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Blood, 15 January 2008, Vol. 111, No. 2, pp. 750-760. Prepublished online as a Blood First Edition Paper on October 17, 2007; DOI 10.1182/blood-2007-03-077222. This Article Full Text (PDF) Supplemental Figures All Versions of this Article: blood-2007-03-077222v1 111/2/750    most recent Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Woodland, R. T Articles by Thompson, C. B Search for Related Content PubMed PubMed Citation Articles by Woodland, R. T Articles by Thompson, C. B Social Bookmarking                   What's this?  Previous Article  |  Next Article  Submitted March 5, 2007 Accepted October 9, 2007 Multiple signaling pathways promote B lymphocyte stimulator (BLyS)-dependent B cell growth and survival Robert T Woodland*, Casey J Fox, Madelyn R Schmidt, Peter S Hammerman, Joseph T Opferman, Stanley J Korsmeyer, David M Hilbert, and Craig B Thompson Dept of Molecular Genetics and Microbiology, and the Immunology and Virology Program, University of Massachusetts Medical School, Worcester, MA, United States Abramson Family Cancer Research Institute, University of Pennsylvania, Philadelphia, PA, United States Howard Hughes Medical Institute, Harvard Medical School, Dana Farber Cancer Center, Boston, MA, United States Human Genome Sciences, Inc, Rockville, MD, United States * Corresponding author; email: robert.woodland{at}umassmed.edu. We investigated the mechanism by which BLyS / BAFF, a TNF superfamily ligand, promotes B cell survival and resistance to atrophy. BLyS stimulation activates two independent signaling pathways, Akt/mTOR and Pim 2, associated with cell growth and survival. BLyS blocks the cell volume loss (atrophy) that freshly isolated B cells normally undergo when maintained in vitro while concurrently increasing glycolytic activity and overall metabolism. This atrophy resistance requires Akt/mTOR. We used a genetic approach to resolve the contributions of Akt/mTOR and Pim kinase pathways to BLyS-mediated survival. Pim 2 deficient B cells are readily protected from death by BLyS stimulation but this protection is completely abrogated by treatment with the mTOR inhibitor rapamycin. Furthermore, rapamycin treatment in vivo significantly reduces both follicular and marginal zone B cells in Pim deficient but not normal hosts. BLyS-dependent survival requires the anti-apoptotic protein Mcl-1. Mcl-1 protein levels rise and fall in response to BLyS addition and withdrawal respectively and conditional deletion of the mcl-1 gene renders B cells refractory to BLyS-mediated protection. As BlyS is required for the normal homeostasis of all B cells, these data suggest a therapeutic strategy simultaneously inhibiting mTOR and Pim 2 could potentially target pathogenic B cells. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: K. L. Hoek, G. Carlesso, E. S. Clark, and W. N. Khan Absence of Mature Peripheral B Cell Populations in Mice with Concomitant Defects in B Cell Receptor and BAFF-R Signaling J. Immunol., November 1, 2009; 183(9): 5630 - 5643. [Abstract] [Full Text] [PDF] W. N. Khan B Cell Receptor and BAFF Receptor Signaling Regulation of B Cell Homeostasis J. Immunol., September 15, 2009; 183(6): 3561 - 3567. [Abstract] [Full Text] [PDF] M. Gupta, S. R. Dillon, S. C. Ziesmer, A. L. Feldman, T. E. Witzig, S. M. Ansell, J. R. Cerhan, and A. J. Novak A proliferation-inducing ligand mediates follicular lymphoma B-cell proliferation and cyclin D1 expression through phosphatidylinositol 3-kinase-regulated mammalian target of rapamycin activation Blood, May 21, 2009; 113(21): 5206 - 5216. [Abstract] [Full Text] [PDF] A. Meyer-Bahlburg, A. D. Bandaranayake, S. F. Andrews, and D. J. Rawlings Reduced c-myc Expression Levels Limit Follicular Mature B Cell Cycling in Response to TLR Signals J. Immunol., April 1, 2009; 182(7): 4065 - 4075. [Abstract] [Full Text] [PDF] J. E. Crowley, J. E. Stadanlick, J. C. Cambier, and M. P. Cancro Fc{gamma}RIIB signals inhibit BLyS signaling and BCR-mediated BLyS receptor up-regulation Blood, February 12, 2009; 113(7): 1464 - 1473. [Abstract] [Full Text] [PDF] S. J. Tabrizi, H. Niiro, M. Masui, G. Yoshimoto, T. Iino, Y. Kikushige, T. Wakasaki, E. Baba, S. Shimoda, T. Miyamoto, et al. T Cell Leukemia/Lymphoma 1 and Galectin-1 Regulate Survival/Cell Death Pathways in Human Naive and IgM+ Memory B Cells through Altering Balances in Bcl-2 Family Proteins J. Immunol., February 1, 2009; 182(3): 1490 - 1499. [Abstract] [Full Text] [PDF] V. Gandhi, K. Balakrishnan, and L. S. Chen Mcl-1: the 1 in CLL Blood, November 1, 2008; 112(9): 3538 - 3540. [Full Text] [PDF] K. L. Otipoby, Y. Sasaki, M. Schmidt-Supprian, A. Patke, R. Gareus, M. Pasparakis, A. Tarakhovsky, and K. Rajewsky BAFF activates Akt and Erk through BAFF-R in an IKK1-dependent manner in primary mouse B cells PNAS, August 26, 2008; 105(34): 12435 - 12438. [Abstract] [Full Text] [PDF]

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