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

• The mutant EBNA-2 genes were assayed for lymphocyte transformation after recombination with the EBNA-2-deleted P3HR-1 EBV genome and for LMP-1 transactivation following transfection into P3HR-1-infected B-lymphoma cells [26].

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

• We have previously shown that the EBV latent genes LMP-1 and LMP-2A (for latent membrane proteins 1 and 2A), transactivate a human endogenous retrovirus (HERV), HERV-K18, in infected B lymphocytes [29].
• These results indicate that EBNA-3C directly activates the expression of LMP-1 and LMP-2B but is unlikely to significantly regulate EBNA expression via Cp under normal growth conditions [15].
• Chromatin immunoprecipitation assays furthermore indicated that EBNA-3C is present at the bidirectional LMP-1/LMP-2B promoter [15].
• This paper describes the development of two multiplex-nested RT-PCR devised to evaluate latent/immortalizing (EBNA1, EBNA2, LMP1 and LMP2) and lytic [immediate early (Zebra), early, and late (VCA), respectively] Epstein Barr virus (EBV) transcripts [30].
• The lymphomas were infected with monoclonal EBV and expressed the EBV latency genes EBNA-1, LMP-1, and LMP-2 [4].

Analytical, diagnostic and therapeutic context of LMP-1

• The expression of EBV nuclear antigen 1 (EBNA1) and LMP1 were determined by immunohistochemistry, and the expression of EBV-encoded RNAs (EBERs) was detected by in situ hybridization [3].
• We monitored EBV-induced transformation by assessing the clearly visible cell clusters by microscopy and analyzing the expression of EBV-encoded latent membrane oncoprotein-1 (LMP-1) and the EBV nuclear antigen (EBNA) complex by immunoblotting and immunofluorescence techniques, respectively [31].
• In addition, EBV strain typing and detection of the characteristic 30-bp deletion of the latent membrane protein-1 (LMP-1) gene were performed by PCR [32].
• Moreover, Southern blot analysis of one of these cell lines shows the presence of circular episomic EBV DNA, and by Northern blot or reverse transcriptase-PCR analysis, only the expression of Epstein-Barr nuclear antigen-1 (EBNA-1) and latent membrane protein-1 (LMP-1) genes was detected [33].
• The relationship between Epstein-Barr virus (EBV) and HD was determined by an in situ hybridization technique, immunostaining for EBV-encoded latent membrane protein-1 (LMP-1) expression, and Southern blotting [34].

References