Bruton's tyrosine kinase targets NF‐κB to the <i>bcl‐x</i> promoter via a mechanism involving phospholipase C‐γ2 following B cell antigen receptor engagement

Petro, James B.; Castro, Iris; Lowe, John; Khan, Wasif N.

doi:10.1016/s0014-5793(02)03623-2

Cited by 20 publications

(16 citation statements)

References 31 publications

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“…Btk has been shown to couple IB kinase, IB␣, and NF-B to the BCR, linking these key pathways (30); additionally, BTK directly regulates bcl-x expression by transcriptional control in response to BCR engagement (31).…”

Section: Resultsmentioning

confidence: 99%

Variability in the Degree of Expression of Phosphorylated IκBα in Chronic Lymphocytic Leukemia Cases With Nodal Involvement

Rodríguez

Martínez

Camacho

et al. 2004

Clinical Cancer Research

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Purpose: Based on previous preliminary observations, we hypothesize that the molecular and clinical variability of chronic lymphocytic leukemia (CLL) reflects differences in the degree of nuclear factor (NF)-B activation, as determined by the expression of phosphorylated IB␣ (p-IB␣).Experimental Design: The expression profile (mRNA and protein expression) was analyzed with the Centro Nacional de Investigaciones Oncológicas Oncochip, a cDNA microarray containing 6386 cancer-related genes, and a tissue microarray (

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Section: Resultsmentioning

confidence: 99%

Variability in the Degree of Expression of Phosphorylated IκBα in Chronic Lymphocytic Leukemia Cases With Nodal Involvement

Rodríguez

Martínez

Camacho

et al. 2004

Clinical Cancer Research

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“…Consistently, deletion of I B kinase results in a reduction of the mature FoB cell compartment (31,32). We have also shown that the transcription factor NF-B up-regulates the antiapoptotic protein Bcl-x L in response to BCR cross-linking in a BTK/PLC-␥2-dependent manner (33). Moreover, BCR-induced NF-B activation proceeds via protein kinase C␤ (PKC␤) (34 -36).…”

mentioning

confidence: 75%

“…It was recently proposed that DAG-dependent activation of conventional PKC␤ initiates a survival, but not a differentiation, program in response to BCR cross-linking through the activation of NF-B and induction of Bcl-x L (33,36). Thus, DAG at least in part may regulate T2 B cell survival via activation of the PKC pathway.…”

Section: Discussionmentioning

confidence: 99%

Transitional B Cell Fate Is Associated with Developmental Stage-Specific Regulation of Diacylglycerol and Calcium Signaling upon B Cell Receptor Engagement

Hoek¹,

Antony²,

Lowe³

et al. 2006

The Journal of Immunology

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Functional peripheral mature follicular B (FoB) lymphocytes are thought to develop from immature transitional cells in a BCR-dependent manner. We have previously shown that BCR cross-linking in vitro results in death of early transitional (T1) B cells, whereas late transitional (T2) B cells survive and display phenotypic characteristics of mature FoB cells. We now demonstrate that diacylglycerol (DAG), a lipid second messenger implicated in cell survival and differentiation, is produced preferentially in T2 compared with T1 B cells upon BCR cross-linking. Consistently, inositol 1,4,5-triphosphate is also produced preferentially in T2 compared with T1 B cells. Unexpectedly, the initial calcium peak appears similar in both T1 and T2 B cells, whereas sustained calcium levels are higher in T1 B cells. Pretreatment with 2-aminoethoxydiphenylborate, an inhibitor of inositol 1,4,5-triphosphate receptor-mediated calcium release, and verapamil, an inhibitor of L-type calcium channels, preferentially affects T1 B cells, suggesting that distinct mechanisms regulate calcium mobilization in each of the two transitional B cell subsets. Finally, BCR-mediated DAG production is dependent upon Bruton’s tyrosine kinase and phospholipase C-γ2, enzymes required for the development of FoB from T2 B cells. These results suggest that calcium signaling in the absence of DAG-mediated signals may lead to T1 B cell tolerance, whereas the combined action of DAG and calcium signaling is necessary for survival and differentiation of T2 into mature FoB lymphocytes.

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“…Previous gene targeting experiments have demonstrated that signals transduced via BCR promote survival of quiescent mature B cells (Lam et al, 1997). Other studies have demonstrated that Btk is required for the induction of the antiapoptosis Bcl-2 family member, Bcl-xL, via the transcription factor NF-kB in B cells (Petro et al, 2002). It is therefore likely that p85a and Btk participate in the formation of the multi-component B-cell signalosome complexes which are required for the expression of the survival protein Bcl-xL following BCR stimulation, and pertubation of this B-cell signalling axis contributes to defective Bcl-xL expression and thus compromised survival of B cells.…”

Section: Discussionmentioning

confidence: 99%

BCR targets cyclin D2 via Btk and the p85α subunit of PI3-K to induce cell cycle progression in primary mouse B cells

et al. 2003

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The p85a subunit of PI3-K and Btk are two crucial components of the B-cell receptor (BCR) signalling pathway. In the present study, we showed that primary splenic B cells from p85a null and xid (Btk-deficient) mice fail to induce cyclin D2 expression and enter early G1, but not S phase of the cell cycle in response to BCR engagement. Furthermore, these Btk or p85a null B cells displayed increased cell death compared with wild type following BCR engagement. These findings are further confirmed by studies showing that specific pharmacological inhibitors of Btk (LFM-A13), PI3-K (LY294002 and Wortmannin) and PLCc (U73122) also block cyclin D2 expression and S phase entry following BCR stimulation, as well as triggering apoptosis. Collectively, these data provide evidence for the concept that the B-cell signalosome (p85a, Btk, BLNK and PLCc) is involved in regulating cyclin D2 expression in response to BCR engagement. PKC and intracellular calcium are two major downstream effectors of the B-cell signalosome and can be activated by PMA and ionomycin, respectively. In small resting (G0) B cells, costimulation with PMA and ionomycin, but not PMA or ionomycin alone, induces cyclin D2 expression and cell-cycle progression. Consistent with this, we also showed that the BCR-mediated cyclin D2 induction could be abolished by pretreatment of resting B cells with specific inhibitors of capacitative Ca 2+ entry (SK&F 96365) or PKC (Go¨6850). Our present results lead us to propose a model in which the B-cell signalosome targets cyclin D2 via the Ca 2+ and PKCdependent signalling cascades to mediate cell-cycle progression in response to BCR engagement.

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Bruton's tyrosine kinase targets NF‐κB to the bcl‐x promoter via a mechanism involving phospholipase C‐γ2 following B cell antigen receptor engagement

Cited by 20 publications

References 31 publications

Variability in the Degree of Expression of Phosphorylated IκBα in Chronic Lymphocytic Leukemia Cases With Nodal Involvement

Variability in the Degree of Expression of Phosphorylated IκBα in Chronic Lymphocytic Leukemia Cases With Nodal Involvement

Transitional B Cell Fate Is Associated with Developmental Stage-Specific Regulation of Diacylglycerol and Calcium Signaling upon B Cell Receptor Engagement

BCR targets cyclin D2 via Btk and the p85α subunit of PI3-K to induce cell cycle progression in primary mouse B cells

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