The Epstein-Barr Virus Promoter Initiating B-Cell Transformation Is Activated by RFX Proteins and the B-Cell-Specific Activator Protein BSAP/Pax5

Tierney, Rosemary J.; Kirby, Helen; Nagra, Jasdeep; Rickinson, Alan B.; Bell, Andrew I.

doi:10.1128/jvi.74.22.10458-10467.2000

Cited by 54 publications

(52 citation statements)

References 70 publications

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“…Binding of RFX-1 to genes encoding cMyc, proliferating cell nuclear antigen, and collagen a2 has a negative effect on gene expression (50). This is in contrast to RFX-1 binding to the genes for ribosomal protein rpL30 or interleukin-5 receptor where it functions as a positive regulatory protein (47)(48)(49)51). In human keratinocytes, RFX-1 in cooperation with c-jun/JunD was shown to regulate the expression of peptidylarginine deiminase-1 and -3 genes during keratinocyte differentiation (52).…”

Section: Discussionmentioning

confidence: 79%

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Breast Cancer Cells Proliferation Is Regulated by Tyrosine Phosphatase SHP1 through c-jun N-Terminal Kinase and Cooperative Induction of RFX-1 and AP-4 Transcription Factors

Amin

Kumar

Nilchi

et al. 2011

Molecular Cancer Research

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In this study, we show that proliferation of breast cancer cells is suppressed by IGF-1-activated JNK MAPK pathway. The molecular mechanism by which c-jun-NH,-kinase (JNK) activation induces antiproliferative signals in IGF-1-stimulated breast cancer cells remains unknown. Tyrosine phosphatase SHP1 is known to negatively regulate signal transduction pathways activated by cell surface receptors including IGF-1. Moreover, SHP1 transcript and protein levels are increased in epithelial tumors. Therefore, we hypothesized that IGF-activated JNK induces expression of SHP1 in breast cancer cells. To further clarify the role of SHP1 in tumor growth, we correlated the proliferation rates of breast adenocarcinoma cells with SHP1 expression and JNK activation. We show that proliferation of serum-or IGF-1-stimulated breast adenocarcinoma cells is negatively regulated by SHP1 and show for the first time that IGF-1-activated JNK induces SHP1 expression in MCF-7 cells used as experimental model. In an attempt to understand the mechanism by which serum-or IGF-1-activated JNK induces SHP1 expression resulting in suppression of cell proliferation, we reveal for the first time that in serum-or IGF-1-stimulated breast cancer MCF-7 cells, JNK induces SHP1 expression through the binding of AP-4 and RFX-1 transcription factors to the epithelial tissue-specific SHP1 promoter. Overall, we show for the first time that IGF-1-stimulated proliferation of breast adenocarcinoma cells is negatively regulated by SHP1 through activation of JNK. Mol Cancer Res; 9(8); 1112-25. Ó2011 AACR.

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Section: Discussionmentioning

confidence: 79%

“…Partially palindromic sequences to which RFX-1 binds were found in the enhancers of hepatitis B, polyoma, cytomegalovirus, and EpsteinBarr viruses (47). The target genes to which RFX-1 binds include genes encoding the IL-5 receptor and ribosomal rpL30 proteins (48)(49)(50).…”

Section: Discussionmentioning

confidence: 99%

Breast Cancer Cells Proliferation Is Regulated by Tyrosine Phosphatase SHP1 through c-jun N-Terminal Kinase and Cooperative Induction of RFX-1 and AP-4 Transcription Factors

Amin

Kumar

Nilchi

et al. 2011

Molecular Cancer Research

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“…EBF developmentally activates PAX5 and is frequently linked to PAX5 in transcription up-regulatory effects. PAX5 was previously shown to be important for initial transcription from the Wp EBNA promoter in LCLs (42).…”

Section: Discussionmentioning

confidence: 99%

Epstein-Barr virus exploits intrinsic B-lymphocyte transcription programs to achieve immortal cell growth

Zhao¹,

Zou

Wang

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

187

267

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Epstein-Barr virus nuclear antigen 2 (EBNA2) regulation of transcription through the cell transcription factor RBPJ is essential for resting B-lymphocyte (RBL) conversion to immortal lymphoblast cell lines (LCLs). ChIP-seq of EBNA2 and RBPJ sites in LCL DNA found EBNA2 at 5,151 and RBPJ at 10,529 sites. EBNA2 sites were enriched for RBPJ (78%), early B-cell factor (EBF, 39%), RUNX (43%), ETS (39%), NFκB (22%), and PU.1 (22%) motifs. These motif associations were confirmed by LCL RBPJ ChIP-seq finding 72% RBPJ occupancy and Encyclopedia Of DNA Elements LCL ChIP-seq finding EBF, NFκB RELA, and PU.1 at 54%, 31%, and 17% of EBNA2 sites. EBNA2 and RBPJ were predominantly at intergene and intron sites and only 14% at promoter sites. K-means clustering of EBNA2 site transcription factors identified RELA-ETS, EBF-RUNX, EBF, ETS, RBPJ, and repressive RUNX clusters, which ranked from highest to lowest in H3K4me1 signals and nucleosome depletion, indicative of active chromatin. Surprisingly, although quantitatively less, the same genome sites in RBLs exhibited similar high-level H3K4me1 signals and nucleosome depletion. The EBV genome also had an LMP1 promoter EBF site, which proved critical for EBNA2 activation. LCL HiC data mapped intergenic EBNA2 sites to EBNA2 upregulated genes. FISH and chromatin conformation capture linked EBNA2/RBPJ enhancers 428 kb 5′ of MYC to MYC. These data indicate that EBNA2 evolved to target RBL H3K4me1 modified, nucleosome-depleted, nonpromoter sites to drive B-lymphocyte proliferation in primary human infection. The primed RBL program likely supports antigen-induced proliferation.pstein Barr virus (EBV) infection is highly prevalent in all human populations. EBV is also an important cause of endemic Burkitt Lymphoma (1), Hodgkin Lymphoma (2), and lymphoproliferative disorders in immune-suppressed (3) and HIV-infected people (4). In early primary human infection, EBV infects peripheral resting B lymphocytes (RBLs) and expresses six nuclear (Epstein-Barr virus nuclear antigen, EBNA) and two integral membrane (LMP) proteins. EBNAs and LMPs convert RBLs into proliferating lymphoblastoid cells (LCLs), which are malignant in the absence of effective T-cell responses. Because EBNAs and LMPs include >4,000 amino acids, T-cell immune responses normally eliminate most EBV-infected cells. Lymphocytes with down-regulated EBV protein expression persist in tonsils and lymph nodes and are reservoirs for reactivated EBV infection (4). EBV conversion of RBLs into LCLs in vitro (5) is a relevant and experimentally useful model for EBV proliferative effects in B-lymphocytes.In converting RBLs to LCLs, EBNA2 and EBNALP are expressed first. EBNA2 up-regulates EBV and cell gene expression, including EBV LMP1 and cell MYC, CD23, and CD21 (6-9). EBNA2 associates with DNA through RBPJ, which also mediates Notch binding to DNA (10, 11). The B-lymphocyte and macrophage lineage ETS protein, PU.1, is also important in EBNA2 activation of the EBV LMP1 promoter (12, 13). The EBNA2 C-terminal acidic domain recruits basal ...

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“…To complicate the matter, recently identified translocations in B cell acute lymphoblastic leukemia involving PAX5 result in the creation of its dominant-negative or loss-of-function versions, rather than gainof-function mutants (27,28). While at the molecular level, Pax5 has been reported to transactivate the Epstein-Barr virus promoter (29) and repress expression of p53 (30), these events have not been validated in tumor contexts.…”

Section: Introductionmentioning

confidence: 99%

B cell activator PAX5 promotes lymphomagenesis through stimulation of B cell receptor signaling

Cozma¹,

Yu²,

Hodawadekar³

et al. 2007

J. Clin. Invest.

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IntroductionBoth normal hematopoiesis and lymphomagenesis are driven, to a large extent, by expression of lineage-specific transcription factors. Many such factors are overtly oncogenic. For example, the hallmark of Burkitt lymphoma and some diffuse large B cell lymphomas (DLBCLs) is the t(8;14) translocation that places the MYC protooncogene under control of the Ig heavy chain gene enhancer (1, 2); a similar translocation has been identified in murine plasmacytomas (3). The causative role of Myc in B-lymphomagenesis has been validated through the generation of various transgenic (4-7) and nontransgenic (8) murine models of non-Hodgkin lymphoma.Other transcription factors are not known to initiate B-lymphomagenesis, but are consistently mutated in full-fledged neoplasms. One such intriguing protein is paired box gene 5 (Pax5), a B cell activator protein (9) with a characteristic paired box DNA-binding motif (10). Inactivation of Pax5 via homologous recombination precludes normal B cell development (11,12), and several lines of evidence implicate Pax5 as an important factor in B-lymphomagenesis as well.

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The Epstein-Barr Virus Promoter Initiating B-Cell Transformation Is Activated by RFX Proteins and the B-Cell-Specific Activator Protein BSAP/Pax5

Cited by 54 publications

References 70 publications

Breast Cancer Cells Proliferation Is Regulated by Tyrosine Phosphatase SHP1 through c-jun N-Terminal Kinase and Cooperative Induction of RFX-1 and AP-4 Transcription Factors

Breast Cancer Cells Proliferation Is Regulated by Tyrosine Phosphatase SHP1 through c-jun N-Terminal Kinase and Cooperative Induction of RFX-1 and AP-4 Transcription Factors

Epstein-Barr virus exploits intrinsic B-lymphocyte transcription programs to achieve immortal cell growth

B cell activator PAX5 promotes lymphomagenesis through stimulation of B cell receptor signaling

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