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Gene Review

LMP1  -  LMP1

Human herpesvirus 4

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Disease relevance of LMP-1

  • Moreover, IL-10 could induce the expression of LMP-1 in tonsillar B cells infected with the nontransforming, EBNA-2-deficient EBV strain P3HR1 and enhance LMP-1 expression in 2 EBV-positive NK lymphoma lines [1].
  • Here we describe functional properties of a rare 69-bp LMP1 deletion mutant (LMP1(69del)) isolated from a patient with polyclonal B-cell lymphocytosis [2].
  • RESULTS: EBV LMP1 exon 3 and W fragment were detected in 27.7% and 32.2% of the 90 colorectal carcinoma specimens, which were significantly higher than the positive rate of EBV gene in the 25 adjacent non-cancerous tissues (4.0%, P<0.001) [3].
  • Genetic studies showed that the virus detected in the T-cell lymphoma was indistinguishable, with respect to type and previously defined LMP-1 and EBNA-1 gene variations, from virus detected in the peripheral blood T cells 19 months earlier [4].
  • Of note, deletions in the LMP-1 gene were detected with similar prevalence values in EBV+ Hodgkin's disease (HD) (13 of 30, 43.3%) and non-Hodgkin's lymphoma (NHL) (2 of 5, 40%) cases from HIV-seronegative patients and in HIV-related, EBV+ NHLs (4 of 7, 57.1%) [5].

Psychiatry related information on LMP-1

  • Expression of two members of the Id (inhibitor of differentiation) family of proteins, Id1 and Id3, was induced in the presence of LMP1 and confirmed by mRNA and protein in C33A and Rat-1 cells [6].

High impact information on LMP-1

  • CONCLUSIONS: LMP1-mediated signaling through the TRAF system has a role in the pathogenesis of the EBV-positive lymphomas that arise in immunosuppressed patients [7].
  • The latent membrane protein 1 (LMP1) of EBV-infected cells plays a central part in this process by mimicking members of the family of tumor necrosis factor (TNF) receptors, thereby transmitting growth signals from the cell membrane to the nucleus through cytoplasmic TNF-receptor-associated factors (TRAFs) [7].
  • Tumors from both patients with AIDS-associated non-Hodgkin's lymphoma were EBV-positive and expressed LMP1, whereas tumors from all three patients with Burkitt's tumors were positive for EBV but negative for LMP1 [7].
  • Transcription of the latent EBV gene products, EBV nuclear antigen 1, LMP-1, LMP-2A, and the BamHI-A fragment, was detected in most of the samples [8].
  • The cytoplasmic C-terminus of Epstein-Barr virus (EBV) latent infection membrane protein 1 (LMP1) is essential for B lymphocyte growth transformation and is now shown to interact with a novel human protein (LMP1-associated protein 1 [LAP1]) [9].

Chemical compound and disease context of LMP-1

  • For EBV associated B and T non-Hodgkin's lymphomas, frozen tissue sections yielded better LMP-1 staining results than formalin fixed material [10].
  • EBV DNA was detected in 14 of 16 NKTCL examined, and 7 of these 14 expressed LMP-1. mRNA expression levels of integrin subunits alpha4, alpha L, alpha M, and beta2 were significantly higher in NKTCL than non-neoplastic controls [11].
  • The latent membrane protein 1 of Epstein-Barr virus, LMP1, is thought to mimic constitutively activated TNF family receptors [12].
  • LMP2A is expressed in latent Epstein-Barr virus (EBV) infection and interacts with LMP1 and members of the src tyrosine kinase family in the plasma membrane [13].
  • Using an EBV-negative Burkitt's lymphoma cell line in which the expression of EBV latent membrane protein 1 (LMP1) is inducibly regulated by tetracycline, we demonstrate that LMP1 expression coincides with a dramatic increase in the level of bfl-1 mRNA [14].

Biological context of LMP-1

  • Transient reporter gene assays have implicated a pivotal role for EBNA-3C in the regulation of transcription of the majority of latency-associated genes expressed during the EBV growth program, including the viral oncoprotein LMP-1 [15].
  • EBV signaling (through EBNA2, LMP1 and LMP2A) and NF-kB activation correlated with upregulation of target proteins: cMYC, JunB, CCL22, TRAF1 and IRF4 [16].
  • Furthermore, LMP1(69del) showed a more effective down-regulation of the EBV lytic cycle master gene BZLF1(Zebra) than did wild-type LMP1 [2].
  • Consequently, LMP-1 triggers the activity of the c-Jun N-terminal transactivation domain which is known to be activated upon JNK-mediated phosphorylation [17].
  • Mutation of the viral genome has indicated that at least six viral genes (LMP-1 and EBNAs 1, 2, 3A, 3C and LP) are essential for immortalization [18].

Anatomical context of LMP-1

  • 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 [1].
  • We show now that both human and EBV-encoded IL-10 can induce LMP-1 in the absence of EBNA-2 in the Daudi, P3HR1, and other BL cell lines [1].
  • It was proposed recently that LMP1 expression in epithelial cells may be regulated through a loop involving activated signal transducer and activator of transcription 3 (STAT3), LMP1, LMP1-mediated induction of interleukin (IL)-6 expression and STAT3 activation through the IL-6 receptor [19].
  • Transient transfectants of B-, T-, epithelial and 3T3 cells, and stable transfectants with ecdysone-inducible LMP1 expression were produced [2].
  • In 40 patients with stage I disease, there was a significant association between EBV latent membrane protein (LMP-1) expression and presentation in neck lymph nodes [20].

Associations of LMP-1 with chemical compounds

  • (ii) Substitutions of this site in each W2 repeat domain with alanine markedly reduced the ability of the protein to induce LMP-1 expression in combination with EBNA-2 in Akata cells [21].
  • For the 303 patients treated with doxorubicin, bleomycin, vinblastine, and dacarbazine or equivalent regimens, the 5-year failure-free survival (FFS) for those with LMP-1-positive tumors was 74% compared with 81% for those with LMP-1-negative tumors (P = 0.23, by log-rank test) [22].
  • The mutation of amino acid 129 to isoleucine greatly increased the LMP-1 half-life [23].
  • The LMP-1 half-life was short when the amino acid encoded at position 129 was methionine, the initiation codon product of lytic LMP-1 (lyLMP-1) [23].
  • In addition, LMP-1 antisense sensitizes LCLs to chemotherapeutic drugs from diverse classes, including etoposide, vincristine and dexamethasone, by enhancing apoptotic cell death [24].

Physical interactions of LMP-1

  • Their substitution with six membrane-spanning domains from the LMP-2A protein of EBV yields a derivative which neither coimmunoprecipitates with LMP-1 nor signals to increase the activity of NF-kappaB as does wild-type LMP-1 [25].

Enzymatic interactions of LMP-1


Regulatory relationships of LMP-1

  • However, in most cases, this was not accompanied by detectable expression of LMP1, suggesting either that LMP2A expression may suffice to suppress LMP1 expression or that additional factors may be operational [19].
  • Expression of the Epstein-Barr virus (EBV) latent membrane protein 1 (LMP-1) oncogene is regulated by the EBV nuclear protein 2 (EBNA-2) transactivator [27].
  • We show here that Bmi-1 and LMP1 down-regulate the ataxia telangiectasia-mutated (ATM) tumor suppressor and conclude that Bmi-1 contributes to LMP1-induced oncogenesis in HL [28].

Other interactions of LMP-1


Analytical, diagnostic and therapeutic context of LMP-1


  1. 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. Kis, L.L., Takahara, M., Nagy, N., Klein, G., Klein, E. Blood (2006) [Pubmed]
  2. Functional analysis of the mutated Epstein-Barr virus oncoprotein LMP1(69del): implications for a new role of naturally occurring LMP1 variants. Larcher, C., Bernhard, D., Schaadt, E., Adler, B., Ausserlechner, M.J., Mitterer, M., Huemer, H.P. Haematologica (2003) [Pubmed]
  3. Infection of Epstein-Barr virus in Colorectal Cancer in Chinese. Song, L.B., Zhang, X., Zhang, C.Q., Zhang, Y., Pan, Z.Z., Liao, W.T., Li, M.Z., Zeng, M.S. Ai Zheng (2006) [Pubmed]
  4. A syndrome of peripheral blood T-cell infection with Epstein-Barr virus (EBV) followed by EBV-positive T-cell lymphoma. Kanegane, H., Bhatia, K., Gutierrez, M., Kaneda, H., Wada, T., Yachie, A., Seki, H., Arai, T., Kagimoto, S., Okazaki, M., Oh-ishi, T., Moghaddam, A., Wang, F., Tosato, G. Blood (1998) [Pubmed]
  5. Epstein-Barr virus strains with latent membrane protein-1 deletions: prevalence in the Italian population and high association with human immunodeficiency virus-related Hodgkin's disease. Dolcetti, R., Zancai, P., De Re, V., Gloghini, A., Bigoni, B., Pivetta, B., De Vita, S., Carbone, A., Boiocchi, M. Blood (1997) [Pubmed]
  6. 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. Everly, D.N., Mainou, B.A., Raab-Traub, N. J. Virol. (2004) [Pubmed]
  7. Epstein-Barr virus and a cellular signaling pathway in lymphomas from immunosuppressed patients. Liebowitz, D. N. Engl. J. Med. (1998) [Pubmed]
  8. Clonal proliferations of cells infected with Epstein-Barr virus in preinvasive lesions related to nasopharyngeal carcinoma. Pathmanathan, R., Prasad, U., Sadler, R., Flynn, K., Raab-Traub, N. N. Engl. J. Med. (1995) [Pubmed]
  9. The Epstein-Barr virus transforming protein LMP1 engages signaling proteins for the tumor necrosis factor receptor family. Mosialos, G., Birkenbach, M., Yalamanchili, R., VanArsdale, T., Ware, C., Kieff, E. Cell (1995) [Pubmed]
  10. Immunohistochemical demonstration of different latent membrane protein-1 epitopes of Epstein-Barr virus in lymphoproliferative diseases. Jiwa, N.M., Oudejans, J.J., Dukers, D.F., Vos, W., Horstman, A., van der Valk, P., Middledorp, J.M., Walboomers, J.M., Meijer, C.J. J. Clin. Pathol. (1995) [Pubmed]
  11. Expression of cell adhesion molecules and chemokine receptors: angioinvasiveness in nasal NK/T-cell lymphoma. Liu, A., Nakatsuka, S., Yang, W.I., Kojya, S., Aozasa, K. Oncol. Rep. (2005) [Pubmed]
  12. Activation of the small GTPase Cdc42 by the inflammatory cytokines TNF(alpha) and IL-1, and by the Epstein-Barr virus transforming protein LMP1. Puls, A., Eliopoulos, A.G., Nobes, C.D., Bridges, T., Young, L.S., Hall, A. J. Cell. Sci. (1999) [Pubmed]
  13. Epstein-Barr virus latent membrane protein 2A blocks calcium mobilization in B lymphocytes. Miller, C.L., Longnecker, R., Kieff, E. J. Virol. (1993) [Pubmed]
  14. The bfl-1 gene is transcriptionally upregulated by the Epstein-Barr virus LMP1, and its expression promotes the survival of a Burkitt's lymphoma cell line. D'Souza, B., Rowe, M., Walls, D. J. Virol. (2000) [Pubmed]
  15. Epstein-Barr Virus EBNA-3C Is Targeted to and Regulates Expression from the Bidirectional LMP-1/2B Promoter. Jim??nez-Ram??rez, C., Brooks, A.J., Forshell, L.P., Yakimchuk, K., Zhao, B., Fulgham, T.Z., Sample, C.E. J. Virol. (2006) [Pubmed]
  16. Identification of rare Epstein-Barr virus infected memory B cells and plasma cells in non-monomorphic post-transplant lymphoproliferative disorders and the signature of viral signaling. Shaknovich, R., Basso, K., Bhagat, G., Mansukhani, M., Hatzivassiliou, G., Murty, V.V., Buettner, M., Niedobitek, G., Alobeid, B., Cattoretti, G. Haematologica (2006) [Pubmed]
  17. Epstein-Barr virus latent membrane protein-1 triggers AP-1 activity via the c-Jun N-terminal kinase cascade. Kieser, A., Kilger, E., Gires, O., Ueffing, M., Kolch, W., Hammerschmidt, W. EMBO J. (1997) [Pubmed]
  18. EBNA-2 and EBNA-LP cooperate to cause G0 to G1 transition during immortalization of resting human B lymphocytes by Epstein-Barr virus. Sinclair, A.J., Palmero, I., Peters, G., Farrell, P.J. EMBO J. (1994) [Pubmed]
  19. Expression of Epstein-Barr virus (EBV)-encoded latent membrane proteins and STAT3 activation in nasopharyngeal carcinoma. Buettner, M., Heussinger, N., Niedobitek, G. Virchows Arch. (2006) [Pubmed]
  20. Epstein-Barr virus in Hodgkin's disease and site of origin of tumour. O'Grady, J., Stewart, S., Elton, R.A., Krajewski, A.S. Lancet (1994) [Pubmed]
  21. Identification of major phosphorylation sites of Epstein-Barr virus nuclear antigen leader protein (EBNA-LP): ability of EBNA-LP to induce latent membrane protein 1 cooperatively with EBNA-2 is regulated by phosphorylation. Yokoyama, A., Tanaka, M., Matsuda, G., Kato, K., Kanamori, M., Kawasaki, H., Hirano, H., Kitabayashi, I., Ohki, M., Hirai, K., Kawaguchi, Y. J. Virol. (2001) [Pubmed]
  22. Expression of Epstein-Barr virus latent membrane protein-1 in Hodgkin and Reed-Sternberg cells of classical Hodgkin's lymphoma: associations with presenting features, serum interleukin 10 levels, and clinical outcome. Herling, M., Rassidakis, G.Z., Medeiros, L.J., Vassilakopoulos, T.P., Kliche, K.O., Nadali, G., Viviani, S., Bonfante, V., Giardini, R., Chilosi, M., Kittas, C., Gianni, A.M., Bonadonna, G., Pizzolo, G., Pangalis, G.A., Cabanillas, F., Sarris, A.H. Clin. Cancer Res. (2003) [Pubmed]
  23. Epstein-Barr virus latent membrane protein 1 (LMP-1) half-life in epithelial cells is down-regulated by lytic LMP-1. Pandya, J., Walling, D.M. J. Virol. (2004) [Pubmed]
  24. Antisense to the Epstein-Barr virus (EBV)-encoded latent membrane protein 1 (LMP-1) sensitizes EBV-immortalized B cells to transforming growth factor-beta and chemotherapeutic agents. Kenney, J.L., Guinness, M.E., Reiss, M., Lacy, J. Int. J. Cancer (2001) [Pubmed]
  25. LMP-1's transmembrane domains encode multiple functions required for LMP-1's efficient signaling. Kaykas, A., Worringer, K., Sugden, B. J. Virol. (2002) [Pubmed]
  26. Epstein-Barr virus nuclear protein 2 mutations define essential domains for transformation and transactivation. Cohen, J.I., Wang, F., Kieff, E. J. Virol. (1991) [Pubmed]
  27. Epstein-Barr virus nuclear protein 2 transactivation of the latent membrane protein 1 promoter is mediated by J kappa and PU.1. Johannsen, E., Koh, E., Mosialos, G., Tong, X., Kieff, E., Grossman, S.R. J. Virol. (1995) [Pubmed]
  28. Bmi-1 is induced by the Epstein-Barr virus oncogene LMP1 and regulates the expression of viral target genes in Hodgkin lymphoma cells. Dutton, A., Woodman, C.B., Chukwuma, M.B., Last, J.I., Wei, W., Vockerodt, M., Baumforth, K.R., Flavell, J.R., Rowe, M., Taylor, A.M., Young, L.S., Murray, P.G. Blood (2007) [Pubmed]
  29. Cutting edge: Epstein-Barr virus transactivates the HERV-K18 superantigen by docking to the human complement receptor 2 (CD21) on primary B cells. Hsiao, F.C., Lin, M., Tai, A., Chen, G., Huber, B.T. J. Immunol. (2006) [Pubmed]
  30. Multiplex-nested RT-PCR to evaluate latent and lytic Epstein Barr virus gene expression. Bergallo, M., Costa, C., Baro, S., Musso, T., Balbo, L., Merlino, C., Cavallo, R. J. Biotechnol. (2007) [Pubmed]
  31. Interleukin 15-mediated induction of cytotoxic effector cells capable of eliminating Epstein-Barr virus-transformed/immortalized lymphocytes in culture. Sharif-Askari, E., Fawaz, L.M., Tran, P., Ahmad, A., Menezes, J. J. Natl. Cancer Inst. (2001) [Pubmed]
  32. Fulminant EBV(+) T-cell lymphoproliferative disorder following acute/chronic EBV infection: a distinct clinicopathologic syndrome. Quintanilla-Martinez, L., Kumar, S., Fend, F., Reyes, E., Teruya-Feldstein, J., Kingma, D.W., Sorbara, L., Raffeld, M., Straus, S.E., Jaffe, E.S. Blood (2000) [Pubmed]
  33. Isolation and characterization of transformed human T-cell lines infected by Epstein-Barr virus. Groux, H., Cottrez, F., Montpellier, C., Quatannens, B., Coll, J., Stehelin, D., Auriault, C. Blood (1997) [Pubmed]
  34. Hodgkin's disease and human immunodeficiency virus infection: clinicopathologic and virologic features of 114 patients from the Italian Cooperative Group on AIDS and Tumors. Tirelli, U., Errante, D., Dolcetti, R., Gloghini, A., Serraino, D., Vaccher, E., Franceschi, S., Boiocchi, M., Carbone, A. J. Clin. Oncol. (1995) [Pubmed]
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