Analysis of the Major Patterns of B Cell Gene Expression Changes in Response to Short-Term Stimulation with 33 Single Ligands

Zhu, Xiaocui; Hart, Rebecca; Chang, Mi-Sook; Kim, Jong-Woo; Lee, Sun Young; Cao, Yun Anna; Mock, Dennis; Ke, Eugene; Saunders, Brian; Alexander, Angela; Grossoehme, Joella; Lin, Keng-Mean; Yan, Zhen; Hsueh, Robert C.; Lee, Jamie A.; Scheuermann, Richard H.; Fruman, David A.; Seaman, William E.; Subramaniam, Shankar; Sternweis, Paul C.; Simon, Melvin I.; Choi, Sangdun

doi:10.4049/jimmunol.173.12.7141

Cited by 52 publications

(59 citation statements)

References 72 publications

(39 reference statements)

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“…2, A and D), indicating a previously unidentified role for PI3K in the control of FOXO1 at the transcriptional level in addition to its known posttranslational effects. Our results were confirmed by microarray data generated through the Alliance for Cellular Signaling showing that stimulation of primary murine B cells with anti-IgM for 4 h induces downregulation of FOXO1 mRNA (33). Consistent with the change in mRNA levels, total FOXO1 protein was observed to decrease 16 h poststimulation with anti-IgM (Fig.…”

Section: Resultssupporting

confidence: 77%

B Cell Receptor Signaling Down-Regulates Forkhead Box Transcription Factor Class O 1 mRNA Expression via Phosphatidylinositol 3-Kinase and Bruton’s Tyrosine Kinase

Hinman

Bushanam

Nichols

et al. 2007

The Journal of Immunology

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BCR cross-linking promotes mature B cell proliferation and survival. PI3K-mediated down-regulation of proapoptotic and antimitogenic genes such as forkhead box transcription factor class O 1 (FOXO1) is an important component of this process. Previously, BCR-induced phosphorylation of FOXO1 was shown to lead to a block in nuclear localization and subsequent protein degradation. We demonstrate that the BCR also signals through PI3K to down-regulate FOXO1 mRNA expression. Bruton’s tyrosine kinase (Btk), a downstream effector of PI3K, signals through B cell linker protein (BLNK) and phospholipase C (PLC)γ2 to mediate B cell proliferation and survival in response to BCR cross-linking. BCR-induced down-regulation of FOXO1 mRNA was impaired in murine knockouts of Btk, BLNK, and PLCγ2. Because B cells in these models are predominantly immature, experiments were also performed using mature B cells expressing low levels of Btk and BLNK. Similar results were obtained. Inhibitors of downstream components of the Btk/BLNK/PLCγ2 pathway were used to define the mechanism by which Btk signaling inhibits FOXO1 expression. The protein kinase Cβ inhibitor Gö6850 had minimal effects on BCR-mediated FOXO1 mRNA down-regulation. However, cyclosporin A, an inhibitor of the Ca2+-dependent phosphatase calcineurin, had similar effects on FOXO1 mRNA expression as the PI3K inhibitor LY294002. Neither Btk deficiency nor cyclosporin A prevented FOXO1 protein phosphorylation, indicating that PI3K down-regulates FOXO1 via two independent pathways. We show that the Btk/BLNK/PLCγ2 pathway mediates BCR-induced changes in expression of the FOXO1 target gene cyclin G2. These observations support the hypothesis that Btk mediates BCR-induced proliferation and survival in part via inhibition of FOXO expression.

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Section: Resultssupporting

confidence: 77%

B Cell Receptor Signaling Down-Regulates Forkhead Box Transcription Factor Class O 1 mRNA Expression via Phosphatidylinositol 3-Kinase and Bruton’s Tyrosine Kinase

Hinman

Bushanam

Nichols

et al. 2007

The Journal of Immunology

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“…This is supported by the similarity of gene expression profiles of primary B cells stimulated with distinct mitogenic agonists (23). The BCR appeared to specifically control PI-3K signaling in the cells, in that a key PI-3K target, Akt, was not phosphorylated in BCR neg cells on CpG stimulation (Fig.…”

Section: Inactivation Of Glycogen Synthase Kinase 3β Is Necessary Forsupporting

confidence: 50%

The B-cell antigen receptor integrates adaptive and innate immune signals

Otipoby

Waisman

Derudder

et al. 2015

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

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B cells respond to antigens by engagement of their B-cell antigen receptor (BCR) and of coreceptors through which signals from helper T cells or pathogen-associated molecular patterns are delivered. We show that the proliferative response of B cells to the latter stimuli is controlled by BCR-dependent activation of phosphoinositidyl 3-kinase (PI-3K) signaling. Glycogen synthase kinase 3β and Foxo1 are two PI-3K-regulated targets that play important roles, but to different extents, depending on the specific mitogen. These results suggest a model for integrating signals from the innate and the adaptive immune systems in the control of the B-cell immune response.BCR | B-cell proliferation | PI-3K | GSK3β | Foxo1

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“…On a global front, the analysis of high throughput experimental data has demonstrated more detailed understanding of large scale gene expressions in innate immune system (Ricciardi-Castagnoli and Granucci, 2002;Zhu et al, 2004Zhu et al, , 2006Hirotani et al, 2005;Nilsson et al, 2006). Despite this, we are yet to have a comprehensive view of TLR signaling events due to the lack of understanding in the interplay between the dynamics of gene regulatory networks and signaling pathways.…”

Section: )mentioning

confidence: 99%