Multiple signaling pathways promote B lymphocyte stimulator dependent B-cell growth and survival
Department of Molecular Genetics and Microbiology
Animals; Atrophy; B-Cell Activating Factor; B-Lymphocytes; Cell Death; Cell Size; Cell Survival; Germinal Center; Glycolysis; Immunosuppressive Agents; Mice; Mice, Knockout; Neoplasm Proteins; Protein Kinases; Protein-Serine-Threonine Kinases; Proto-Oncogene Proteins; Proto-Oncogene Proteins c-akt; Proto-Oncogene Proteins c-bcl-2; Signal Transduction; Sirolimus
Life Sciences | Medicine and Health Sciences
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.
DOI of Published Version
Blood. 2008 Jan 15;111(2):750-60. Epub 2007 Oct 17. Link to article on publisher's site
Woodland, Robert T.; Fox, Casey J.; Schmidt, Madelyn R.; Hammerman, Peter S.; Opferman, Joseph T.; Korsmeyer, Stanley J.; Hilbert, David M.; and Thompson, Craig B., "Multiple signaling pathways promote B lymphocyte stimulator dependent B-cell growth and survival" (2007). Open Access Articles. 2060.