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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.

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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.