-mediated BH3-only protein inhibition via Bid BH3-B mimicry. PLoS Pathog. 8:e1002748.10.1371/journal.ppat.1002748 PubMed DOI PMC

Angell JE, Lindner DJ, Shapiro PS, Hofmann ER, Kalvakolanu DV. 2000. Identification of GRIM-19, a novel cell death-regulatory gene induced by the interferon-beta and retinoic acid combination, using a genetic approach. J. Biol. Chem. 275:33416–33426 PubMed

Seo T, Lee D, Shim YS, Angell JE, Chidambaram NV, Kalvakolanu DV, Choe J. 2002. Viral interferon regulatory factor 1 of Kaposi's sarcoma-associated herpesvirus interacts with a cell death regulator, GRIM19, and inhibits interferon/retinoic acid-induced cell death. J. Virol. 76:8797–8807 PubMed PMC

Hu J, Angell JE, Zhang J, Ma X, Seo T, Raha A, Hayashi J, Choe J, Kalvakolanu DV. 2002. Characterization of monoclonal antibodies against GRIM-19, a novel IFN-beta and retinoic acid-activated regulator of cell death. J. Interferon Cytokine Res. 22:1017–1026 PubMed

Krammer PH. 1999. CD95(APO-1/Fas)-mediated apoptosis: live and let die. Adv. Immunol. 71:163–210 PubMed

Peter ME, Hellbardt S, Schwartz-Albiez R, Westendorp MO, Walczak H, Moldenhauer G, Grell M, Krammer PH. 1995. Cell surface sialylation plays a role in modulating sensitivity towards APO-1-mediated apoptotic cell death. Cell Death Differ. 2:163–171 PubMed

Krammer PH, Galle PR, Moller P, Debatin KM. 1998. CD95(APO-1/Fas)-mediated apoptosis in normal and malignant liver, colon, and hematopoietic cells. Adv. Cancer Res. 75:251–273 PubMed

Kirchhoff S, Sebens T, Baumann S, Krueger A, Zawatzky R, Li-Weber M, Meinl E, Neipel F, Fleckenstein B, Krammer PH. 2002. Viral IFN-regulatory factors inhibit activation-induced cell death via two positive regulatory IFN-regulatory factor 1-dependent domains in the CD95 ligand promoter. J. Immunol. 168:1226–1234 PubMed

Burysek L, Yeow WS, Pitha PM. 1999. Unique properties of a second human herpesvirus 8-encoded interferon regulatory factor (vIRF-2). J. Hum. Virol. 2:19–32 PubMed

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 PubMed PMC

Aresté C, Mutocheluh M, Blackbourn DJ. 2009. Identification of caspase-mediated decay of interferon regulatory factor-3, exploited by a Kaposi sarcoma-associated herpesvirus immunoregulatory protein. J. Biol. Chem. 284:23272–23285 PubMed PMC

Fuld S, Cunningham C, Klucher K, Davison AJ, Blackbourn DJ. 2006. Inhibition of interferon signaling by the Kaposi's sarcoma-associated herpesvirus full-length viral interferon regulatory factor 2 protein. J. Virol. 80:3092–3097 PubMed PMC

Mutocheluh M, Hindle L, Areste C, Chanas SA, Butler LM, Lowry K, Shah K, Evans DJ, Blackbourn DJ. 2011. Kaposi's sarcoma-associated herpesvirus viral interferon regulatory factor-2 inhibits type 1 interferon signalling by targeting interferon-stimulated gene factor-3. J. Gen. Virol. 92:2394–2398 PubMed

Burýsek L, Pitha PM. 2001. Latently expressed human herpesvirus 8-encoded interferon regulatory factor 2 inhibits double-stranded RNA-activated protein kinase. J. Virol. 75:2345–2352 PubMed PMC

Gil J, Alcami J, Esteban M. 1999. Induction of apoptosis by double-stranded-RNA-dependent protein kinase (PKR) involves the alpha subunit of eukaryotic translation initiation factor 2 and NF-kappaB. Mol. Cell. Biol. 19:4653–4663 PubMed PMC

Nakayama Y, Plisch EH, Sullivan J, Thomas C, Czuprynski CJ, Williams BR, Suresh M. 2010. Role of PKR and type I IFNs in viral control during primary and secondary infection. PLoS Pathog. 6:e1000966. PubMed PMC

Sadler AJ, Williams BR. 2007. Structure and function of the protein kinase R. Curr. Top. Microbiol. Immunol. 316:253–292 PubMed

Williams BR. 1997. Role of the double-stranded RNA-activated protein kinase (PKR) in cell regulation. Biochem. Soc. Trans. 25:509–513 PubMed

Chow WA, Fang JJ, Yee JK. 2000. The IFN regulatory factor family participates in regulation of Fas ligand gene expression in T cells. J. Immunol. 164:3512–3518 PubMed

Rivas C, Thlick AE, Parravicini C, Moore PS, Chang Y. 2001. Kaposi's sarcoma-associated herpesvirus LANA2 is a B-cell-specific latent viral protein that inhibits p53. J. Virol. 75:429–438 PubMed PMC

Wies E, Mori Y, Hahn A, Kremmer E, Sturzl M, Fleckenstein B, Neipel F. 2008. The viral interferon-regulatory factor-3 is required for the survival of KSHV-infected primary effusion lymphoma cells. Blood 111:320–327 PubMed

Lubyova B, Kellum MJ, Frisancho AJ, Pitha PM. 2004. Kaposi's sarcoma-associated herpesvirus-encoded vIRF-3 stimulates the transcriptional activity of cellular IRF-3 and IRF-7. J. Biol. Chem. 279:7643–7654 PubMed

Ozato K, Tailor P, Kubota T. 2007. The interferon regulatory factor family in host defense: mechanism of action. J. Biol. Chem. 282:20065–20069 PubMed

Joo CH, Shin YC, Gack M, Wu L, Levy D, Jung JU. 2007. Inhibition of interferon regulatory factor 7 (IRF7)-mediated interferon signal transduction by the Kaposi's sarcoma-associated herpesvirus viral IRF homolog vIRF3. J. Virol. 81:8282–8292 PubMed PMC

Bi X, Yang L, Mancl ME, Barnes BJ. 2011. Modulation of interferon regulatory factor 5 activities by the Kaposi sarcoma-associated herpesvirus-encoded viral interferon regulatory factor 3 contributes to immune evasion and lytic induction. J. Interferon Cytokine Res. 31:373–382 PubMed

Wies E, Hahn AS, Schmidt K, Viebahn C, Rohland N, Lux A, Schellhorn T, Holzer A, Jung JU, Neipel F. 2009. The Kaposi's sarcoma-associated herpesvirus-encoded vIRF-3 inhibits cellular IRF-5. J. Biol. Chem. 284:8525–8538 PubMed PMC

Martin HJ, Lee JM, Walls D, Hayward SD. 2007. Manipulation of the Toll-like receptor 7 signaling pathway by Epstein-Barr virus. J. Virol. 81:9748–9758 PubMed PMC

Zhang L, Pagano JS. 2001. Interferon regulatory factor 7: a key cellular mediator of LMP-1 in EBV latency and transformation. Semin. Cancer Biol. 11:445–453 PubMed

Paun A, Reinert JT, Jiang Z, Medin C, Balkhi MY, Fitzgerald KA, Pitha PM. 2008. Functional characterization of murine interferon regulatory factor 5 (IRF-5) and its role in the innate antiviral response. J. Biol. Chem. 283:14295–14308 PubMed PMC

Takaoka A, Yanai H, Kondo S, Duncan G, Negishi H, Mizutani T, Kano S, Honda K, Ohba Y, Mak TW, Taniguchi T. 2005. Integral role of IRF-5 in the gene induction programme activated by Toll-like receptors. Nature 434:243–249 PubMed

Hu G, Barnes BJ. 2009. IRF-5 is a mediator of the death receptor-induced apoptotic signaling pathway. J. Biol. Chem. 284:2767–2777 PubMed

Silverman N, Maniatis T. 2001. NF-kappaB signaling pathways in mammalian and insect innate immunity. Genes Dev. 15:2321–2342 PubMed

Karin M, Lin A. 2002. NF-kappaB at the crossroads of life and death. Nat. Immunol. 3:221–227 PubMed

Ghosh S, Karin M. 2002. Missing pieces in the NF-kappaB puzzle. Cell 109(Suppl.):S81–S96 PubMed

Seo T, Park J, Lim C, Choe J. 2004. Inhibition of nuclear factor kappaB activity by viral interferon regulatory factor 3 of Kaposi's sarcoma-associated herpesvirus. Oncogene 23:6146–6155 PubMed

Reith W, LeibundGut-Landmann S, Waldburger JM. 2005. Regulation of MHC class II gene expression by the class II transactivator. Nat. Rev. Immunol. 5:793–806 PubMed

Schmidt K, Wies E, Neipel F. 2011. Kaposi's sarcoma-associated herpesvirus viral interferon regulatory factor 3 inhibits gamma interferon and major histocompatibility complex class II expression. J. Virol. 85:4530–4537 PubMed PMC

Lubyova B, Kellum MJ, Frisancho JA, Pitha PM. 2007. Stimulation of c-Myc transcriptional activity by vIRF-3 of Kaposi sarcoma-associated herpesvirus. J. Biol. Chem. 282:31944–31953 PubMed

Muñoz-Fontela C, Marcos-Villar L, Hernandez F, Gallego P, Rodriguez E, Arroyo J, Gao SJ, Avila J, Rivas C. 2008. Induction of paclitaxel resistance by the Kaposi's sarcoma-associated herpesvirus latent protein LANA2. J. Virol. 82:1518–1525 PubMed PMC

Hussain SP, Harris CC. 1999. p53 mutation spectrum and load: the generation of hypotheses linking the exposure of endogenous or exogenous carcinogens to human cancer. Mutat. Res. 428:23–32 PubMed

Lin CY, Loven J, Rahl PB, Paranal RM, Burge CB, Bradner JE, Lee TI, Young RA. 2012. Transcriptional amplification in tumor cells with elevated c-Myc. Cell 151:56–67 PubMed PMC

Hermeking H, Funk JO, Reichert M, Ellwart JW, Eick D. 1995. Abrogation of p53-induced cell cycle arrest by c-Myc: evidence for an inhibitor of p21WAF1/CIP1/SDI1. Oncogene 11:1409–1415 PubMed

Knudsen KJ, Nelander Holm GM, Krabbe JS, Listov-Saabye N, Kiehr B, Dufva M, Svendsen JE, Oleksiewicz MB. 2009. Driving gradual endogenous c-myc overexpression by flow-sorting: intracellular signaling and tumor cell phenotype correlate with oncogene expression. Arch. Toxicol. 83:1061–1074 PubMed

Grandori C, Cowley SM, James LP, Eisenman RN. 2000. The Myc/Max/Mad network and the transcriptional control of cell behavior. Annu. Rev. Cell Dev. Biol. 16:653–699 PubMed

Nie Z, Hu G, Wei G, Cui K, Yamane A, Resch W, Wang R, Green DR, Tessarollo L, Casellas R, Zhao K, Levens D. 2012. c-Myc is a universal amplifier of expressed genes in lymphocytes and embryonic stem cells. Cell 151:68–79 PubMed PMC

Mori K, Maeda Y, Kitaura H, Taira T, Iguchi-Ariga SM, Ariga H. 1998. MM-1, a novel c-Myc-associating protein that represses transcriptional activity of c-Myc. J. Biol. Chem. 273:29794–29800 PubMed

Kimura Y, Nagao A, Fujioka Y, Satou A, Taira T, Iguchi-Ariga SM, Ariga H. 2007. MM-1 facilitates degradation of c-Myc by recruiting proteasome and a novel ubiquitin E3 ligase. Int. J. Oncol. 31:829–836 PubMed

Baresova P, Pitha PM, Lubyova B. 2012. Kaposi sarcoma-associated herpesvirus vIRF-3 protein binds to F-box of Skp2 protein and acts as a regulator of c-Myc protein function and stability. J. Biol. Chem. 287:16199–16208 PubMed PMC

Ferbeyre G, de Stanchina E, Querido E, Baptiste N, Prives C, Lowe SW. 2000. PML is induced by oncogenic ras and promotes premature senescence. Genes Dev. 14:2015–2027 PubMed PMC

Ishov AM, Sotnikov AG, Negorev D, Vladimirova OV, Neff N, Kamitani T, Yeh ET, Strauss JF, III, Maul GG. 1999. PML is critical for ND10 formation and recruits the PML-interacting protein Daxx to this nuclear structure when modified by SUMO-1. J. Cell Biol. 147:221–234 PubMed PMC

Yip KW, Cuddy M, Pinilla C, Giulanotti M, Heynen-Genel S, Matsuzawa S, Reed JC. 2011. A high-content screening (HCS) assay for the identification of chemical inducers of PML oncogenic domains (PODs). J. Biomol. Screen. 16:251–258 PubMed PMC

Maul GG, Negorev D, Bell P, Ishov AM. 2000. Review: properties and assembly mechanisms of ND10, PML bodies, or PODs. J. Struct. Biol. 129:278–287 PubMed

Marcos-Villar L, Lopitz-Otsoa F, Gallego P, Munoz-Fontela C, Gonzalez-Santamaria J, Campagna M, Shou-Jiang G, Rodriguez MS, Rivas C. 2009. Kaposi's sarcoma-associated herpesvirus protein LANA2 disrupts PML oncogenic domains and inhibits PML-mediated transcriptional repression of the survivin gene. J. Virol. 83:8849–8858 PubMed PMC

Marcos-Villar L, Campagna M, Lopitz-Otsoa F, Gallego P, Gonzalez-Santamaria J, Gonzalez D, Rodriguez MS, Rivas C. 2011. Covalent modification by SUMO is required for efficient disruption of PML oncogenic domains by Kaposi's sarcoma-associated herpesvirus latent protein LANA2. J. Gen. Virol. 92:188–194 PubMed

Zhao J. 2007. Sumoylation regulates diverse biological processes. Cell. Mol. Life Sci. 64:3017–3033 PubMed PMC

Marcos-Villar L, Gallego P, Munoz-Fontela C, de la Cruz-Herrera CF, Campagna M, Gonzalez D, Lopitz-Otsoa F, Rodriguez MS, Rivas C. 14 January 2013. Kaposi's sarcoma-associated herpesvirus LANA2 protein interacts with the pocket proteins and inhibits their sumoylation. Oncogene.10.1038/onc.2012.603 PubMed DOI

Tanimoto K, Makino Y, Pereira T, Poellinger L. 2000. Mechanism of regulation of the hypoxia-inducible factor-1 alpha by the von Hippel-Lindau tumor suppressor protein. EMBO J. 19:4298–4309 PubMed PMC

Kallio PJ, Okamoto K, O'Brien S, Carrero P, Makino Y, Tanaka H, Poellinger L. 1998. Signal transduction in hypoxic cells: inducible nuclear translocation and recruitment of the CBP/p300 coactivator by the hypoxia-inducible factor-1alpha. EMBO J. 17:6573–6586 PubMed PMC

Shin YC, Joo CH, Gack MU, Lee HR, Jung JU. 2008. Kaposi's sarcoma-associated herpesvirus viral IFN regulatory factor 3 stabilizes hypoxia-inducible factor-1 alpha to induce vascular endothelial growth factor expression. Cancer Res. 68:1751–1759 PubMed

Fu H, Subramanian RR, Masters SC. 2000. 14-3-3 proteins: structure, function, and regulation. Annu. Rev. Pharmacol. Toxicol. 40:617–647 PubMed

Biggs WH, III, Meisenhelder J, Hunter T, Cavenee WK, Arden KC. 1999. Protein kinase B/Akt-mediated phosphorylation promotes nuclear exclusion of the winged helix transcription factor FKHR1. Proc. Natl. Acad. Sci. U. S. A. 96:7421–7426 PubMed PMC

Brunet A, Bonni A, Zigmond MJ, Lin MZ, Juo P, Hu LS, Anderson MJ, Arden KC, Blenis J, Greenberg ME. 1999. Akt promotes cell survival by phosphorylating and inhibiting a Forkhead transcription factor. Cell 96:857–868 PubMed

Gilley J, Coffer PJ, Ham J. 2003. FOXO transcription factors directly activate bim gene expression and promote apoptosis in sympathetic neurons. J. Cell Biol. 162:613–622 PubMed PMC

Dobson M, Ramakrishnan G, Ma S, Kaplun L, Balan V, Fridman R, Tzivion G. 2011. Bimodal regulation of FoxO3 by AKT and 14-3-3. Biochim. Biophys. Acta 1813:1453–1464 PubMed PMC

Tzivion G, Dobson M, Ramakrishnan G. 2011. FoxO transcription factors; regulation by AKT and 14-3-3 proteins. Biochim. Biophys. Acta 1813:1938–1945 PubMed

Muñoz-Fontela C, Marcos-Villar L, Gallego P, Arroyo J, Da Costa M, Pomeranz KM, Lam EW, Rivas C. 2007. Latent protein LANA2 from Kaposi's sarcoma-associated herpesvirus interacts with 14-3-3 proteins and inhibits FOXO3a transcription factor. J. Virol. 81:1511–1516 PubMed PMC

Esteban M, Garcia MA, Domingo-Gil E, Arroyo J, Nombela C, Rivas C. 2003. The latency protein LANA2 from Kaposi's sarcoma-associated herpesvirus inhibits apoptosis induced by dsRNA-activated protein kinase but not RNase L activation. J. Gen. Virol. 84:1463–1470 PubMed

Balachandran S, Barber GN. 2007. PKR in innate immunity, cancer, and viral oncolysis. Methods Mol. Biol. 383:277–301 PubMed

Xi X, Persson LM, O'Brien MW, Mohr I, Wilson AC. 2012. Cooperation between viral interferon regulatory factor 4 and RTA to activate a subset of Kaposi's sarcoma-associated herpesvirus lytic promoters. J. Virol. 86:1021–1033 PubMed PMC

Lee HR, Toth Z, Shin YC, Lee JS, Chang H, Gu W, Oh TK, Kim MH, Jung JU. 2009. Kaposi's sarcoma-associated herpesvirus viral interferon regulatory factor 4 targets MDM2 to deregulate the p53 tumor suppressor pathway. J. Virol. 83:6739–6747 PubMed PMC

Lee HR, Choi WC, Lee S, Hwang J, Hwang E, Guchhait K, Haas J, Toth Z, Jeon YH, Oh TK, Kim MH, Jung JU. 2011. Bilateral inhibition of HAUSP deubiquitinase by a viral interferon regulatory factor protein. Nat. Struct. Mol. Biol. 18:1336–1344 PubMed PMC

Hayward SD. 2004. Viral interactions with the Notch pathway. Semin. Cancer Biol. 14:387–396 PubMed

Curry CL, Reed LL, Golde TE, Miele L, Nickoloff BJ, Foreman KE. 2005. Gamma secretase inhibitor blocks Notch activation and induces apoptosis in Kaposi's sarcoma tumor cells. Oncogene 24:6333–6344 PubMed

Lan K, Murakami M, Bajaj B, Kaul R, He Z, Gan R, Feldman M, Robertson ES. 2009. Inhibition of KSHV-infected primary effusion lymphomas in NOD/SCID mice by gamma-secretase inhibitor. Cancer Biol. Ther. 8:2136–2143 PubMed PMC

Kopan R, Ilagan MX. 2009. The canonical Notch signaling pathway: unfolding the activation mechanism. Cell 137:216–233 PubMed PMC

Heinzelmann K, Scholz BA, Nowak A, Fossum E, Kremmer E, Haas J, Frank R, Kempkes B. 2010. Kaposi's sarcoma-associated herpesvirus viral interferon regulatory factor 4 (vIRF4/K10) is a novel interaction partner of CSL/CBF1, the major downstream effector of Notch signaling. J. Virol. 84:12255–12264 PubMed PMC

Robinson BA, Estep RD, Messaoudi I, Rogers KS, Wong SW. 2012. Viral interferon regulatory factors decrease the induction of type I and type II interferon during rhesus macaque rhadinovirus infection. J. Virol. 86:2197–2211 PubMed PMC

Robinson BA, O'Connor MA, Li H, Engelmann F, Poland B, Grant R, DeFilippis V, Estep RD, Axthelm MK, Messaoudi I, Wong SW. 2012. Viral interferon regulatory factors are critical for delay of the host immune response against rhesus macaque rhadinovirus infection. J. Virol. 86:2769–2779 PubMed PMC

West J, Damania B. 2008. Upregulation of the TLR3 pathway by Kaposi's sarcoma-associated herpesvirus during primary infection. J. Virol. 82:5440–5449 PubMed PMC

Gregory SM, West JA, Dillon PJ, Hilscher C, Dittmer DP, Damania B. 2009. Toll-like receptor signaling controls reactivation of KSHV from latency. Proc. Natl. Acad. Sci. U. S. A. 106:11725–11730 PubMed PMC

Gregory SM, Damania B. 2009. KSHV and the toll of innate immune activation. Cell Cycle 8:3246–3247 PubMed PMC

Katano H, Sato Y, Itoh H, Sata T. 2001. Expression of human herpesvirus 8 (HHV-8)-encoded immediate early protein, open reading frame 50, in HHV-8-associated diseases. J. Hum. Virol. 4:96–102 PubMed

Petre CE, Sin SH, Dittmer DP. 2007. Functional p53 signaling in Kaposi's sarcoma-associated herpesvirus lymphomas: implications for therapy. J. Virol. 81:1912–1922 PubMed PMC

Jacobs SR, Gregory SM, West JA, Wollish AC, Blackbourn DJ, Heise MT, Damania B. 2013. The viral interferon regulatory factors of Kaposi's sarcoma-associated herpesvirus differ in their inhibition of interferon activation mediated by Toll-like receptor 3. J. Virol. 87:798–806 PubMed PMC

p53 tumor suppressor protein stability and transcriptional activity are targeted by Kaposi's sarcoma-associated herpesvirus-encoded viral interferon regulatory factor 3