Abstract
Almost exactly twenty years after the discovery of Epstein-Barr virus (EBV), the latent membrane protein 1 (LMP1) entered the EBV stage, and soon thereafter, it was recognized as the primary transforming gene product of the virus. LMP1 is expressed in most EBV-associated lymphoproliferative diseases and malignancies, and it critically contributes to pathogenesis and disease phenotypes. Thirty years of LMP1 research revealed its high potential as a deregulator of cellular signal transduction pathways leading to target cell proliferation and the simultaneous subversion of cell death programs. However, LMP1 has multiple roles beyond cell transformation and immortalization, ranging from cytokine and chemokine induction, immune modulation, the global alteration of gene and microRNA expression patterns to the regulation of tumor angiogenesis, cell–cell contact, cell migration, and invasive growth of tumor cells. By acting like a constitutively active receptor, LMP1 recruits cellular signaling molecules associated with tumor necrosis factor receptors such as tumor necrosis factor receptor-associated factor (TRAF) proteins and TRADD to mimic signals of the costimulatory CD40 receptor in the EBV-infected B lymphocyte. LMP1 activates NF-κB, mitogen-activated protein kinase (MAPK), phosphatidylinositol 3-kinase (PI3-K), IRF7, and STAT pathways. Here, we review LMP1’s molecular and biological functions, highlighting the interface between LMP1 and the cellular signal transduction network as an important factor of virus–host interaction and a potential therapeutic target.
Access this chapter
Tax calculation will be finalised at checkout
Purchases are for personal use only
Abbreviations
- AP1:
-
Activator protein 1
- CTAR:
-
C-terminal activating region
- cIAP:
-
Cellular inhibitor of apoptosis
- EBV:
-
Epstein-Barr virus
- ERK:
-
Extracellular signal-regulated kinase
- GCM:
-
Germinal center model
- Id:
-
Inhibitor of DNA binding
- IFNγ:
-
Interferon-γ
- IL:
-
Interleukin
- IRF7:
-
Interferon regulatory factor 7
- IκB:
-
Inhibitor of NF-κB
- IKK:
-
IκB kinase
- IRAK1:
-
Interleukin 1 receptor-associated kinase 1
- JAK3:
-
Janus kinase 3
- JNK:
-
c-Jun N-terminal kinase
- LMP1:
-
Latent membrane protein 1
- LCL:
-
Lymphoblastoid cell line
- MAPK:
-
Mitogen-activated protein kinase
- MEF:
-
Mouse embryonic fibroblast
- NF-κB:
-
Nuclear factor of kappa light polypeptide gene enhancer in B cells
- NIK:
-
NF-κB-inducing kinase
- NPC:
-
Nasopharyngeal carcinoma
- UPR:
-
Unfolded protein response
- PI3-K:
-
Phosphatidylinositol 3-kinase
- PKCδ:
-
Protein kinase C δ
- PTLD:
-
Post-transplant lymphoproliferative disease
- Rb:
-
Retinoblastoma protein
- RIP1:
-
Receptor-interacting protein 1
- RING:
-
Really interesting new gene, protein domain with E3 ubiquitin ligase activity
- STAT:
-
Signal transducers and activators of transcription
- SUMO:
-
Small ubiquitin-like modifier
- TAK1:
-
Transforming growth factor β-activated kinase 1
- TAB:
-
TAK1-binding protein
- TES:
-
Transformation effector site
- TNF-R:
-
Tumor necrosis factor receptor
- TNIK:
-
TRAF2- and Nck-interacting kinase
- TM:
-
Transmembrane domain
- TRAF:
-
Tumor necrosis factor receptor-associated factor
References
Adler B, Schaadt E, Kempkes B, Zimber-Strobl U, Baier B, Bornkamm GW (2002) Control of Epstein-Barr virus reactivation by activated CD40 and viral latent membrane protein 1. Proc Natl Acad Sci USA 99(1):437–442
Allday MJ, Crawford DH, Griffin BE (1989) Epstein-Barr virus latent gene expression during the initiation of B cell immortalization. J Gen Virol 70(Pt 7):1755–1764
Amort M, Nachbauer B, Tuzlak S, Kieser A, Schepers A, Villunger A, Polacek A (2015) Expression of the vault RNA protects cells from undergoing apoptosis. Nat Com 6:7030
Arcipowski KM, Stunz LL, Graham JP, Kraus ZJ, Vanden Bush TJ, Bishop GA (2011) Molecular mechanisms of TNFR-associated factor 6 (TRAF6) utilization by the oncogenic viral mimic of CD40, latent membrane protein 1 (LMP1). J Biol Chem 286(12):9948–9955
Ardila-Osorio H, Clausse B, Mishal Z, Wiels J, Tursz T, Busson P (1999) Evidence of LMP1-TRAF3 interactions in glycosphingolipid-rich complexes of lymphoblastoid and nasopharyngeal carcinoma cells. Int J Cancer 81(4):645–649
Atkinson PG, Coope HJ, Rowe M, Ley SC (2003) Latent membrane protein 1 of Epstein-Barr virus stimulates processing of NF-kappa B2 p100 to p52. J Biol Chem 278(51):51134–51142
Aviel S, Winberg G, Massucci M, Ciechanover A (2000) Degradation of the Epstein-Barr virus latent membrane protein 1 (LMP1) by the ubiquitin-proteasome pathway. Targeting via ubiquitination of the N-terminal residue. J Biol Chem 275(31):23491–23499
Babcock GJ, Hochberg D, Thorley-Lawson AD (2000) The expression pattern of Epstein-Barr virus latent genes in vivo is dependent upon the differentiation stage of the infected B cell. Immunity 13(4):497–506
Baichwal VR, Sugden B (1987) Posttranslational processing of an Epstein-Barr virus-encoded membrane protein expressed in cells transformed by Epstein-Barr virus. J Virol 61(3):866–875
Baichwal VR, Sugden B (1988) Transformation of Balb 3T3 cells by the BNLF-1 gene of Epstein-Barr virus. Oncogene 2(5):461–467
Bentz GL, Whitehurst CB, Pagano JS (2011) Epstein-Barr virus latent membrane protein 1 (LMP1) C-terminal-activating region 3 contributes to LMP1-mediated cellular migration via its interaction with Ubc9. J Virol 85(19):10144–10153
Bentz GL, Shackelford J, Pagano JS (2012) Epstein-Barr virus latent membrane protein 1 regulates the function of interferon regulatory factor 7 by inducing its sumoylation. J Virol 86(22):12251–12261
Blake SM, Eliopoulos AG, Dawson CW, Young LS (2001) The transmembrane domains of the EBV-encoded latent membrane protein 1 (LMP1) variant CAO regulate enhanced signalling activity. Virology 282(2):278–287
Boehm D, Gewurz BE, Kieff E, Cahir-McFarland E (2010) Epstein-Barr latent membrane protein 1 transformation site 2 activates NF-kappaB in the absence of NF-kappaB essential modifier residues 133–224 or 373–419. Proc Natl Acad Sci USA 107(42):18103–18108
Brodeur SR, Cheng G, Baltimore D, Thorley-Lawson DA (1997) Localization of the major NF-kappaB-activating site and the sole TRAF3 binding site of LMP-1 defines two distinct signaling motifs. J Biol Chem 272(32):19777–19784
Brown KD, Hostager BS, Bishop GA (2001) Differential signaling and tumor necrosis factor receptor-associated factor (TRAF) degradation mediated by CD40 and the Epstein-Barr virus oncoprotein latent membrane protein 1 (LMP1). J Exp Med 193(8):943–954
Busch LK, Bishop GA (1999) The EBV transforming protein, latent membrane protein 1, mimics and cooperates with CD40 signaling in B lymphocytes. J Immunol 162(5):2555–2561
Cahir-McFarland ED, Izumi KM, Mosialos G (1999) Epstein-barr virus transformation: involvement of latent membrane protein 1-mediated activation of NF-kappaB. Oncogene 18(49):6959–6964
Cahir-McFarland ED, Carter K, Rosenwald A, Giltnane JM, Henrickson SE, Staudt LM, Kieff E (2004) Role of NF-kappa B in cell survival and transcription of latent membrane protein 1-expressing or Epstein-Barr virus latency III-infected cells. J Virol 78(8):4108–4119
Cao Y, Yang L, Jiang W, Wang X, Liao W, Tan G, Liao Y, Qiu Y, Feng D, Tang F, Hou BL, Zhang L, Fu J, He F, Liu X, Jiang W, Yang T, Sun LQ (2014) Therapeutic evaluation of Epstein-Barr virus-encoded latent membrane protein-1 targeted DNAzyme for treating of nasopharyngeal carcinomas. Mol Ther 22(2):371–377
Chatterjee B, Leung CS, Munz C (2014) Animal models of Epstein Barr virus infection. J Immunol Methods 410:80–87
Chen H, Lee JM, Zong Y, Borowitz M, Ng MH, Ambinder RF, Hayward SD (2001) Linkage between STAT regulation and Epstein-Barr virus gene expression in tumors. J Virol 75(6):2929–2937
Chen H, Hutt-Fletcher L, Cao L, Hayward SD (2003) A positive autoregulatory loop of LMP1 expression and STAT activation in epithelial cells latently infected with Epstein-Barr virus. J Virol 77(7):4139–4148
Chen CC, Liu HP, Chao M, Liang Y, Tsang NM, Huang HY, Wu CC, Chang YS (2014) NF-kappaB-mediated transcriptional upregulation of TNFAIP2 by the Epstein-Barr virus oncoprotein, LMP1, promotes cell motility in nasopharyngeal carcinoma. Oncogene 33(28):3648–3659
Chew MM, Gan SY, Khoo AS, Tan EL (2010) Interleukins, laminin and Epstein-Barr virus latent membrane protein 1 (EBV LMP1) promote metastatic phenotype in nasopharyngeal carcinoma. BMC Cancer 10:574
Coffin WF 3rd, Erickson KD, Hoedt-Miller M, Martin JM (2001) The cytoplasmic amino-terminus of the Latent Membrane Protein-1 of Epstein-Barr virus: relationship between transmembrane orientation and effector functions of the carboxy-terminus and transmembrane domain. Oncogene 20(38):5313–5330
Coffin WF 3rd, Geiger TR, Martin JM (2003) Transmembrane domains 1 and 2 of the latent membrane protein 1 of Epstein-Barr virus contain a lipid raft targeting signal and play a critical role in cytostasis. J Virol 77(6):3749–3758
Cohen JI (2000) Epstein-Barr virus infection. N Engl J Med 343(7):481–492
Curran JA, Laverty FS, Campbell D, Macdiarmid J, Wilson JB (2001) Epstein-Barr virus encoded latent membrane protein-1 induces epithelial cell proliferation and sensitizes transgenic mice to chemical carcinogenesis. Cancer Res 61(18):6730–6738
Dawson CW, Rickinson AB, Young LS (1990) Epstein-Barr virus latent membrane protein inhibits human epithelial cell differentiation. Nature 344:777–780
Dawson CW, Tramountanis G, Eliopoulos AG, Young LS (2003) Epstein-Barr virus latent membrane protein 1 (LMP1) activates the phosphatidylinositol 3-kinase/Akt pathway to promote cell survival and induce actin filament remodeling. J Biol Chem 278(6):3694–3704
Dawson CW, Laverick L, Morris MA, Tramoutanis G, Young LS (2008) Epstein-Barr virus-encoded LMP1 regulates epithelial cell motility and invasion via the ERK-MAPK pathway. J Virol 82(7):3654–3664
Demetriades C, Mosialos G (2009) The LMP1 promoter can be transactivated directly by NF-kappaB. J Virol 83(10):5269–5277
Devergne O, Hatzivassiliou E, Izumi KM, Kaye KM, Kleijnen MF, Kieff E, Mosialos G (1996) Association of TRAF1, TRAF2, and TRAF3 with an Epstein-Barr virus LMP1 domain important for B-lymphocyte transformation: role in NF-kappaB activation. Mol Cell Biol 16(12):7098–7108
Devergne O, Cahir-McFarland ED, Mosialos G, Izumi KM, Ware CF, Kieff E (1998) Role of the TRAF binding site and NF-kappaB activation in Epstein-Barr virus latent membrane protein 1-induced cell gene expression. J Virol 72(10):7900–7908
Ding L, Li L, Yang J, Zhou S, Li W, Tang M, Shi Y, Yi W, Cao Y (2007) Latent membrane protein 1 encoded by Epstein-Barr virus induces telomerase activity via p16INK4A/Rb/E2F1 and JNK signaling pathways. J Med Virol 79(8):1153–1163
Dirmeier U, Neuhierl B, Kilger E, Reisbach G, Sandberg ML, Hammerschmidt W (2003) Latent membrane protein 1 is critical for efficient growth transformation of human B cells by Epstein-Barr virus. Cancer Res 63(11):2982–2989
Dirmeier U, Hoffmann R, Kilger E, Schultheiss U, Briseno C, Gires O, Kieser A, Eick D, Sugden B, Hammerschmidt W (2005) Latent membrane protein 1 of Epstein-Barr virus coordinately regulates proliferation with control of apoptosis. Oncogene 24(10):1711–1717
D’Souza BN, Edelstein LC, Pegman PM, Smith SM, Loughran ST, Clarke A, Mehl A, Rowe M, Gelinas C, Walls D (2004) Nuclear factor kappa B-dependent activation of the antiapoptotic bfl-1 gene by the Epstein-Barr virus latent membrane protein 1 and activated CD40 receptor. J Virol 78(4):1800–1816
Dukers DF, Meij P, Vervoort MB, Vos W, Scheper RJ, Meijer CJ, Bloemena E, Middeldorp JM (2000) Direct immunosuppressive effects of EBV-encoded latent membrane protein 1. J Immunol 165(2):663–670
Eliopoulos AG, Young LS (1998) Activation of the cJun N-terminal kinase (JNK) pathway by the Epstein-Barr virus-encoded latent membrane protein 1 (LMP1). Oncogene 16(13):1731–1742
Eliopoulos AG, Blake SM, Floettmann JE, Rowe M, Young LS (1999a) Epstein-Barr virus-encoded latent membrane protein 1 activates the JNK pathway through its extreme C terminus via a mechanism involving TRADD and TRAF2. J Virol 73(2):1023–1035
Eliopoulos AG, Gallagher NJ, Blake SM, Dawson CW, Young LS (1999b) Activation of the p38 mitogen-activated protein kinase pathway by Epstein-Barr virus-encoded latent membrane protein 1 coregulates interleukin-6 and interleukin-8 production. J Biol Chem 274(23):16085–16096
Eliopoulos AG, Caamano JH, Flavell J, Reynolds GM, Murray PG, Poyet JL, Young LS (2003a) Epstein-Barr virus-encoded latent infection membrane protein 1 regulates the processing of p100 NF-kappaB2 to p52 via an IKKgamma/NEMO-independent signalling pathway. Oncogene 22(48):7557–7569
Eliopoulos AG, Waites ER, Blake SM, Davies C, Murray P, Young LS (2003b) TRAF1 is a critical regulator of JNK signaling by the TRAF-binding domain of the Epstein-Barr virus-encoded latent infection membrane protein 1 but not CD40. J Virol 77(2):1316–1328
Endo K, Kondo S, Shackleford J, Horikawa T, Kitagawa N, Yoshizaki T, Furukawa M, Zen Y, Pagano JS (2009) Phosphorylated ezrin is associated with EBV latent membrane protein 1 in nasopharyngeal carcinoma and induces cell migration. Oncogene 28(14):1725–1735
Erickson KD, Martin JM (1997) Early detection of the lytic LMP-1 protein in EBV-infected B-cells suggests its presence in the virion. Virology 234(1):1–13
Erickson KD, Martin JM (2000) The late lytic LMP-1 protein of Epstein-Barr virus can negatively regulate LMP-1 signaling. J Virol 74(2):1057–1060
Everly DN Jr, Mainou BA, Raab-Traub N (2004) Induction of Id1 and Id3 by latent membrane protein 1 of Epstein-Barr virus and regulation of p27/Kip and cyclin-dependent kinase 2 in rodent fibroblast transformation. J Virol 78(24):13470–13478
Fahraeus R, Jansson A, Ricksten A, Sjoblom A, Rymo L (1990) Epstein-Barr virus-encoded nuclear antigen 2 activates the viral latent membrane protein promoter by modulating the activity of a negative regulatory element. Proc Natl Acad Sci USA 87(19):7390–7394
Faumont N, Durand-Panteix S, Schlee M, Gromminger S, Schuhmacher M, Holzel M, Laux G, Mailhammer R, Rosenwald A, Staudt LM, Bornkamm GW, Feuillard J (2009) c-Myc and Rel/NF-kappaB are the two master transcriptional systems activated in the latency III program of Epstein-Barr virus-immortalized B cells. J Virol 83(10):5014–5027
Fennewald S, van Santen V, Kieff E (1984) Nucleotide sequence of an mRNA transcribed in latent growth-transforming virus infection indicates that it may encode a membrane protein. J Virol 51(2):411–419
Feuillard J, Schuhmacher M, Kohanna S, Asso-Bonnet M, Ledeur F, Joubert-Caron R, Bissieres P, Polack A, Bornkamm GW, Raphael M (2000) Inducible loss of NF-kappaB activity is associated with apoptosis and Bcl-2 down-regulation in Epstein-Barr virus-transformed B lymphocytes. Blood 95(6):2068–2075
Fielding CA, Sandvej K, Mehl A, Brennan P, Jones M, Rowe M (2001) Epstein-Barr virus LMP-1 natural sequence variants differ in their potential to activate cellular signaling pathways. J Virol 75(19):9129–9141
Floettmann JE, Rowe M (1997) Epstein-Barr virus latent membrane protein-1 (LMP1) C-terminus activation region 2 (CTAR2) maps to the far C-terminus and requires oligomerisation for NF-kappaB activation. Oncogene 15(15):1851–1858
Floettmann JE, Eliopoulos AG, Jones M, Young LS, Rowe M (1998) Epstein-Barr virus latent membrane protein-1 (LMP1) signalling is distinct from CD40 and involves physical cooperation of its two C-terminus functional regions. Oncogene 17(18):2383–2392
Gewurz BE, Mar JC, Padi M, Zhao B, Shinners NP, Takasaki K, Bedoya E, Zou JY, Cahir-McFarland E, Quackenbush J, Kieff E (2011) Canonical NF-kappaB activation is essential for Epstein-Barr virus latent membrane protein 1 TES2/CTAR2 gene regulation. J Virol 85(13):6764–6773
Gewurz BE, Towfic F, Mar JC, Shinners NP, Takasaki K, Zhao B, Cahir-McFarland ED, Quackenbush J, Xavier RJ, Kieff E (2012) Genome-wide siRNA screen for mediators of NF-kappaB activation. Proc Natl Acad Sci USA 109(7):2467–2472
Gires O, Zimber-Strobl U, Gonnella R, Ueffing M, Marschall G, Zeidler R, Pich D, Hammerschmidt W (1997) Latent membrane protein 1 of Epstein-Barr virus mimics a constitutively active receptor molecule. EMBO J 16(20):6131–6140
Gires O, Kohlhuber F, Kilger E, Baumann M, Kieser A, Kaiser C, Zeidler R, Scheffer B, Ueffing M, Hammerschmidt W (1999) Latent membrane protein 1 of Epstein-Barr virus interacts with JAK3 and activates STAT proteins. EMBO J 18(11):3064–3073
Grimm T, Schneider S, Naschberger E, Huber J, Guenzi E, Kieser A, Reitmeir P, Schulz TF, Morris CA, Sturzl M (2005) EBV latent membrane protein-1 protects B cells from apoptosis by inhibition of BAX. Blood 105(8):3263–3269
Guasparri I, Bubman D, Cesarman E (2008) EBV LMP2A affects LMP1-mediated NF-κB signaling and survival of lymphoma cells by regulating TRAF2 expression. Blood 111(7):3813–3820
Hammerschmidt W, Sugden B, Baichwal VR (1989) The transforming domain alone of the latent membrane protein of Epstein-Barr virus is toxic to cells when expressed at high levels. J Virol 63(6):2469–2475
Hannigan A, Qureshi AM, Nixon C, Tsimbouri PM, Jones S, Philbey AW, Wilson JB (2011) Lymphocyte deficiency limits Epstein-Barr virus latent membrane protein 1 induced chronic inflammation and carcinogenic pathology in vivo. Mol Cancer 10(1):11
Hatton O, Lambert SL, Krams SM, Martinez OM (2012) Src kinase and Syk activation initiate PI3K signaling by a chimeric latent membrane protein 1 in Epstein-Barr virus (EBV)+ B cell lymphomas. PLoS ONE 7(8):e42610
Hatton OL, Harris-Arnold A, Schaffert S, Krams SM, Martinez OM (2014) The interplay between Epstein-Barr virus and B lymphocytes: implications for infection, immunity, and disease. Immunol Res 58(2–3):268–276
Hatzivassiliou E, Miller WE, Raab-Traub N, Kieff E, Mosialos G (1998) A fusion of the EBV latent membrane protein-1 (LMP1) transmembrane domains to the CD40 cytoplasmic domain is similar to LMP1 in constitutive activation of epidermal growth factor receptor expression, nuclear factor-kappa B, and stress-activated protein kinase. J Immunol 160(3):1116–1121
Hau PM, Tsang CM, Yip YL, Huen MS, Tsao SW (2011) Id1 interacts and stabilizes the Epstein-Barr virus latent membrane protein 1 (LMP1) in nasopharyngeal epithelial cells. PLoS ONE 6(6):e21176
Henderson S, Rowe M, Gregory C, Croom-Carter D, Wang F, Longnecker R, Kieff E, Rickinson A (1991) Induction of bcl-2 expression by Epstein-Barr virus latent membrane protein 1 protects infected B cells from programmed cell death. Cell 65(7):1107–1115
Hennessy K, Fennewald S, Hummel M, Cole T, Kieff E (1984) A membrane protein encoded by Epstein-Barr virus in latent growth-transforming infection. Proc Natl Acad Sci USA 81(22):7207–7211
Higuchi M, Izumi KM, Kieff E (2001) Epstein-Barr virus latent-infection membrane proteins are palmitoylated and raft-associated: protein 1 binds to the cytoskeleton through TNF receptor cytoplasmic factors. Proc Natl Acad Sci USA 98(8):4675–4680
Higuchi M, Kieff E, Izumi KM (2002) The Epstein-Barr virus latent membrane protein 1 putative Janus kinase 3 (JAK3) binding domain does not mediate JAK3 association or activation in B-lymphoma or lymphoblastoid cell lines. J Virol 76(1):455–459
Hu LF, Zabarovsky ER, Chen F, Cao SL, Ernberg I, Klein G, Winberg G (1991) Isolation and sequencing of the Epstein-Barr virus BNLF-1 gene (LMP1) from a Chinese nasopharyngeal carcinoma. J Gen Virol 72(Pt 10):2399–2409
Huang YT, Sheen TS, Chen CL, Lu J, Chang Y, Chen JY, Tsai CH (1999) Profile of cytokine expression in nasopharyngeal carcinomas: a distinct expression of interleukin 1 in tumor and CD4+ T cells. Cancer Res 59(7):1599–1605
Huang S, Stupack D, Liu A, Cheresh D, Nemerow GR (2000) Cell growth and matrix invasion of EBV-immortalized human B lymphocytes is regulated by expression of alpha(v) integrins. Oncogene 19(15):1915–1923
Hudson GS, Farrell PJ, Barrell BG (1985) Two related but differentially expressed potential membrane proteins encoded by the EcoRI Dhet region of Epstein-Barr virus B95-8. J Virol 53(2):528–535
Huen DS, Henderson SA, Croom-Carter D, Rowe M (1995) The Epstein-Barr virus latent membrane protein-1 (LMP1) mediates activation of NF-kappa B and cell surface phenotype via two effector regions in its carboxy-terminal cytoplasmic domain. Oncogene 10(3):549–560
Huye LE, Ning S, Kelliher M, Pagano JS (2007) Interferon regulatory factor 7 is activated by a viral oncoprotein through RIP-dependent ubiquitination. Mol Cell Biol 27(8):2910–2918
Izumi KM, Kieff ED (1997) The Epstein-Barr virus oncogene product latent membrane protein 1 engages the tumor necrosis factor receptor-associated death domain protein to mediate B lymphocyte growth transformation and activate NF-kappaB. Proc Natl Acad Sci USA 94(23):12592–12597
Izumi KM, Kaye KM, Kieff ED (1994) Epstein-Barr virus recombinant molecular genetic analysis of the LMP1 amino-terminal cytoplasmic domain reveals a probable structural role, with no component essential for primary B-lymphocyte growth transformation. J Virol 68(7):4369–4376
Izumi KM, Kaye KM, Kieff ED (1997) The Epstein-Barr virus LMP1 amino acid sequence that engages tumor necrosis factor receptor associated factors is critical for primary B lymphocyte growth transformation. Proc Natl Acad Sci USA 94(4):1447–1452
Izumi KM, Cahir-McFarland ED, Riley EA, Rizzo D, Chen Y, Kieff E (1999) The residues between the two transformation effector sites of Epstein-Barr virus latent membrane protein 1 are not critical for B-lymphocyte growth transformation. J Virol 73(12):9908–9916
Johansson P, Jansson A, Ruetschi U, Rymo L (2009) Nuclear factor-kappaB binds to the Epstein-Barr virus LMP1 promoter and upregulates its expression. J Virol 83(3):1393–1401
Johansson P, Jansson A, Ruetschi U, Rymo L (2010) The p38 signaling pathway upregulates expression of the Epstein-Barr virus LMP1 oncogene. J Virol 84(6):2787–2797
Kaye KM, Izumi KM, Kieff E (1993) Epstein-Barr virus latent membrane protein 1 is essential for B-lymphocyte growth transformation. Proc Natl Acad Sci USA 90(19):9150–9154
Kaye KM, Izumi KM, Mosialos G, Kieff E (1995) The Epstein-Barr virus LMP1 cytoplasmic carboxy terminus is essential for B-lymphocyte transformation; fibroblast cocultivation complements a critical function within the terminal 155 residues. J Virol 69(2):675–683
Kaye KM, Devergne O, Harada JN, Izumi KM, Yalamanchili R, Kieff E, Mosialos G (1996) Tumor necrosis factor receptor associated factor 2 is a mediator of NF-kappa B activation by latent infection membrane protein 1, the Epstein-Barr virus transforming protein. Proc Natl Acad Sci USA 93(20):11085–11090
Kaye KM, Izumi KM, Li H, Johannsen E, Davidson D, Longnecker R, Kieff E (1999) An Epstein-Barr virus that expresses only the first 231 LMP1 amino acids efficiently initiates primary B-lymphocyte growth transformation. J Virol 73(12):10525–10530
Kieser A (2008) Pursuing different ‘TRADDes’: TRADD signaling induced by TNF-receptor 1 and the Epstein-Barr virus oncoprotein LMP1. Biol Chem 389(10):1261–1271
Kieser A, Kilger E, Gires O, Ueffing M, Kolch W, Hammerschmidt W (1997) Epstein-Barr virus latent membrane protein-1 triggers AP-1 activity via the c-Jun N-terminal kinase cascade. EMBO J 16(21):6478–6485
Kieser A, Kaiser C, Hammerschmidt W (1999) LMP1 signal transduction differs substantially from TNF receptor 1 signaling in the molecular functions of TRADD and TRAF2. EMBO J 18(9):2511–2521
Kilger E, Kieser A, Baumann M, Hammerschmidt W (1998) Epstein-Barr virus-mediated B-cell proliferation is dependent upon latent membrane protein 1, which simulates an activated CD40 receptor. EMBO J 17(6):1700–1709
Kim JE, Kim SY, Lim SY, Kieff E, Song YJ (2014) Role of Ca2+/Calmodulin-dependent Kinase II-IRAK1 interaction in LMP1-induced NF-kappaB activation. Mol Cell Biol 34(3):325–334
Kis LL, Takahara M, Nagy N, Klein G, Klein E (2006) IL-10 can induce the expression of EBV-encoded latent membrane protein-1 (LMP-1) in the absence of EBNA-2 in B lymphocytes and in Burkitt lymphoma- and NK lymphoma-derived cell lines. Blood 107(7):2928–2935
Kis LL, Salamon D, Persson EK, Nagy N, Scheeren FA, Spits H, Klein G, Klein E (2010) IL-21 imposes a type II EBV gene expression on type III and type I B cells by the repression of C- and activation of LMP-1-promoter. Proc Natl Acad Sci USA 107(2):872–877
Kis LL, Gerasimcik N, Salamon D, Persson EK, Nagy N, Klein G, Severinson E, Klein E (2011) STAT6 signaling pathway activated by the cytokines IL-4 and IL-13 induces expression of the Epstein-Barr virus-encoded protein LMP-1 in absence of EBNA-2: implications for the type II EBV latent gene expression in Hodgkin lymphoma. Blood 117(1):165–174
Kondo S, Wakisaka N, Schell MJ, Horikawa T, Sheen TS, Sato H, Furukawa M, Pagano JS, Yoshizaki T (2005) Epstein-Barr virus latent membrane protein 1 induces the matrix metalloproteinase-1 promoter via an Ets binding site formed by a single nucleotide polymorphism: Enhanced susceptibility to nasopharyngeal carcinoma. Int J Cancer 115(3):368–376
Kulwichit W, Edwards RH, Davenport EM, Baskar JF, Godfrey V, Raab-Traub N (1998) Expression of the Epstein-Barr virus latent membrane protein 1 induces B cell lymphoma in transgenic mice. Proc Natl Acad Sci USA 95(20):11963–11968
Kung CP, Meckes DG Jr, Raab-Traub N (2011) Epstein-Barr virus LMP1 activates EGFR, STAT3, and ERK through effects on PKCdelta. J Virol 85(9):4399–4408
Kutz H, Reisbach G, Schultheiss U, Kieser A (2008) The c-Jun N-terminal kinase pathway is critical for cell transformation by the latent membrane protein 1 of Epstein-Barr virus. Virology 371(2):246–256
Laherty CD, Hu HM, Opipari AW, Wang F, Dixit VM (1992) The Epstein-Barr virus LMP1 gene product induces A20 zinc finger protein expression by activating nuclear factor kappa B. J Biol Chem 267(34):24157–24160
Lai HC, Hsiao JR, Chen CW, Wu SY, Lee CH, Su IJ, Takada K, Chang Y (2010) Endogenous latent membrane protein 1 in Epstein-Barr virus-infected nasopharyngeal carcinoma cells attracts T lymphocytes through upregulation of multiple chemokines. Virology 405(2):464–473
Lam N, Sugden B (2003) LMP1, a viral relative of the TNF receptor family, signals principally from intracellular compartments. EMBO J 22(12):3027–3038
Lambert SL, Martinez OM (2007) Latent membrane protein 1 of EBV activates phosphatidylinositol 3-kinase to induce production of IL-10. J Immunol 179(12):8225–8234
Le Clorennec C, Ouk TS, Youlyouz-Marfak I, Panteix S, Martin CC, Rastelli J, Adriaenssens E, Zimber-Strobl U, Coll J, Feuillard J, Jayat-Vignoles C (2008) Molecular basis of cytotoxicity of Epstein-Barr virus (EBV) latent membrane protein 1 (LMP1) in EBV latency III B cells: LMP1 induces type II ligand-independent autoactivation of CD95/Fas with caspase 8-mediated apoptosis. J Virol 82(13):6721–6733
Lee J, Sugden B (2007) A membrane leucine heptad contributes to trafficking, signaling, and transformation by latent membrane protein 1. J Virol 81(17):9121–9130
Lee DY, Sugden B (2008a) The latent membrane protein 1 oncogene modifies B-cell physiology by regulating autophagy. Oncogene 27(20):2833–2842
Lee DY, Sugden B (2008b) The LMP1 oncogene of EBV activates PERK and the unfolded protein response to drive its own synthesis. Blood 111(4):2280–2289
Li HM, Zhuang ZH, Wang Q, Pang JC, Wang XH, Wong HL, Feng HC, Jin DY, Ling MT, Wong YC, Eliopoulos AG, Young LS, Huang DP, Tsao SW (2004) Epstein-Barr virus latent membrane protein 1 (LMP1) upregulates Id1 expression in nasopharyngeal epithelial cells. Oncogene 23(25):4488–4494
Li J, Zhang XS, Xie D, Deng HX, Gao YF, Chen QY, Huang WL, Masucci MG, Zeng YX (2007) Expression of immune-related molecules in primary EBV-positive Chinese nasopharyngeal carcinoma: associated with latent membrane protein 1 (LMP1) expression. Cancer Biol Ther 6(12):1997–2004
Li SS, Yang S, Wang S, Yang XM, Tang QL, Wang SH (2011) Latent membrane protein 1 mediates the resistance of nasopharyngeal carcinoma cells to TRAIL-induced apoptosis by activation of the PI3K/Akt signaling pathway. Oncol Rep 26(6):1573–1579
Li L, Li W, Xiao L, Xu J, Chen X, Tang M, Dong Z, Tao Q, Cao Y (2012) Viral oncoprotein LMP1 disrupts p53-induced cell cycle arrest and apoptosis through modulating K63-linked ubiquitination of p53. Cell Cycle 11(12):2327–2336
Li B, Huang G, Zhang X, Li R, Wang J, Dong Z, He Z (2013) Increased phosphorylation of histone H3 at serine 10 is involved in Epstein-Barr virus latent membrane protein-1-induced carcinogenesis of nasopharyngeal carcinoma. BMC Cancer 13:124
Lin SS, Lee DC, Law AH, Fang JW, Chua DT, Lau AS (2010) A role for protein kinase PKR in the mediation of Epstein-Barr virus latent membrane protein-1-induced IL-6 and IL-10 expression. Cytokine 50(2):210–219
Liu LT, Peng JP, Chang HC, Hung WC (2003) RECK is a target of Epstein-Barr virus latent membrane protein 1. Oncogene 22(51):8263–8270
Liu HP, Chen CC, Wu CC, Huang YC, Liu SC, Liang Y, Chang KP, Chang YS (2012) Epstein-Barr virus-encoded LMP1 interacts with FGD4 to activate Cdc42 and thereby promote migration of nasopharyngeal carcinoma cells. PLoS Pathog 8(5):e1002690
Lo AKF, Liu Y, Wang X, Wong YC, Lee CKF, Huang DP, Tsao SW (2001) Identification of downstream target genes of latent membrane protein 1 in nasopharyngeal carcinoma cells by suppression subtractive hybridization. Biochim Biophys Acta 1520(2):131–140
Lorenzetti MA, Gantuz M, Altcheh J, De Matteo E, Chabay PA, Preciado MV (2012) Distinctive Epstein-Barr virus variants associated with benign and malignant pediatric pathologies: LMP1 sequence characterization and linkage with other viral gene polymorphisms. J Clin Microbiol 50(3):609–618
Lu J, Chua HH, Chen SY, Chen JY, Tsai CH (2003) Regulation of matrix metalloproteinase-1 by Epstein-Barr virus proteins. Cancer Res 63(1):256–262
Luftig M, Prinarakis E, Yasui T, Tsichritzis T, Cahir-McFarland E, Inoue J, Nakano H, Mak TW, Yeh WC, Li X, Akira S, Suzuki N, Suzuki S, Mosialos G, Kieff E (2003) Epstein-Barr virus latent membrane protein 1 activation of NF-kappaB through IRAK1 and TRAF6. Proc Natl Acad Sci USA 100(26):15595–15600
Luftig M, Yasui T, Soni V, Kang MS, Jacobson N, Cahir-McFarland E, Seed B, Kieff E (2004) Epstein-Barr virus latent infection membrane protein 1 TRAF-binding site induces NIK/IKK alpha-dependent noncanonical NF-kappaB activation. Proc Natl Acad Sci USA 101(1):141–146
Ma SD, Xu X, Plowshay J, Ranheim EA, Burlingham WJ, Jensen JL, Asimakopoulos F, Tang W, Gulley ML, Cesarman E, Gumperz JE, Kenney SC (2015) LMP1-deficient Epstein-Barr virus mutant requires T cells for lymphomagenesis. J Clin Invest 125(1):304–315
Mainou BA, Raab-Traub N (2006) LMP1 strain variants: biological and molecular properties. J Virol 80(13):6458–6468
Mainou BA, Everly DN, Raab-Traub N (2005) Epstein-Barr virus latent membrane protein 1 CTAR1 mediates rodent and human fibroblast transformation through activation of PI3K. Oncogene 24(46):6917–6924
Mainou BA, Everly DN Jr, Raab-Traub N (2007) Unique signaling properties of CTAR1 in LMP1-mediated transformation. J Virol 81(18):9680–9692
Mancao C, Hammerschmidt W (2007) Epstein-Barr virus latent membrane protein 2A is a B-cell receptor mimic and essential for B-cell survival. Blood 110(10):3715–3721
Mann KP, Thorley-Lawson D (1987) Posttranslational processing of the Epstein-Barr virus-encoded p63/LMP protein. J Virol 61(7):2100–2108
Mann KP, Staunton D, Thorley-Lawson DA (1985) Epstein-Barr virus-encoded protein found in plasma membranes of transformed cells. J Virol 55(3):710–720
Martin J, Sugden B (1991) Transformation by the oncogenic latent membrane protein correlates with its rapid turnover, membrane localization, and cytoskeletal association. J Virol 65(6):3246–3258
Meckes DG Jr, Shair KH, Marquitz AR, Kung CP, Edwards RH, Raab-Traub N (2010) Human tumor virus utilizes exosomes for intercellular communication. Proc Natl Acad Sci USA 107(47):20370–20375
Meckes DG Jr, Menaker NF, Raab-Traub N (2013) Epstein-Barr virus LMP1 modulates lipid raft microdomains and the vimentin cytoskeleton for signal transduction and transformation. J Virol 87(3):1301–1311
Middeldorp JM, Pegtel DM (2008) Multiple roles of LMP1 in Epstein-Barr virus induced immune escape. Semin Cancer Biol 18(6):388–396
Miller WE, Edwards RH, Walling DM, Raab-Traub N (1994) Sequence variation in the Epstein-Barr virus latent membrane protein 1. J Gen Virol 75:2729–2740
Miller WE, Earp HS, Raab-Traub N (1995) The Epstein-Barr virus latent membrane protein 1 induces expression of the epidermal growth factor receptor. J Virol 69(7):4390–4398
Miller WE, Cheshire JL, Raab-Traub N (1998) Interaction of tumor necrosis factor receptor-associated factor signaling proteins with the latent membrane protein 1 PXQXT motif is essential for induction of epidermal growth factor receptor expression. Mol Cell Biol 18(5):2835–2844
Mitchell T, Sugden B (1995) Stimulation of NF-kappa B-mediated transcription by mutant derivatives of the latent membrane protein of Epstein-Barr virus. J Virol 69(5):2968–2976
Modrow S, Wolf H (1986) Characterization of two related Epstein-Barr virus-encoded membrane proteins that are differentially expressed in Burkitt lymphoma and in vitro-transformed cell lines. Proc Natl Acad Sci USA 83(15):5703–5707
Mohr CF, Kalmer M, Gross C, Mann MC, Sterz KR, Kieser A, Fleckenstein B, Kress AK (2014) The tumor marker Fascin is induced by the Epstein-Barr virus-encoded oncoprotein LMP1 via NF-kappaB in lymphocytes and contributes to their invasive migration. Cell Commun Signal 12(1):46
Moorthy RK, Thorley-Lawson DA (1993a) All three domains of the Epstein-Barr virus-encoded latent membrane protein LMP-1 are required for transformation of rat-1 fibroblasts. J Virol 67(3):1638–1646
Moorthy RK, Thorley-Lawson DA (1993b) Biochemical, genetic, and functional analyses of the phosphorylation sites on the Epstein-Barr virus-encoded oncogenic latent membrane protein LMP-1. J Virol 67(5):2637–2645
Morris MA, Dawson CW, Wei W, O’Neil JD, Stewart SE, Jia J, Bell AI, Young LS, Arrand JR (2008) Epstein-Barr virus-encoded LMP1 induces a hyperproliferative and inflammatory gene expression programme in cultured keratinocytes. J Gen Virol 89(Pt 11):2806–2820
Mosialos G, Birkenbach M, Yalamanchili R, VanArsdale T, Ware C, Kieff E (1995) The Epstein-Barr virus transforming protein LMP1 engages signaling proteins for the tumor necrosis factor receptor family. Cell 80(3):389–399
Motsch N, Pfuhl T, Mrazek J, Barth S, Grasser FA (2007) Epstein-Barr Virus-encoded latent membrane protein 1 (LMP1) induces the expression of the cellular microRNA miR-146a. RNA Biol 4(3):131–137
Murono S, Inoue H, Tanabe T, Joab I, Yoshizaki T, Furukawa M, Pagano JS (2001) Induction of cyclooxygenase-2 by Epstein-Barr virus latent membrane protein 1 is involved in vascular endothelial growth factor production in nasopharyngeal carcinoma cells. Proc Natl Acad Sci USA 98(12):6905–6910
Niedobitek G (1999) The Epstein-Barr virus: a group 1 carcinogen? Virchows Arch 435(2):79–86
Ning S, Pagano JS (2010) The A20 deubiquitinase activity negatively regulates LMP1 activation of IRF7. J Virol 84(12):6130–6138
Ning S, Hahn AM, Huye LE, Pagano JS (2003) Interferon regulatory factor 7 regulates expression of Epstein-Barr virus latent membrane protein 1: a regulatory circuit. J Virol 77(17):9359–9368
Ning S, Huye LE, Pagano JS (2005) Interferon regulatory factor 5 represses expression of the Epstein-Barr virus oncoprotein LMP1: braking of the IRF7/LMP1 regulatory circuit. J Virol 79(18):11671–11676
Ning S, Campos AD, Darnay BG, Bentz GL, Pagano JS (2008) TRAF6 and the three C-terminal lysine sites on IRF7 are required for its ubiquitination-mediated activation by the tumor necrosis factor receptor family member latent membrane protein 1. Mol Cell Biol 28(20):6536–6546
Noda C, Murata T, Kanda T, Yoshiyama H, Sugimoto A, Kawashima D, Saito S, Isomura H, Tsurumi T (2011) Identification and characterization of CCAAT enhancer-binding protein (C/EBP) as a transcriptional activator for Epstein-Barr virus oncogene latent membrane protein 1. J Biol Chem 286(49):42524–42533
Paine E, Scheinman RI, Baldwin AS Jr, Raab-Traub N (1995) Expression of LMP1 in epithelial cells leads to the activation of a select subset of NF-kappa B/Rel family proteins. J Virol 69(7):4572–4576
Pratt ZL, Zhang J, Sugden B (2012) The latent membrane protein 1 (LMP1) oncogene of Epstein-Barr virus can simultaneously induce and inhibit apoptosis in B cells. J Virol 86(8):4380–4393
Price AM, Tourigny JP, Forte E, Salinas RE, Dave SS, Luftig MA (2012) Analysis of Epstein-Barr virus-regulated host gene expression changes through primary B-cell outgrowth reveals delayed kinetics of latent membrane protein 1-mediated NF-kappaB activation. J Virol 86(20):11096–11106
Prince S, Keating S, Fielding C, Brennan P, Floettmann E, Rowe M (2003) Latent membrane protein 1 inhibits Epstein-Barr virus lytic cycle induction and progress via different mechanisms. J Virol 77(8):5000–5007
Rastelli J, Homig-Holzel C, Seagal J, Muller W, Hermann AC, Rajewsky K, Zimber-Strobl U (2008) LMP1 signaling can replace CD40 signaling in B cells in vivo and has unique features of inducing class-switch recombination to IgG1. Blood 111(3):1448–1455
Renzette N, Somasundaran M, Brewster F, Coderre J, Weiss ER, McManus M, Greenough T, Tabak B, Garber M, Kowalik TF, Luzuriaga K (2014) Epstein-barr virus latent membrane protein 1 genetic variability in peripheral blood B cells and oropharyngeal fluids. J Virol 88(7):3744–3755
Rothenberger S, Burns K, Rousseaux M, Tschopp J, Bron C (2003) Ubiquitination of the Epstein-Barr virus-encoded latent membrane protein 1 depends on the integrity of the TRAF binding site. Oncogene 22(36):5614–5618
Saito N, Courtois G, Chiba A, Yamamoto N, Nitta T, Hironaka N, Rowe M, Yamaoka S (2003) Two carboxyl-terminal activation regions of Epstein-Barr virus latent membrane protein 1 activate NF-kappaB through distinct signaling pathways in fibroblast cell lines. J Biol Chem 278(47):46565–46575
Sandberg M, Hammerschmidt W, Sugden B (1997) Characterization of LMP-1’s association with TRAF1, TRAF2, and TRAF3. J Virol 71(6):4649–4656
Sandvej K, Gratama JW, Munch M, Zhou XG, Bolhuis RL, Andresen BS, Gregersen N, Hamilton-Dutoit S (1997) Sequence analysis of the Epstein-Barr virus (EBV) latent membrane protein-1 gene and promoter region: identification of four variants among wild-type EBV isolates. Blood 90(1):323–330
Schneider F, Neugebauer J, Griese J, Liefold N, Kutz H, Briseno C, Kieser A (2008) The viral oncoprotein LMP1 exploits TRADD for signaling by masking its apoptotic activity. PLoS Biol 6(1):e8
Schultheiss U, Puschner S, Kremmer E, Mak TW, Engelmann H, Hammerschmidt W, Kieser A (2001) TRAF6 is a critical mediator of signal transduction by the viral oncogene latent membrane protein 1. EMBO J 20(20):5678–5691
Shair KH, Raab-Traub N (2012) Transcriptome changes induced by Epstein-Barr virus LMP1 and LMP2A in transgenic lymphocytes and lymphoma. mBio 3(5). doi:10.1128/mBio.00288-12
Shair KH, Bendt KM, Edwards RH, Bedford EC, Nielsen JN, Raab-Traub N (2007) EBV latent membrane protein 1 activates Akt, NFkappaB, and Stat3 in B cell lymphomas. PLoS Pathog 3(11):e166
Shair KH, Schnegg CI, Raab-Traub N (2008) EBV latent membrane protein 1 effects on plakoglobin, cell growth, and migration. Cancer Res 68(17):6997–7005
Shkoda A, Town JA, Griese J, Romio M, Sarioglu H, Knofel T, Giehler F, Kieser A (2012) The germinal center kinase TNIK is required for canonical NF-kappaB and JNK signaling in B-cells by the EBV oncoprotein LMP1 and the CD40 receptor. PLoS Biol 10(8):e1001376
Siouda M, Frecha C, Accardi R, Yue J, Cuenin C, Gruffat H, Manet E, Herceg Z, Sylla BS, Tommasino M (2014) Epstein-Barr virus down-regulates tumor suppressor DOK1 expression. PLoS Pathog 10(5):e1004125
Song YJ, Kang MS (2010) Roles of TRAF2 and TRAF3 in Epstein-Barr virus latent membrane protein 1-induced alternative NF-kappaB activation. Virus Genes 41(2):174–180
Song YJ, Jen KY, Soni V, Kieff E, Cahir-McFarland E (2006) IL-1 receptor-associated kinase 1 is critical for latent membrane protein 1-induced p65/RelA serine 536 phosphorylation and NF-kappaB activation. Proc Natl Acad Sci USA 103(8):2689–2694
Song YJ, Izumi KM, Shinners NP, Gewurz BE, Kieff E (2008) IRF7 activation by Epstein-Barr virus latent membrane protein 1 requires localization at activation sites and TRAF6, but not TRAF2 or TRAF3. Proc Natl Acad Sci USA 105(47):18448–18453
Soni V, Yasui T, Cahir-McFarland E, Kieff E (2006) LMP1 transmembrane domain 1 and 2 (TM1-2) FWLY mediates intermolecular interactions with TM3-6 to activate NF-kappaB. J Virol 80(21):10787–10793
Souza TA, Stollar BD, Sullivan JL, Luzuriaga K, Thorley-Lawson DA (2005) Peripheral B cells latently infected with Epstein-Barr virus display molecular hallmarks of classical antigen-selected memory B cells. Proc Natl Acad Sci USA 102(50):18093–18098
Stevenson D, Charalambous C, Wilson JB (2005) Epstein-Barr virus latent membrane protein 1 (CAO) up-regulates VEGF and TGF alpha concomitant with hyperlasia, with subsequent up-regulation of p16 and MMP9. Cancer Res 65(19):8826–8835
Stunz LL, Busch LK, Munroe ME, Sigmund CD, Tygrett LT, Waldschmidt TJ, Bishop GA (2004) Expression of the cytoplasmic tail of LMP1 in mice induces hyperactivation of B lymphocytes and disordered lymphoid architecture. Immunity 21(2):255–266
Thorley-Lawson DA, Hawkins JB, Tracy SI, Shapiro M (2013) The pathogenesis of Epstein-Barr virus persistent infection. Curr Opin Virol 3(3):227–232
Thornburg NJ, Raab-Traub N (2007) Induction of epidermal growth factor receptor expression by Epstein-Barr virus latent membrane protein 1 C-terminal-activating region 1 is mediated by NF-kappaB p50 homodimer/Bcl-3 complexes. J Virol 81(23):12954–12961
Thornburg NJ, Pathmanathan R, Raab-Traub N (2003) Activation of nuclear factor-kappaB p50 homodimer/Bcl-3 complexes in nasopharyngeal carcinoma. Cancer Res 63(23):8293–8301
Tsai CN, Tsai CL, Tse KP, Chang HY, Chang YS (2002) The Epstein-Barr virus oncogene product, latent membrane protein 1, induces the downregulation of E-cadherin gene expression via activation of DNA methyltransferases. Proc Natl Acad Sci USA 99(15):10084–10089
Tsai CL, Li HP, Lu YJ, Hsueh C, Liang Y, Chen CL, Tsao SW, Tse KP, Yu JS, Chang YS (2006) Activation of DNA methyltransferase 1 by EBV LMP1 Involves c-Jun NH(2)-terminal kinase signaling. Cancer Res 66(24):11668–11676
Tsao SW, Tramoutanis G, Dawson CW, Lo AK, Huang DP (2002) The significance of LMP1 expression in nasopharyngeal carcinoma. Semin Cancer Biol 12(6):473–487
Uchida J, Yasui T, Takaoka-Shichijo Y, Muraoka M, Kulwichit W, Raab-Traub N, Kikutani H (1999) Mimicry of CD40 signals by Epstein-Barr virus LMP1 in B lymphocyte responses. Science 286(5438):300–303
Uemura N, Kajino T, Sanjo H, Sato S, Akira S, Matsumoto K, Ninomiya-Tsuji J (2006) TAK1 is a component of the Epstein-Barr virus LMP1 complex and is essential for activation of JNK but not of NF-kappaB. J Biol Chem 281(12):7863–7872
Vallabhapurapu S, Karin M (2009) Regulation and function of NF-kappaB transcription factors in the immune system. Annu Rev Immunol 27:693–733
Vaysberg M, Lambert SL, Krams SM, Martinez OM (2009) Activation of the JAK/STAT pathway in Epstein Barr virus+-associated posttransplant lymphoproliferative disease: role of interferon-gamma. Am J Transplant 9(10):2292–2302
Vockerodt M, Haier B, Buttgereit P, Tesch H, Kube D (2001) The Epstein-Barr virus latent membrane protein 1 induces interleukin-10 in Burkitt’s lymphoma cells but not in Hodgkin’s cells involving the p38/SAPK2 pathway. Virology 280(2):183–198
Vockerodt M, Morgan SL, Kuo M, Wei W, Chukwuma MB, Arrand JR, Kube D, Gordon J, Young LS, Woodman CB, Murray PG (2008) The Epstein-Barr virus oncoprotein, latent membrane protein-1, reprograms germinal centre B cells towards a Hodgkin’s Reed-Sternberg-like phenotype. J Pathol 216(1):83–92
Wakisaka N, Murono S, Yoshizaki T, Furukawa M, Pagano JS (2002) Epstein-barr virus latent membrane protein 1 induces and causes release of fibroblast growth factor-2. Cancer Res 62(21):6337–6344
Wan J, Sun L, Mendoza JW, Chui YL, Huang DP, Chen ZJ, Suzuki N, Suzuki S, Yeh WC, Akira S, Matsumoto K, Liu ZG, Wu Z (2004) Elucidation of the c-Jun N-terminal kinase pathway mediated by Estein-Barr virus-encoded latent membrane protein 1. Mol Cell Biol 24(1):192–199
Wan J, Zhang W, Wu L, Bai T, Zhang M, Lo KW, Chui YL, Cui Y, Tao Q, Yamamoto M, Akira S, Wu Z (2006) BS69, a specific adaptor in the latent membrane protein 1-mediated c-Jun N-terminal kinase pathway. Mol Cell Biol 26(2):448–456
Wang D, Liebowitz D, Kieff E (1985) An EBV membrane protein expressed in immortalized lymphocytes transforms established rodent cells. Cell 43(3 Pt 2):831–840
Wang D, Liebowitz D, Kieff E (1988a) The truncated form of the Epstein-Barr virus latent-infection membrane protein expressed in virus replication does not transform rodent fibroblasts. J Virol 62(7):2337–2346
Wang D, Liebowitz D, Wang F, Gregory C, Rickinson A, Larson R, Springer T, Kieff E (1988b) Epstein-Barr virus latent infection membrane protein alters the human B-lymphocyte phenotype: deletion of the amino terminus abolishes activity. J Virol 62(11):4173–4184
Wilson JB, Weinberg W, Johnson R, Yuspa S, Levine AJ (1990) Expression of the BNLF-1 oncogene of Epstein-Barr virus in the skin of transgenic mice induces hyperplasia and aberrant expression of keratin 6. Cell 61:1315–1327
Wu L, Nakano H, Wu Z (2006) The C-terminal activating region 2 of the Epstein-Barr virus-encoded latent membrane protein 1 activates NF-kappaB through TRAF6 and TAK1. J Biol Chem 281(4):2162–2169
Xiao L, Hu ZY, Dong X, Tan Z, Li W, Tang M, Chen L, Yang L, Tao Y, Jiang Y, Li J, Yi B, Li B, Fan S, You S, Deng X, Hu F, Feng L, Bode AM, Dong Z, Sun LQ, Cao Y (2014) Targeting Epstein-Barr virus oncoprotein LMP1-mediated glycolysis sensitizes nasopharyngeal carcinoma to radiation therapy. Oncogene 33(37):4568–4578
Xie P, Bishop GA (2004) Roles of TNF receptor-associated factor 3 in signaling to B lymphocytes by carboxyl-terminal activating regions 1 and 2 of the EBV-encoded oncoprotein latent membrane protein 1. J Immunol 173(9):5546–5555
Xie P, Hostager BS, Bishop GA (2004) Requirement for TRAF3 in signaling by LMP1 but not CD40 in B lymphocytes. J Exp Med 199(5):661–671
Xu D, Zhang Y, Zhao L, Cao M, Lingel A, Zhang L (2015) Interferon regulatory factor 7 is involved in the growth of Epstein-Barr virus-transformed human B lymphocytes. Virus Res 195:112–118
Yang L, Xu Z, Liu L, Luo X, Lu J, Sun L, Cao Y (2014) Targeting EBV-LMP1 DNAzyme enhances radiosensitivity of nasopharyngeal carcinoma cells by inhibiting telomerase activity. Cancer Biol Ther 15(1):61–68
Yasui T, Luftig M, Soni V, Kieff E (2004) Latent infection membrane protein transmembrane FWLY is critical for intermolecular interaction, raft localization, and signaling. Proc Natl Acad Sci USA 101(1):278–283
Ye H, Park YC, Kreishman M, Kieff E, Wu H (1999) The structural basis for the recognition of diverse receptor sequences by TRAF2. Mol Cell 4(3):321–330
Yoshizaki T (2002) Promotion of metastasis in nasopharyngeal carcinoma by Epstein-Barr virus latent membrane protein-1. Histol Histopathol 17(3):845–850
Yoshizaki T, Sato H, Furukawa M, Pagano JS (1998) The expression of matrix metalloproteinase 9 is enhanced by Epstein-Barr virus latent membrane protein 1. Proc Natl Acad Sci USA 95(7):3621–3626
Yoshizaki T, Horikawa T, Qing-Chun R, Wakisaka N, Takeshita H, Sheen TS, Lee SY, Sato H, Furukawa M (2001) Induction of interleukin-8 by Epstein-Barr virus latent membrane protein-1 and its correlation to angiogenesis in nasopharyngeal carcinoma. Clin Cancer Res 7(7):1946–1951
Yoshizaki T, Kondo S, Wakisaka N, Murono S, Endo K, Sugimoto H, Nakanishi S, Tsuji A, Ito M (2013) Pathogenic role of Epstein-Barr virus latent membrane protein-1 in the development of nasopharyngeal carcinoma. Cancer Lett 337:1–7
Young LS, Rickinson AB (2004) Epstein-Barr virus: 40 years on. Nat Rev Cancer 4(10):757–768
Zhang L, Pagano JS (2000) Interferon regulatory factor 7 is induced by Epstein-Barr virus latent membrane protein 1. J Virol 74(3):1061–1068
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(6):445–453
Zhang B, Kracker S, Yasuda T, Casola S, Vanneman M, Homig-Holzel C, Wang Z, Derudder E, Li S, Chakraborty T, Cotter SE, Koyama S, Currie T, Freeman GJ, Kutok JL, Rodig SJ, Dranoff G, Rajewsky K (2012) Immune surveillance and therapy of lymphomas driven by Epstein-Barr virus protein LMP1 in a mouse model. Cell 148(4):739–751
Zhao B, Barrera LA, Ersing I, Willox B, Schmidt SC, Greenfeld H, Zhou H, Mollo SB, Shi TT, Takasaki K, Jiang S, Cahir-McFarland E, Kellis M, Bulyk ML, Kieff E, Gewurz BE (2014) The NF-kappaB genomic landscape in lymphoblastoid B cells. Cell reports 8(5):1595–1606
Zimber-Strobl U, Kempkes B, Marschall G, Zeidler R, Van Kooten C, Banchereau J, Bornkamm GW, Hammerschmidt W (1996) Epstein-Barr virus latent membrane protein (LMP1) is not sufficient to maintain proliferation of B cells but both it and activated CD40 can prolong their survival. EMBO J 15(24):7070–7078
Author information
Authors and Affiliations
Corresponding author
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2015 Springer International Publishing Switzerland
About this chapter
Cite this chapter
Kieser, A., Sterz, K.R. (2015). The Latent Membrane Protein 1 (LMP1). In: Münz, C. (eds) Epstein Barr Virus Volume 2. Current Topics in Microbiology and Immunology, vol 391. Springer, Cham. https://doi.org/10.1007/978-3-319-22834-1_4
Download citation
DOI: https://doi.org/10.1007/978-3-319-22834-1_4
Published:
Publisher Name: Springer, Cham
Print ISBN: 978-3-319-22833-4
Online ISBN: 978-3-319-22834-1
eBook Packages: Biomedical and Life SciencesBiomedical and Life Sciences (R0)