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

Glassford, Janet; Soeiro, Inês; Skarell, Sara M; Banerji, Lolita; Holman, Mary; Klaus, G. G. B.; Kadowaki, Takashi; Koyasu, Shigeo; Lam, Eric W.‐F.

doi:10.1038/sj.onc.1206425

Cited by 54 publications

(55 citation statements)

References 69 publications

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“…Previous research has suggested a connection between Btk and FOXO1. In quiescent cells, cyclin D2 expression is blocked by FOXO1 (35), whereas Btk is known to promote cyclin D2 expression in response to BCR cross-linking (27,28,36). We therefore asked whether BCR-mediated downregulation of FOXO1 may be mediated by Btk.…”

Section: Resultsmentioning

confidence: 99%

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: Resultsmentioning

confidence: 99%

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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“…In addition, calcium-dependent signaling is required for BCRinduced cyclin D expression, activation of CDK4/6 complexes and cell cycle progression [36]. Hence, we examined BCR-induced calcium release following labeling of WT or Bim KO B cells with the cell-permeable calcium-specific fluorophore, Indo-1AM.…”

Section: Anti-igm-mediated Intracellular Calcium Release Is Reduced Imentioning

confidence: 99%

Bim regulates BCR‐induced entry of B cells into the cell cycle

2007

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BH3-only Bcl-2 homologs are key regulators of the intrinsic apoptotic pathway. In particular, Bim, is critical for mediating apoptosis of hematopoietic cells including B cells. While studies using Bcl-2 Tg mice have defined an important role for Bcl-2 in cell cycle control, the role of BH3-only proteins is less clear. Using Bim KO mice, we show that Bim is required for B cells to enter the cell cycle normally. Bim KO B cells had reduced cell division compared to WT B cells in response to BCR, TLR3 or TLR4 signaling, whereas Bim deficiency did not affect TLR9-induced B cell division. Cell cycle progression in BCR-and LPS-stimulated Bim KO B cells was blocked at the G0-G1 stage. BCR-induced p130 degradation and pRb hyperphosphorylation on Ser807/811, which are critical for G1 entry, were reduced in Bim KO compared to WT B cells. Likewise, BCR-induced p27Kip1 degradation was decreased in Bim KO compared to WT B cells. These defects in BCR-induced cell cycle entry correlated with a proximal defect in BCRmediated intracellular calcium release in Bim KO B cells. Our results suggest that the balance of pro-and anti-apoptotic Bcl-2 family proteins is critical for controlling both cell cycle progression and apoptosis in B cells.

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“…To identify why cyclin D2 induction is defective in p85␣ Ϫ/Ϫ splenic B cells, we investigated the activation of NF-B signaling, which is known to regulate genes involved in cell proliferation and survival (61)(62)(63)(64). We found that BCR-induced IKK␤ and I B␣ phosphorylation is impaired in p85␣ Ϫ/Ϫ splenic B cells.…”

Section: Discussionmentioning

confidence: 99%

“…An important consideration is the downstream effector of PI-3K, Akt, which has been reported to directly interact with and phosphorylate IKK (65,66). However, the protein kinase C (PKC) inhibitor, Gö6983 blocks BCR-induce I B␣ degradation without affecting Akt phosphorylation, suggesting that PKC may represent an upstream regulator of IKK in splenic B cells (64,67). Of note, inhibition of BCR-mediated capacitative calcium entry and PKC activation blocks cyclin D2 induction (37,64).…”

Section: Discussionmentioning

confidence: 99%

“…However, the protein kinase C (PKC) inhibitor, Gö6983 blocks BCR-induce I B␣ degradation without affecting Akt phosphorylation, suggesting that PKC may represent an upstream regulator of IKK in splenic B cells (64,67). Of note, inhibition of BCR-mediated capacitative calcium entry and PKC activation blocks cyclin D2 induction (37,64). A direct role for PKC in NF-B signaling is supported by a recent report that BCR-induced IKK␣/IKK␤-I B␣ phosphorylation is impaired in PKC-␤ Ϫ/Ϫ splenic B cells (54).…”

Section: Discussionmentioning

confidence: 99%

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Phosphatidylinositol 3-Kinase-Dependent Mitogen-Activated Protein/Extracellular Signal-Regulated Kinase Kinase 1/2 and NF-κB Signaling Pathways Are Required for B Cell Antigen Receptor-Mediated Cyclin D2 Induction in Mature B Cells

Piatelli

Wardle

Blois

et al. 2004

The Journal of Immunology

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Phosphatidylinositol 3-kinase (PI-3K) has been linked to promitogenic responses in splenic B cells following B cell Ag receptor (BCR) cross-linking; however identification of the signaling intermediates that link PI-3K activity to the cell cycle remains incomplete. We show that cyclin D2 induction is blocked by the PI-3K inhibitors wortmannin and LY294002, which coincides with impaired BCR-mediated mitogen-activated protein/extracellular signal-related kinase kinase (MEK)1/2 and p42/44ERK phosphorylation on activation residues. Cyclin D2 induction is virtually absent in B lymphocytes from mice deficient in the class IA PI-3K p85α regulatory subunit. In contrast to studies with PI-3K inhibitors, which inhibit all classes of PI-3Ks, the p85α regulatory subunit is not required for BCR-induced MEK1/2 and p42/44ERK phosphorylation, suggesting the contribution of another PI-3K family members in MEK1/2 and p42/44ERK activation. However, p85α−/− splenic B cells are defective in BCR-induced IκB kinase β and IκBα phosphorylation. We demonstrate that NF-κB signaling is required for cyclin D2 induction via the BCR in normal B cells, implicating a possible link with the defective IκB kinase β and IκBα phosphorylation in p85α−/− splenic B cells and their ability to induce cyclin D2. These results indicate that MEK1/2-p42/44ERK and NF-κB pathways link PI-3K activity to Ag receptor-mediated cyclin D2 induction in splenic B cells.

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

Cited by 54 publications

References 69 publications

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

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

Bim regulates BCR‐induced entry of B cells into the cell cycle

Phosphatidylinositol 3-Kinase-Dependent Mitogen-Activated Protein/Extracellular Signal-Regulated Kinase Kinase 1/2 and NF-κB Signaling Pathways Are Required for B Cell Antigen Receptor-Mediated Cyclin D2 Induction in Mature B Cells

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