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B Cell Receptor Signaling Down-Regulates Forkhead Box Transcription Factor Class O 1 mRNA Expression via Phosphatidylinositol 3-Kinase and Bruton’s Tyrosine Kinase¹

Department of Internal Medicine, Division of Rheumatology, University of Texas Southwestern Medical Center, Dallas, TX 75390

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)2 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 PLC2. 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/PLC2 pathway were used to define the mechanism by which Btk signaling inhibits FOXO1 expression. The protein kinase C 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/PLC2 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.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Copyright © 2007 by The American Association of Immunologists, Inc. 0022-1767/07/$2.00

¹ This work was supported by National Institutes of Health Grant AI049248 (to A.B.S.), National Institutes of Health Training Grant 2 T32 AI 005284-28 (to R.M.H.), and the University of Texas Southwestern Summer Undergraduate Research Fellowship Program (to J.N.B. and W.A.N.). A.B.S. is a Southwestern Medical Foundation Scholar in Biomedical Research.

² Address correspondence and reprint requests to Dr. Anne B. Satterthwaite, Department of Internal Medicine, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75390-8884. E-mail address: anne.satterthwaite{at}utsouthwestern.edu

³ Abbreviations used in this paper: FOXO1, forkhead box transcription factor class O 1; BLNK, B cell linker protein; Btk, Bruton’s tyrosine kinase; CsA, cyclosporin A; Ct, comparative threshold cycle; PIP5K, phosphatidylinositol-4-phosphate 5-kinase; PKC, protein kinase C; PLC, phospholipase C; Q-PCR, quantitative real-time PCR.

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