Latent Membrane Protein 1 Regulates STAT1 through NF-κB-Dependent Interferon Secretion in Epstein-Barr Virus-Immortalized B Cells

Najjar, Imen; Baran‐Marszak, Fanny; Clorennec, Christophe Le; Laguillier, Christelle; Schischmanoff, Olivier; Youlyouz-Marfak, Ibtissam; Schlee, Martin; Bornkamm, Georg W.; Raphaël, Martine; Feuillard, Jean; Fagard, Rémi

doi:10.1128/jvi.79.8.4936-4943.2005

Cited by 55 publications

(48 citation statements)

References 39 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…This was confirmed in PRI cells, a p53wt LCL cell line in which STAT1 activation is related to autocrine secretion of IFNg. 19 As expected in this cell line, BFA markedly decreased STAT1 autocrine activation ( Figure 2c and Najjar et al 19 ). Treatment of PRI cells with fludarabine* (not shown) or Dx induced Y701-STAT1 phosphorylation in the presence of BFA.…”

Section: Resultssupporting

confidence: 76%

Identification of a novel p53-dependent activation pathway of STAT1 by antitumour genotoxic agents

et al. 2007

View full text Add to dashboard Cite

Chemotherapeutic drugs such as fludarabine*, doxorubicin or cisplatin are very potent activators of the anti-oncogene p53. Convergent studies suggest that p53 and STAT1 (signal transducer and activator of transcription 1) cooperate in the induction of cell death. We show that these drugs are also activators of STAT1 in p53-expressing cells, but not in p53-null cells. STAT1 activation was obtained in the presence of both the secretion inhibitor brefeldine A and the inhibitor of RNA synthesis, actinomycin D. p53-dependent STAT1 activation was reversed by overexpression of MDM2 and siRNAs against p53. Genetic analysis of p53 showed that expression of transcriptionally inactive p53 punctual mutants markedly increased Y701-STAT1 phosphorylation, and suggests that the p53 DNA-binding domain was alternatively involved in STAT1 activation or p53 multimerization. Immunoprecipitation experiments showed that ataxia telangiectasia mutated, p53, STAT1 and c-Abl1 (Abelson murine leukaemia viral oncogene homologue 1) were associated together. Treatment of cells with the c-Abl1 tyrosine kinase inhibitor STI571 decreased STAT1 activation by genotoxic drugs. Finally, genotoxic agents sensitized cells in response to very low doses of both interferon a and c (IFNa and c). These results show that genotoxic drugs induce STAT1 activation, an effect that depends on p53 protein but not on p53 transcriptional activity, and point to a novel pathway of STAT1 activation by genotoxic drugs, with involvement of c-Abl1 tyrosine kinase in sensitizing cells to IFN response.

show abstract

Section: Resultssupporting

confidence: 76%

Identification of a novel p53-dependent activation pathway of STAT1 by antitumour genotoxic agents

et al. 2007

View full text Add to dashboard Cite

show abstract

“…Actually, LMP-1 is reported to induce NF-κB-dependent IFN-γ secretion in lymphoblastoid cell lines [37]. On the basis of these findings, we suggest that LMP-1 enhance sICAM-1 secretion via IFN-γ−induced proteolytic cleavage.…”

Section: Discussionmentioning

confidence: 56%

Soluble ICAM-1 secretion and its functional role as an autocrine growth factor in nasal NK/T cell lymphoma cells

Takahara

Nagato

Komabayashi

et al. 2013

Experimental Hematology

View full text Add to dashboard Cite

“…HEK 293 (a human embryonic kidney cell line) was grown in Dulbecco's modified Eagle's medium supplemented with 10% fetal calf serum, 2 mM glutamine, penicillin, and streptomycin. PRI (a lymphoblastoid cell line) (41) and TE1 (a monocytic cell line) (39) are both transformed by EBV and were propagated in RPMI 1640 medium supplemented with 10% fetal calf serum, 2 mM glutamine, 1 mM sodium pyruvate, 1% nonessential amino acids, penicillin, streptomycin, and gentamicin. All cells were maintained at 37°C in a humidified atmosphere with 5% CO 2 .…”

Section: Methodsmentioning

confidence: 99%

Autoactivation of the Epstein-Barr Virus Oncogenic Protein LMP1 during Type II Latency through Opposite Roles of the NF-κB and JNK Signaling Pathways

Goormachtigh

Ouk

Mougel

et al. 2006

J Virol

Self Cite

View full text Add to dashboard Cite

Epstein-Barr virus (EBV)is associated with several human malignancies where it expresses limited subsets of latent proteins. Of the latent proteins, latent membrane protein 1 (LMP1) is a potent transforming protein that constitutively induces multiple cell signaling pathways and contributes to EBV-associated oncogenesis. Regulation of LMP1 expression has been extensively described during the type III latency of EBV. Nevertheless, in the majority of EBV-associated tumors, the virus is commonly found to display a type II latency program in which it is still unknown which viral or cellular protein is really involved in maintaining LMP1 expression. Here, we demonstrate that LMP1 activates its own promoter pLMP1 through the JNK signaling pathway emerging from the TES2 domain. Our results also reveal that this activation is tightly controlled by LMP1, since pLMP1 is inhibited by LMP1-activated NF-B signaling pathway. By using our physiological models of EBV-infected cells displaying type II latency as well as lymphoblastoid cell lines expressing a type III latency, we also demonstrate that this balanced autoregulation of LMP1 is shared by both latency programs. Finally, we show that this autoactivation is the most important mechanism to maintain LMP1 expression during the type II latency program of EBV.Epstein-Barr virus (EBV) is a widespread herpesvirus, found in more than 90% of healthy adults and persisting, in the vast majority of individuals, as a lifelong and asymptomatic infection. EBV classically infects B cells, causing sometimes a benign disease (infectious mononucleosis) but also malignant disorders, such as B-lymphoproliferative diseases, in patients with severe immunodeficiency. In immunocompetent hosts, EBV is also associated with other malignancies, including Burkitt's lymphoma, nasopharyngeal carcinoma, Hodgkin's disease, peripheral or nasal NK/T-cell lymphomas, and gastric, breast, and hepatocellular adenocarcinomas (46,50). In all EBV-associated tumors, the virus displays mainly a latency program of infection with a restricted pattern of gene expression, which can be classified in three types. Type I latency, during which only the EBV-encoded nuclear antigen 1 (EBNA1) is expressed, is found in Burkitt's lymphoma. Type II latency is characterized by coexpression of EBNA1 and latent membrane proteins LMP1, LMP2A, and LMP2B and is found in nasopharyngeal carcinoma, Hodgkin's disease, NK/T-cell lymphomas, and AIDS-related non-Hodgkin's lymphomas. Type III latency with expression of the five EBNAs and three latent membrane proteins is restricted to B lymphomas of immunodeficient patients (50).Cellular models allowing investigation of the roles of LMP1 during type II and type III latencies have been developed. In vitro, EBV can infect and immortalize resting B cells to yield permanent growth of lymphoblastoid cell lines (LCLs) displaying a full latency III program (27). We previously showed that EBV can also infect and transform T cells and monocytes. We have described and extensively characterized two cel...

show abstract

Latent Membrane Protein 1 Regulates STAT1 through NF-κB-Dependent Interferon Secretion in Epstein-Barr Virus-Immortalized B Cells

Cited by 55 publications

References 39 publications

Identification of a novel p53-dependent activation pathway of STAT1 by antitumour genotoxic agents

Identification of a novel p53-dependent activation pathway of STAT1 by antitumour genotoxic agents

Soluble ICAM-1 secretion and its functional role as an autocrine growth factor in nasal NK/T cell lymphoma cells

Autoactivation of the Epstein-Barr Virus Oncogenic Protein LMP1 during Type II Latency through Opposite Roles of the NF-κB and JNK Signaling Pathways

Contact Info

Product

Resources

About