Modulation of E2F activity in primary mouse B cells following stimulation via surface IgM and CD40 receptors

Lam, Eric; Glassford, Janet; Sman, Jeroen van der; Banerji, Lolita; Pizzey, Arnold; Shaun, N.; Thomas, B. C.; Klaus, G. G. B.

doi:10.1002/(sici)1521-4141(199910)29:10<3380::aid-immu3380>3.0.co;2-c

Cited by 22 publications

(19 citation statements)

References 42 publications

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“…The CIP/KIP proteins are potent inhibitors of cyclin E-and Adependent CDK2, but also act as assembly factors for cyclin D-dependent kinases at low stoichiometric levels. In B cells, we have identified cyclin D2 as the key regulator of cell-cycle progression and pocket protein phosphorylation in response to BCR stimulation (Lam et al, 1999Banerji et al, 2001).…”

Section: Introductionmentioning

confidence: 79%

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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Section: Introductionmentioning

confidence: 79%

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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“…Protein products of 2 of these genes, Rb2/p130 and cyclin G2, have known growthsuppressive activity. [19][20][21][22] We used Q-PCR to verify PI3K-dependent down-regulation of p130 and cyclin G2 mRNA in murine B cells activated with anti-IgM ( Figure 1A). The genes encoding human Rb2/p130 and cyclin G2 have been shown to be direct targets of FOXO proteins.…”

Section: Resultsmentioning

confidence: 99%

Optimal B-cell proliferation requires phosphoinositide 3-kinase–dependent inactivation of FOXO transcription factors

Yusuf

Zhu

Kharas

et al. 2004

Blood

127

118

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Transcription factors of the Forkhead Box, class O (FOXO) family promote cell-cycle arrest and/or apoptosis in a variety of cell types. Mitogenic stimuli inactivate FOXO function by way of an evolutionarily conserved pathway involving the activation of phosphoinositide 3-kinase (PI3K) and its downstream effector, Akt. Although PI3K activation is required for B-lymphocyte proliferation, it is not known whether PI3K-dependent inactivation of FOXO proteins is important for cell-cycle progression and survival of these cells. Here, we show that B-cell receptor (BCR) engagement triggers PI3K-dependent phosphorylation and nuclear export of FOXO1. Furthermore, forced expression of PI3K-independent variants of FOXO1 or FOXO3a in activated B cells induces partial arrest in G1 phase of the cell cycle and increases apoptosis. These findings establish that FOXO inactivation is a functionally important consequence of PI3K signaling in primary B cells.

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“…29 were cultured in RPMI 1640 medium (Invitrogen) supplemented with 10% fetal calf serum, 2 mM glutamine, 100 units/ml penicillin/streptomycin and 50 M ␤-mercaptoethanol, and were stimulated with 10 g/ml of monoclonal anti-IgM (clone b.7.6 purchased from Cappel/ICN, Costa Mesa, CA). 293T cells were cultured in Dulbecco's modified Eagle's medium (Invitrogen) supplemented with 10% fetal calf serum, 2 mM glutamine, and 100 units/ml penicillin/streptomycin.…”

Section: Cell Culture Transfections and Cell Linesmentioning

confidence: 99%

“…Cell cycle analyses were performed by propidium iodide staining as described previously (29). Briefly, cells were washed with phosphatebuffered saline and fixed in 90% ethanol, 10% phosphate-buffered saline.…”

Section: Cell Cycle Analysismentioning

confidence: 99%

“…To this end, we sought to generate WEHI-231 and WEHI-bcl-XL cell lines expressing M2 protein (29). WEHI-231 and WEHI-bcl-XL were infected with Screening of an MHV-68 latently infected B-cell cDNA library with the latency-associated M2 protein Yeast cells (Y190) sequentially transformed with M2 in-frame with Gal4BD in pGBT9 (pGBT9-M2) and a spleen B-cell cDNA library in pACT2 (pACT2-cDNA/B220ϩ) were selected on ϪTrp, ϪLeu, ϪHis medium containing 50 mM 3-AT.…”

Section: M2 Interacts With Vav1 and Vav2mentioning

confidence: 99%

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Murine γ-Herpesvirus 68 Latency Protein M2 Binds to Vav Signaling Proteins and Inhibits B-cell Receptor-induced Cell Cycle Arrest and Apoptosis in WEHI-231 B Cells

Madureira

Matos

Soeiro

et al. 2005

Journal of Biological Chemistry

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The MHV-68 latent protein, M2, does not have homology to any known viral or cellular proteins, and its function is unclear. To define the role played by M2 during MHV-68 latency as well as the molecular mechanism involved, we used M2 as bait to screen a yeast two-hybrid mouse B-cell cDNA library. Vav1 was identified as an M2-interacting protein in two independent screenings. Subsequent yeast two-hybrid interaction studies showed that M2 also binds to Vav2, but not Vav3, and that three "PXXP " motifs located at the C terminus of M2 are important for this interaction. The interactions between M2 and Vav proteins were also confirmed in vivo in 293T and WEHI-231 B-cells by co-immunoprecipitation assays. Rac1/ GST-PAK "pull-down" experiments and Western blot analysis using a phospho-Vav antibody demonstrated that expression of M2 in WEHI-231 cells enhances Vav activity. We further showed in WEHI-231 cells that M2 expression promotes proliferation and survival and is associated with enhanced cyclin D2 and repressed p27 Kip1 , p130, and Bim expression. Taken together, these experiments suggest that M2 might have an important role in disseminating the latent virus during the establishment and maintenance of latency by modulating B-cell receptor-mediated signaling events through Vav to promote B-cell activation, proliferation, and survival.

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Modulation of E2F activity in primary mouse B cells following stimulation via surface IgM and CD40 receptors

Cited by 22 publications

References 42 publications

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

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

Optimal B-cell proliferation requires phosphoinositide 3-kinase–dependent inactivation of FOXO transcription factors

Murine γ-Herpesvirus 68 Latency Protein M2 Binds to Vav Signaling Proteins and Inhibits B-cell Receptor-induced Cell Cycle Arrest and Apoptosis in WEHI-231 B Cells

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