Epstein-Barr Virus LMP2A Interferes with Global Transcription Factor Regulation When Expressed during B-Lymphocyte Development

Portis, Toni; Longnecker, Richard

doi:10.1128/jvi.77.1.105-114.2003

Cited by 71 publications

(57 citation statements)

References 79 publications

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“…An association between the presence of Epstein-Barr virus and a decrease in the levels of the transcription factors that regulate B-cell lineage in experimental studies has been observed, 42,43 but more studies are necessary to determine the role of Epstein-Barr virus in Ig gene expression.…”

Section: Discussionmentioning

confidence: 99%

Analysis of transcription factor OCT.1, OCT.2 and BOB.1 expression using tissue arrays in classical Hodgkin's lymphoma

et al. 2004

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Hodgkin's lymphoma can be considered in most cases a B-cell lymphoma due to the presence of potentially functional immunoglobulin (Ig) gene rearrangements in the neoplastic cells. In contrast to lymphocytepredominant Hodgkin's lymphoma, Hodgkin/Reed-Sternberg (HRS) cells from classical Hodgkin's lymphoma have low frequency of B-cell marker expression and lack Ig light and Ig heavy messenger RNA. Recent studies have shown transcription machinery deficiency in Hodgkin's lymphoma caused by an absence of the transcription factors OCT.1, OCT.2 and/or BOB.1. By using the tissue microarray technique, we have performed an immunohistochemical study of OCT.1, OCT.2 and BOB.1 in 325 classical Hodgkin's lymphoma cases. The results have been correlated with the expression of the B-cell markers CD20, CD79a, B-cell-specific activator protein (BSAP) and MUM.1, the presence of Epstein-Barr virus and the histological subtype. The percentage of CD20 and CD79a positivity was low (18 and 18%, respectively), whereas MUM.1 and BSAP were positive in the majority of cases. Considering the positive cases with independence of the intensity of staining, 62% of them expressed OCT.2, 59% OCT.1 and 37% BOB.1. Nevertheless, when we considered only the strongly positive cases, the results were similar to those previously described by others. No statistical association was found between the transcription factor expression, histological subtype and Epstein-Barr virus presence. To our knowledge, this is the largest series of classical Hodgkin's lymphoma cases in which the expression of transcription factors has been studied. We have found a notorious percentage of cases displaying weak positivity for OCT.2 and BOB.1 factors in HRS cells. We propose that other mechanisms different from the absence of transcription factors OCT.2 and BOB.1 might be involved in the control of Ig transcription and B lineage in classical Hodgkin's lymphoma.

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Section: Discussionmentioning

confidence: 99%

Analysis of transcription factor OCT.1, OCT.2 and BOB.1 expression using tissue arrays in classical Hodgkin's lymphoma

et al. 2004

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“…DNA Pulldown Assay-DNA pulldown assay was performed as described previously with minor modifications (53). Briefly, CRE or ARE oligonucleotides used in EMSA were labeled with biotinylated dUTP by random labeling kit (Pierce) following the manufacturer's protocol.…”

Section: Methodsmentioning

confidence: 99%

cAMP Stringently Regulates Human Cathelicidin Antimicrobial Peptide Expression in the Mucosal Epithelial Cells by Activating cAMP-response Element-binding Protein, AP-1, and Inducible cAMP Early Repressor

Chakraborty

Maity

Sil

et al. 2009

Journal of Biological Chemistry

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Little is known about the regulation of the innate host defense peptide cathelicidin at the mucosal surfaces. Expression is believed to be transcriptionally regulated, and several cis-acting elements have been identified in the cathelicidin putative promoter. However, the trans-acting factors have not been clearly defined. We have recently reported that bacterial exotoxins suppress cathelicidin expression in sodium butyrate-differentiated intestinal epithelial cells (ECs), and this may be mediated through inducible cAMP early repressor. Here we have shown that cAMP-signaling pathways transcriptionally regulate cathelicidin expression in various ECs. cAMP-response elementbinding protein (CREB) and AP-1 (activator protein-1) bind to the cathelicidin putative promoter in vitro. Additionally, transcriptional complexes containing CREB, AP-1, and cathelicidin upstream regulatory sequences are formed within ECs. We have also shown that these complexes may activate cathelicidin promoter and are required for its inducible expression in ECs. This is underscored by the fact that silencing of CREB and AP-1 results in failure of ECs to up-regulate cathelicidin, and hepatitis B virus X protein may use CREB to induce cathelicidin. On the other hand, inducible cAMP early repressor competes with CREB and AP-1 for binding to the cathelicidin promoter and represses transcription, thus functioning as a counter-regulatory mechanism. Finally, both CREB and AP-1 were shown to play major roles in the regulation of cathelicidin in sodium butyrate-differentiated HT-29 cells. This is the first report of a detailed mechanistic study of inducible cathelicidin expression in the mucosal ECs. At the same time, it describes a novel immunomodulatory function of cAMP.

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“…Microarray studies reveal that the gene transcription alteration of many MAPKrelated molecules is induced by LMP2A. These include the upregulation of Ras, the Ras homolog, Ras GTPase-activating protein-binding protein 1, MAPK2K2, and MAPK2K1; and the suppression of Ras suppressor protein [58]. It has been shown that c-Jun can cooperate with activated Ras to effectively carry out the transformation [113,114].…”

Section: Mapk Pathwaymentioning

confidence: 99%

“…Microarray analysis has identified a number of LMP2A-mediated transcriptional changes in the genes encoding ubiquitination [58]. It was shown that proteasome subunits (Psm a4, c3, d3, d8, d9, d11), ubiquitin-conjugating enzyme E2C (Ube2c, 21), WW domaincontaining protein 4 (Wwp2), Ubiquitin fusion degradation 1-like 11 (Ufd11), ubiquitin-specific protease (Usp15), and F-box and leucine-rich repeat protein 7 (Fb17) are induced by LMP2A, while autophagy 12-like (Apg121), ubiquilin 1 (Ubqln1), ubiquitin-specific protease 15 (Usp15) and WW domain-containing protein 4 (Wwp2) are repressed by LMP2A in different cell types [58]. The binding of these ubiquitin ligases to LMP2A is important for targeting LMP2A and LMP2A-associated proteins such as Lyn for ubiquitination, followed by internalization and degradation [54].…”

Section: The N-terminal Domainmentioning

confidence: 99%

“…In this section, we will discuss the involvement of the MAPK signaling pathways triggered by LMP2A and their role in the development of malignancy. Several direct and indirect pieces of evidence suggest that LMP2A is involved in the activation of MAPK signaling in various EBV-infected cell lines in vitro [20,58,60]. A study on lymphoblastoid B-cell lines and Burkitt lymphoma cell lines suggests that LMP2A activates ERK/MAPK [60].…”

Section: Mapk Pathwaymentioning

confidence: 99%

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The signaling pathways of Epstein-Barr virus-encoded latent membrane protein 2A (LMP2A) in latency and cancer

Pang

Lin

Peh

2009

Cellular and Molecular Biology Letters

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Epstein-Barr virus (EBV) is a ubiquitous virus with infections commonly resulting in a latency carrier state. Although the exact role of EBV in cancer pathogenesis remains not entirely clear, it is highly probable that it causes several lymphoid and epithelial malignancies, such as Hodgkin's lymphoma, NK-T cell lymphoma, Burkitt's lymphoma, and nasopharyngeal carcinoma. EBV-associated malignancies are associated with a latent form of infection, and several of these EBV-encoded latent proteins are known to mediate cellular transformation. These include six nuclear antigens and three latent membrane proteins. Studies have shown that EBV displays distinct patterns of viral latent gene expression in these lymphoid and epithelial tumors. The constant expression of latent membrane protein 2A (LMP2A) at the RNA level in both primary and metastatic tumors suggests that this protein might be a driving factor in the tumorigenesis of EBV-associated malignancies. LMP2A may cooperate with the aberrant host genome, and thereby contribute to malignant transformation by intervening in signaling pathways at multiple points, especially in the cell cycle and apoptotic pathway. This review summarizes the role of EBV-encoded LMP2A in EBV-associated viral latency and cancers. We will focus our discussions on the molecular interactions of each of the conserved motifs in LMP2A, and their involvement in various signaling pathways, namely the B-cell receptor blockade mechanism, the ubiquitin-mediated (Notch and Wnt) pathways, and the MAPK, PI3-K/Akt, NK-κB and STAT pathways, which can provide us with important insights into the roles of LMP2A in the EBVassociated latency state and various malignancies.

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Epstein-Barr Virus LMP2A Interferes with Global Transcription Factor Regulation When Expressed during B-Lymphocyte Development

Abstract: Epstein-Barr virus (EBV) is

Cited by 71 publications

References 79 publications

Analysis of transcription factor OCT.1, OCT.2 and BOB.1 expression using tissue arrays in classical Hodgkin's lymphoma

Analysis of transcription factor OCT.1, OCT.2 and BOB.1 expression using tissue arrays in classical Hodgkin's lymphoma

cAMP Stringently Regulates Human Cathelicidin Antimicrobial Peptide Expression in the Mucosal Epithelial Cells by Activating cAMP-response Element-binding Protein, AP-1, and Inducible cAMP Early Repressor

The signaling pathways of Epstein-Barr virus-encoded latent membrane protein 2A (LMP2A) in latency and cancer

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