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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 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 Citation Map 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 CrossRef Google Scholar Articles by Woodland, R. T. Articles by Thompson, C. B. PubMed PubMed Citation Articles by Woodland, R. T. Articles by Thompson, C. B. Related Collections Apoptosis Cell Cycle Signal Transduction Immunobiology Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  IMMUNOBIOLOGY Multiple signaling pathways promote B lymphocyte stimulator–dependent B-cell growth and survival Robert T. Woodland1, Casey J. Fox2, Madelyn R. Schmidt1, Peter S. Hammerman2, Joseph T. Opferman3, Stanley J. Korsmeyer3, David M. Hilbert4, and Craig B. Thompson2 1 Department of Molecular Genetics and Microbiology and the Immunology and Virology Program, University of Massachusetts Medical School, Worcester; 2 Abramson Family Cancer Research Institute, University of Pennsylvania, Philadelphia; 3 Howard Hughes Medical Institute, Harvard Medical School, Dana-Farber Cancer Center, Boston, MA; and 4 Human Genome Sciences, Rockville, MD We investigated the mechanism by which B lymphocyte stimulator (BLyS)/BAFF, a tumor necrosis factor superfamily ligand, promotes B-cell survival and resistance to atrophy. BLyS stimulation activates 2 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 healthy hosts. BLyS-dependent survival requires the antiapoptotic 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. Because BlyS is required for the normal homeostasis of all B cells, these data suggest a therapeutic strategy simultaneously inhibiting mTOR and Pim 2 could target pathogenic B cells. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

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