Role of OCA-B in 3′-IgH Enhancer Function

Stevens, Sean; Ong, Jane; Kim, Unkyu; Eckhardt, Laurel A.; Roeder, Robert G.

doi:10.4049/jimmunol.164.10.5306

Cited by 48 publications

(54 citation statements)

References 44 publications

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“…This regulatory program must suppress cell survival genes, such as TCL1, to foster negative selection and promote apoptosis. Our work exposed a regulatory circuit in which GC B cell signaling through CD40 and the BCR activates pCREB-133-responsive genes, such as OCA-B and BCL2 (36,37), and also represses certain CREB-dependent genes, of which TCL1 is an important example, through Ser-171 phosphorylation and nuclear exclusion of TORC2. We have shown that TCL1 is a direct target of the CREB-TORC2 complex and that repression depends on pTORC2-171 but not pCREB-133.…”

Section: Discussionmentioning

confidence: 99%

TORC2 regulates germinal center repression of the TCL1 oncoprotein to promote B cell development and inhibit transformation

Kuraishy

French

Sherman

et al. 2007

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

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Aberrant expression of the TCL1 oncoprotein promotes malignant transformation of germinal center (GC) B cells. Repression of TCL1in GC B cells facilitates FAS-mediated apoptosis and prevents lymphoma formation. However, the mechanism for this repression is unknown. Here we show that the CREB coactivator TORC2 directly regulates TCL1 expression independent of CREB Ser-133 phosphorylation and CBP/p300 recruitment. GC signaling through CD40 or the BCR, which activates pCREB-dependent genes, caused TORC2 phosphorylation, cytosolic emigration, and TCL1 repression. Signaling via cAMP-inducible pathways inhibited TCL1 repression and reduced apoptosis, consistent with a prosurvival role for TCL1 before GC selection and supporting an initiating role for aberrant TCL1 expression during GC lymphomagenesis. Our data indicate that a novel CREB/TORC2 regulatory mode controls the normal program of GC gene activation and repression that promotes B cell development and circumvents oncogenic progression. Our results also reconcile a paradox in which signals that activate pCREB/CBP/ p300 genes concurrently repress TCL1 to initiate its silencing.gene regulation ͉ lymphomagenesis ͉ signal transduction T he germinal center (GC) is home to T cell-dependent antigen-driven B cell maturation, memory B and plasma cell production, and the site of origin for most human B cell lymphomas (1-3). GC B cells undergo critical changes in gene expression that are required for proper development and protection from oncogenesis (4, 5). The generation of an appropriate humoral response is insured by negative selection, primarily mediated by FAS-induced apoptosis (6-8). Escape from apoptosis results in autoimmunity and B cell transformation (8).TCL1 functions as a coactivator of the cell survival kinase AKT (9, 10). In mature T cell tumors, TCL1 expression is aberrantly elevated by rearrangements into T cell receptor loci (11). Physiologic TCL1 expression is largely limited to B lineage cells and is robust from pre-B cells through peripheral naïve B cells, followed by a critical 40-60% repression in GC B cells and complete silencing in post-GC memory B and plasma cells (12,13). Most B cell lymphomas that arise by transformation of GC-experienced B cells exhibit elevated TCL1 expression by escape from GC mechanism(s) of TCL1 repression (12,14,15). Interestingly, transgenic mice with TCL1 expression levels stabilized in GC lymphocytes develop cancers that resemble a spectrum of human GC B cell lymphomas (16).Unrepressed TCL1 expression inhibits FAS-induced B cell apoptosis independent of activation by BCR survival signaling (17, 18). Impaired apoptosis from failed TCL1 repression in GC B cells connects TCL1 dysregulation in patient lymphomas (12, 14) to a mechanism for increased transformation (16,18). Factors so far suggested to regulate TCL1, including Nur77 (19,20), miRNA-29 and miRNA-181 (21), Sp1 (22), and EBV infection (23), fail to adequately explain TCL1 repression in GC B cells and its continued aberrant expression in lymphomas (11).Its role in ...

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Section: Discussionmentioning

confidence: 99%

TORC2 regulates germinal center repression of the TCL1 oncoprotein to promote B cell development and inhibit transformation

Kuraishy

French

Sherman

et al. 2007

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

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“…When the 3Ј IgH enhancer is deleted in mature B cells, they maintain the ability to class switch to IgG1, but produce a lower level of secreted IgG1 and mature IgG1 transcript compared with wild-type cells (41). The activity of the 3Ј IgH enhancer is known to be regulated by Oct-1/2 and their coactivator OCA-B (40). Since B cells deficient in OCA-B maintain the ability to class switch to IgG1, but the level of IgG1 produced is decreased compared with that in wild-type B cells (57), these published data suggest that activation of the 3Ј IgH enhancer in mature B cells affects mature IgG1 transcript, but not I␥1.…”

Section: Discussionmentioning

confidence: 99%

“…The class switching event is regulated by CD40-and IL-4R-induced NF-B and STAT-6 binding to the germline ␥1 promoter, respectively, to activate transcription of germline ␥1 (referred to as intervening ␥1 (I␥1)) (33)(34)(35)(36)(37)(38)(39). The production of mature IgG1 transcript is regulated by an increase in Oct coactivator from B cells (OCA-B) expression following CD40 stimulation to regulate the activity of the 3Ј IgH enhancer (40). Although B cells in which the 3Ј IgH enhancer has been deleted are able to class switch to IgG1, the ability to attain normal levels of secreted IgG1 and mature IgG1 transcript is lost (41).…”

Section: Selective Regulation Of Mature Igg1 Transcription By Cd86mentioning

confidence: 99%

Selective Regulation of Mature IgG1 Transcription by CD86 and β2-Adrenergic Receptor Stimulation

Podojil

Sanders

2003

The Journal of Immunology

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Stimulation of CD86 and the β2-adrenergic receptor (β2AR) on a B cell, either alone or together, is known to increase the level of IgG1 protein produced by a CD40 ligand/IL-4-activated B cell. It is also known that the mechanism by which CD40 and IL-4R stimulation on a B cell increases the level of IgG1 protein is by increasing germline γ1 transcription, IgG1 class switching, and mature IgG1 transcription, while the molecular mechanism responsible for mediating the CD86- and β2AR-induced effect remains unknown. In the present study using real-time PCR we show that the level of mature IgG1 transcription increases in CD40 ligand/IL-4-activated B cells following stimulation of either CD86 and/or β2AR, and that this increase reflects the increase in IgG1 protein. Furthermore, we show that the CD86- and/or β2AR-induced increase in mature IgG1 transcript is due to an increase in the rate of mature IgG1 transcription, as determined by nuclear run-on analysis. This effect is additive when both receptors are stimulated and is lost when B cells from CD86- and β2AR-deficient mice are used. In contrast, the level of germline γ1 transcription, the stability of mature IgG1 transcript, the number of IgG1-positive B cells, and the number of IgG1-secreting B cells did not change. These results provide the first evidence that CD86 and/or β2AR stimulation on a CD40 ligand/IL-4-activated B cell increases the level of IgG1 protein produced per cell by increasing the rate of mature IgG1 transcription.

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“…Oct-1 has been suggested to be a negative regulator of transcription under certain circumstances (50), and in B cells appears to preferentially associate with C/EBP␤-3, a C/EBP isoform that has a negative regulatory function (51). Hs4 enhancer activity is also likely to require OCA-B, a known coactivator of both Oct-1 and Oct-2 (52) and a predicted contributor to the function of the mouse 3Ј enhancers (53). OCA-B was present in all cell lines in which human hs4 was active, but only low levels were present in Ly8 DLBCL cells, which failed to support hs4 enhancer activity even though Oct-2 and NF-B levels were not reduced.…”

Section: Discussionmentioning

confidence: 99%

NF-κB and Oct-2 Synergize to Activate the Human 3′ Igh hs4 Enhancer in B Cells

Sepúlveda

Emelyanov

Birshtein

2004

The Journal of Immunology

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In B cells, the Igh gene locus contains several DNase I-hypersensitive (hs) sites with enhancer activity. These include the 3′ Igh enhancers, which are located downstream of the Cα gene(s) in both mouse and human. In vivo experiments have implicated murine 3′ enhancers, hs3B and/or hs4, in class switching and somatic hypermutation. We previously reported that murine hs4 was regulated by NF-κB, octamer binding proteins, and Pax5 (B cell-specific activator protein). In this study we report that human hs4 is regulated differently. EMSAs and Western analysis of normal B cells before and after stimulation with anti-IgM plus anti-CD40 showed the same complex binding pattern formed by NF-κB, Oct-1, and Oct-2 (but not by Pax5). A similar EMSA pattern was detected in mature human B cell lines (BL-2, Ramos, and HS-Sultan) and in diffuse large B cell lymphoma cell lines, although yin yang 1 protein (YY1) binding was also observed. We have confirmed the in vivo association of these transcription factors with hs4 in B cells by chromatin immunoprecipitation assays. The diffuse large B cell lymphoma cell lines had a distinctive slow-migrating complex containing YY1 associated with Rel-B. We have confirmed by endogenous coimmunoprecipitation an association of YY1 with Rel-B, but not with other NF-κΒ family members. Transient transfection assays showed robust hs4 enhancer activity in the mature B cell lines, which was dependent on synergistic interactions between NF-κB and octamer binding proteins. In addition, human hs4 enhancer activity required Oct-2 and correlated with expression of Oct coactivator from B cells (OCA-B).

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Role of OCA-B in 3′-IgH Enhancer Function

Cited by 48 publications

References 44 publications

TORC2 regulates germinal center repression of the TCL1 oncoprotein to promote B cell development and inhibit transformation

TORC2 regulates germinal center repression of the TCL1 oncoprotein to promote B cell development and inhibit transformation

Selective Regulation of Mature IgG1 Transcription by CD86 and β2-Adrenergic Receptor Stimulation

NF-κB and Oct-2 Synergize to Activate the Human 3′ Igh hs4 Enhancer in B Cells

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