Signal transduction by the Epstein‐Barr virus oncogene latent membrane protein 1 (LMP1)

Kieser, Arnd

doi:10.1002/sita.200600116

Cited by 21 publications

(25 citation statements)

References 146 publications

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“…It has been well documented that all of these downstream pathways contribute to LMP1 oncogenesis. 8–11 Along with others, we have shown compelling evidence that LMP1 also activates IRF7. 12–14 …”

Section: Introductionsupporting

confidence: 82%

LMP1 signaling pathway activates IRF4 in latent EBV infection and a positive circuit between PI3K and Src is required

Ren

Moorman

et al. 2016

Oncogene

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Interferon (IFN) regulatory factors (IRFs) have crucial roles in immune regulation and oncogenesis. We have recently shown that IRF4 is activated through c-Src-mediated tyrosine phosphorylation in virus-transformed cells. However, the intracellular signaling pathway triggering Src activation of IRF4 remains unknown. In this study, we provide evidence that Epstein–Barr virus (EBV) latent membrane protein 1 (LMP1) promotes IRF4 phosphorylation and markedly stimulates IRF4 transcriptional activity, and that Src mediates LMP1 activation of IRF4. As to more precise mechanism, we show that LMP1 physically interacts with c-Src, and the phosphatidylinositol 3 kinase (PI3K) subunit P85 mediates their interaction. Depletion of P85 by P85-specific short hairpin RNAs disrupts their interaction and diminishes IRF4 phosphorylation in EBV-transformed cells. Furthermore, we show that Src is upstream of PI3K for activation of both IRF4 and Akt. In turn, inhibition of PI3K kinase activity by the PI3K-speicfic inhibitor LY294002 impairs Src activity. Our results show that LMP1 signaling is responsible for IRF4 activation, and further characterize the IRF4 regulatory network that is a promising therapeutic target for specific hematological malignancies.

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Section: Introductionsupporting

confidence: 82%

LMP1 signaling pathway activates IRF4 in latent EBV infection and a positive circuit between PI3K and Src is required

Ren

Moorman

et al. 2016

Oncogene

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“…Many TLR signaling pathways activate IRFs (13,30,36,52). EBV LMP1, a pleiotropic tumor necrosis factor receptor (TNFR) superfamily member (27), also activates IRF7 (23,37,60) and likely IRF4 (73). Type I IFNs (IFN-␣/␤) trigger signals through the IRF9-containing ISGF3 complex.…”

mentioning

confidence: 99%

Oncogenic IRFs Provide a Survival Advantage for Epstein-Barr Virus- or Human T-Cell Leukemia Virus Type 1-Transformed Cells through Induction of BIC Expression

Wang¹,

Toomey²,

Díaz³

et al. 2011

J Virol

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MicroRNAs (miRNAs), like transcription factors, function as regulators of gene expression and are expressed in several eukaryotes as well as in some viruses, particularly in the family of herpesviruses (17). Study of miRNAs has exploded since their relatively recent discovery, and nearly 700 miRNA genes have been identified in humans to date (17). miRNAs have been shown to be key regulators of genes involved in innate immunity, cell growth, differentiation, tumorigenesis, and development acting at the posttranscriptional level (7,11,17,20,43,45,49). Different from small interfering RNA (siRNA), miRNAs inhibit the translation of select groups of mRNA transcripts containing imperfect annealing sequences in their 3Ј-untranslated regions (3Ј-UTRs) and less frequently through other regions of the transcript. Since miRNA profiles are different between normal and cancer cells, miRNA signatures can be used for diagnosis as well as prognosis of human malignancies (3). miR-155 is an evolutionarily conserved miRNA which plays important roles in innate immunity (49,72), and is the first oncogenic miRNA (oncomiR) shown to have increased expression in various types of cancers including lymphomas such as Hodgkin lymphoma and posttransplant lymphoproliferative disease (PTLD) (9,28,64,70), breast cancer, leukemia, pancreatic cancer, and lung cancer (7,15). miR-155 has also been shown to play a critical role in lymphocyte activation in vivo (53,67). Accumulating evidence has revealed high levels of miR-155 in Epstein-Barr virus (EBV) latency 3, but not in latency 1 (4,26,28,77), indicating that miR-155 expression is associated with EBV latency. The importance of miR-155 in cancers is underscored by the fact that at least two oncogenic herpesviruses, Kaposi's sarcoma-associated herpesvirus (KSHV) (19, 59) and Marek's disease virus (81), encode functional orthologs of miR-155. The KSHV ortholog miR-K12-11 also shares 100% seed sequence (first 8 nucleotides [nt]) homology with human miR-155 (59). miR-155 is processed from a primary transcript, B-cell integration cluster (BIC), which can be processed via the intermediate precursor miR-155 (pre-miR-155) to the mature 22-nt miR-155 (63). BIC cDNAs from human, mouse, and chicken have 78% identity over 138 nucleotides. miR-155 preferentially targets SHIP1 (42), and also targets

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“…LMP1 promotes B-cell growth and survival by mimicking constitutive CD40 signaling to activate NF-κB, JNK, MAPK, JAK/STAT, and PI3K signaling pathways (Kieser 2007). These pathways affect many immunological processes and allow LMP1 to steer the host immune response (reviewed in (Middeldorp and Pegtel 2008)).…”

Section: Lmp1mentioning

confidence: 99%

Immune Evasion by Epstein-Barr Virus

Ressing

Gent

Gram

et al. 2015

Current Topics in Microbiology and Immunology

105

106

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Epstein-Bar virus (EBV) is widespread within the human population with over 90% of adults being infected. In response to primary EBV infection, the host mounts an antiviral immune response comprising both innate and adaptive effector functions. Although the immune system can control EBV infection to a large extent, the virus is not cleared. Instead, EBV establishes a latent infection in B lymphocytes characterized by limited viral gene expression. For the production of new viral progeny, EBV reactivates from these latently infected cells. During the productive phase of infection, a repertoire of over 80 EBV gene products is expressed, presenting a vast number of viral antigens to the primed immune system. In particular the EBV-specific CD4+ and CD8+ memory T lymphocytes can respond within hours, potentially destroying the virus-producing cells before viral replication is completed and viral particles have been released. Preceding the adaptive immune response, potent innate immune mechanisms provide a first line of defense during primary and recurrent infections. In spite of this broad range of antiviral immune effector mechanisms, EBV persists for life and continues to replicate. Studies performed over the past decades have revealed a wide array of viral gene products interfering with both innate and adaptive immunity. These include EBV-encoded proteins as well as small noncoding RNAs with immune-evasive properties. The current review presents an overview of the evasion strategies that are employed by EBV to facilitate immune escape during latency and productive infection. These evasion mechanisms may also compromise the elimination of EBV-transformed cells, and thus contribute to malignancies associated with EBV infection.

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Signal transduction by the Epstein‐Barr virus oncogene latent membrane protein 1 (LMP1)

Cited by 21 publications

References 146 publications

LMP1 signaling pathway activates IRF4 in latent EBV infection and a positive circuit between PI3K and Src is required

LMP1 signaling pathway activates IRF4 in latent EBV infection and a positive circuit between PI3K and Src is required

Oncogenic IRFs Provide a Survival Advantage for Epstein-Barr Virus- or Human T-Cell Leukemia Virus Type 1-Transformed Cells through Induction of BIC Expression

Immune Evasion by Epstein-Barr Virus

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