The Balance Between Pax5 and Id2 Activities Is the Key to AID Gene Expression

Gonda, Hiroyuki; Sugai, Manabu; Nambu, Yukiko; Katakai, Tomoya; Agata, Yasutoshi; Mori, Kazuhiro; Yokota, Yoshifumi; Shimizu, Akira

doi:10.1084/jem.20030802

Cited by 199 publications

(205 citation statements)

References 37 publications

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“…The stable levels of the Id proteins that we observe during the inhibition of AID mRNA expression (Fig. 3C) do not contradict previous reports that overexpression of Id2 or Id3 inhibits AID expression (16,18). Instead, our findings imply that the E-protein activity has to be carefully fine-tuned to maintain the right levels of AID activation and sensitivity toward Ca 2ϩ /calmodulin after BCR activations of different strengths, and it is likely that Id proteins have a major role in this optimization of the regulatory system.…”

Section: Discussionsupporting

confidence: 41%

“…Id proteins, which inhibit DNA binding of E-proteins by binding to their helix-loop-helix dimerization domain, participate at several regulatory steps in lymphocyte development (25,26), and enforced overexpression of either Id2 or Id3 can block AID gene expression (16,18). However, during 5 h of BCR activation, we saw no decrease in the amount of E-protein able to bind to the AID enhancer probe in the absence of Ca 2ϩ ( Fig.…”

Section: Bcr Activation Can Inhibit Expression Of Aid and The Inhibitmentioning

confidence: 55%

“…24, and electrophoretic mobility shift assays were performed as described in ref. 23, using an end-labeled DNA probe (5Ј-GGGAGCACAGCTGTCTCAGC-3Ј) containing the E-protein binding sequence from the AID enhancer (16,18). Western blot was performed by using the WesternBreeze immunodetection system (Invitrogen) according to the manufacturer's instructions, using antibodies to E2A (V-18), Id1 (Z-8), Id2 (C-20), Id3 (H-70), or Id4 (H-70) (all from Santa Cruz Biotechnology) or ␣-tubulin (clone B-5-1-2; Sigma-Aldrich).…”

Section: Methodsmentioning

confidence: 99%

“…Specific stimulatory signals activate their proliferation and the diversification of the variable regions of their Ig genes, followed by expression of mutated surface Ig and selection of the mutated B-cell receptors (BCRs) for reactivity with antigen (12)(13)(14). E-protein, NF-B, Pax5, STAT6, and IRF-8 transcription factors participate in expression of the AID gene (15)(16)(17)(18). The gene is induced by IL-4 and ligation of CD40, and, in mice, other inducers have also been identified, including LPS (11,17,19).…”

mentioning

confidence: 99%

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B-cell receptor activation inhibits AID expression through calmodulin inhibition of E-proteins

Hauser

Sveshnikova

Wallenius

et al. 2008

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

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Upon encountering antigens, B-lymphocytes can adapt to produce a highly specific and potent antibody response. Somatic hypermutation, which introduces point mutations in the variable regions of antibody genes, can increase the affinity for antigen, and antibody effector functions can be altered by class switch recombination (CSR), which changes the expressed constant region exons. Activation-induced cytidine deaminase (AID) is the mutagenic antibody diversification enzyme that is essential for both somatic hypermutation and CSR. The mutagenic AID enzyme has to be tightly controlled. Here, we show that engagement of the membranebound antibodies of the B-cell receptor (BCR), which signals that good antibody affinity has been reached, inhibits AID gene expression and that calcium (Ca 2؉ ) signaling is essential for this inhibition. Moreover, we show that overexpression of the Ca 2؉ sensor protein calmodulin inhibits AID gene expression, and that the transcription factor E2A is required for regulation of the AID gene by the BCR. E2A mutated in the binding site for calmodulin, and thus showing calmodulin-resistant DNA binding, makes AID expression resistant to the inhibition through BCR activation. Thus, BCR activation inhibits AID gene expression through Ca 2؉ /calmodulin inhibition of E2A.activation-induced cytidine deaminase ͉ BCR ͉ calcium ͉ E2A P rocesses that diversify antibodies play a major role in protecting higher organisms from pathogens. Upon encountering antigens, antibody-expressing B-lineage lymphocytes adapt to produce a highly specific and potent antibody response. Somatic hypermutation, which introduces point mutations in the variable regions of antibody genes, and gene conversion can increase the affinity for antigen, and antibody effector functions can be altered by class switch recombination (CSR), which changes the expressed constant region exons (1, 2). Activationinduced cytidine deaminase (AID) is the antibody diversification enzyme that is essential for somatic hypermutation, gene conversion, and CSR (3-5). The mutagenic AID enzyme has to be tightly controlled, and both aberrant AID activity and chromosomal translocations involving switch regions of antibody genes are hallmark features of B-cell malignancies (2, 6-9).AID is specifically expressed in a subset of germinal center B-lymphocytes (10, 11). Specific stimulatory signals activate their proliferation and the diversification of the variable regions of their Ig genes, followed by expression of mutated surface Ig and selection of the mutated B-cell receptors (BCRs) for reactivity with antigen (12-14). E-protein, NF-B, Pax5, STAT6, and IRF-8 transcription factors participate in expression of the AID gene (15-18). The gene is induced by IL-4 and ligation of CD40, and, in mice, other inducers have also been identified, including LPS (11,17,19). Only ligation of CD45 has been reported to lead to signaling that inhibits AID gene expression, and this was shown to involve inhibition of signaling to STAT6 (19).In the present study, we show that a...

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Section: Discussionsupporting

confidence: 41%

Section: Bcr Activation Can Inhibit Expression Of Aid and The Inhibitmentioning

confidence: 55%

Section: Methodsmentioning

confidence: 99%

mentioning

confidence: 99%

See 2 more Smart Citations

B-cell receptor activation inhibits AID expression through calmodulin inhibition of E-proteins

Hauser

Sveshnikova

Wallenius

et al. 2008

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

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“…Both Pax5 and Bcl6 are needed to maintain the expression of AID and UNG, thus ensuring active SHM and CSR, which promote Ig affinity maturation and class switching in GC B cells. Whereas Pax5 seems to promote AICDA expression [4,61], Bcl6 binds directly to UNG and is needed for its expression. Here, we show that Bcl6 is not only the direct repressor of PRDM1, but also directly maintains the expression of BACH2, which represses PRDM1 expression [40][41][42].…”

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confidence: 99%

Alternate pathways for Bcl6‐mediated regulation of B cell to plasma cell differentiation

et al. 2011

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The transcription factor Bcl6 regulates germinal center formation and differentiation of B cells into high-affinity antibody-producing plasma cells. The direct double-negative regulatory circuit between Bcl6 and Blimp-1 is well established. We now reveal alternative mechanisms for Bcl6-mediated regulation of B-cell differentiation to plasma cells and show with DT40 cells that Bcl6 directly promotes the expression of Bach2, a known suppressor of Blimp-1. Moreover, Bcl6 suppresses Blimp-1 expression through direct binding to the IRF4 gene, as well as by promoting the expression of MITF, a known suppressor of IRF4. We also provide evidence that Bcl6 is needed for the expression of AID and UNG, the indispensable proteins for somatic hypermutation and class-switch recombination, and UNG appears to be a direct Bcl6 target. Our findings reveal a complex regulatory network in which Bcl6 acts as a key element dictating the transition of DT40 B cells to plasma cells. Supporting Information available online See accompanying Commentary by Tarlinton IntroductionThe transition of activated B cells into high-affinity antibodyproducing plasmablasts, plasma cells and memory B cells in the germinal centers (GCs) is a biologically unique process involving rapid B-cell proliferation coupled with a high rate of mutation in the variable regions of immunoglobulin (Ig) genes. Considering that the majority of B-cell lymphomas originate from the GC B cells [1], a comprehensive understanding of the transcriptional regulation controlling the transition of B cells to plasma cells is essential. The transcription factors Blimp-1, Xbp-1 and IRF4 have been identified to be critical regulators promoting the Ig secretion and plasma cell phenotype, whereas Pax5, Bcl6, MITF and Bach2 are the known inhibitors of plasma cell development [2].Previous studies have shown that the downregulation of B-cell identity factor Pax5 occurs before the induction of the plasma cell transcription program [3,4], and that the loss of Pax5 expression [4] leads to the downregulation of BCL6. Furthermore, B-cell receptor (BCR) signaling of sufficient affinity leads to rapid phosphorylation and degradation of Bcl6 protein [5], while Bcl6 can also be functionally inactivated by acetylation [6]. These features of Bcl6 make it a prominent molecular trigger that controls the plasma cell differentiation.The transcription factor Bcl6 has been demonstrated to be essential for GC B-cell development, as Bcl6 knockout mice fail to develop GCs and do not produce high-affinity antibodies [7][8][9]. Recent work revealed that Bcl6 is also needed for follicular T helper cell development [10][11][12]. Analyses of Bcl6 target genes in B cells indicate that suppression of apoptosis and cell cycle arrest responses occur through p53, p21 and CHEK1 and Bcl6 also regulates DNA damage responses by controlling ATR [13][14][15][16]. Thus, Bcl6 appears to function as a factor permitting rapid B-cell 2404proliferation and tolerance for DNA damage in GCs. Bcl6 also represses genes that are involve...

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The helix‐loop‐helix protein Id2 is expressed differentially and induced by myc in T‐cell lymphomas

Cotta

Leventaki

Atsaves

et al. 2007

Cancer

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BACKGROUND. Inhibitor of DNA binding 2 (Id2), a helix‐loop‐helix protein of the inhibitor of differentiation (ID) family, is involved in hematopoiesis, mainly through interaction with the E‐family of transcription factors. Recent studies have shown that Id2 is overexpressed in some types of B‐cell lymphoma, including classical Hodgkin lymphoma. The authors of the current study hypothesized that Id2 also is overexpressed in T‐cell lymphomas. METHODS. By using reverse‐transcriptase polymerase chain reaction (RT‐PCR) and Western blot analyses, high Id2 messenger RNA (mRNA) and protein levels, respectively, were detected in all 4 T‐cell anaplastic large cell lymphoma (ALCL) cell lines that were tested. RESULTS. Immunohistochemistry results indicated that Id2 was expressed strongly in 21 of 27 (78%) ALCL tumors (79% anaplastic lymphoma kinase [ALK]‐negative and 75% ALK‐positive), in 5 of 10 (50%) extranodal natural killer/T (NK/T)‐cell lymphomas of the nasal type, in 2 of 8 (25%) cutaneous ALCLs, in 2 of 9 (22%) enteropathy type T‐cell lymphomas, in 1 of 5 (20%) peripheral T‐cell lymphomas not otherwise specified, and in 1 of 8 (13%) T‐cell prolymphocytic leukemias. Other types of T‐cell lymphoma were negative for Id2. Because it is known that myc is expressed in ALCL, myc was inhibited selectively in 2 ALCL cell lines, resulting in a concentration‐dependent decrease in Id2 mRNA and protein levels. Conversely, forced expression of myc in HEK 293T cells using an myc/green fluorescent protein adenoviral vector resulted in Id2 up‐regulation. CONCLUSIONS. Taken together, the current data suggest that Id2 commonly is overexpressed in highly proliferative T‐cell lymphomas, and its expression may result from transcriptional activation of myc in these tumors. Cancer 2008. © 2007 American Cancer Society.

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The Balance Between Pax5 and Id2 Activities Is the Key to AID Gene Expression

Cited by 199 publications

References 37 publications

B-cell receptor activation inhibits AID expression through calmodulin inhibition of E-proteins

B-cell receptor activation inhibits AID expression through calmodulin inhibition of E-proteins

Alternate pathways for Bcl6‐mediated regulation of B cell to plasma cell differentiation

The helix‐loop‐helix protein Id2 is expressed differentially and induced by myc in T‐cell lymphomas

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