title: mTOR-Dependent and Independent Survival Signaling by PI3K in B Lymphocytes.
abstract: Peripheral B lymphocyte survival requires the B cell receptor (BCR) and B cell activating factor (BAFF) binding to its receptor (BAFF-R). Deletion of the BCR, or its signal transducing chaperone Igβ, leads to rapid loss of mature B cells, indicating that signals initiated at the BCR are crucial for B cell survival. BAFF or BAFF-R deficiency also significantly reduces the numbers of mature B cells despite normal BCR expression. Together, these observations indicate that continued BCR and BAFF-R signaling are essential for the survival of mature resting B cells in the periphery. Here we demonstrate that tonic BCR signals up-regulate p100 (Nfkb2) as well as Mcl-1 protein expression at a post-transcriptional level via a PI3K-dependent pathway. p100 expression is mTOR-independent, whereas Mcl-1 expression is mTOR-dependent. BAFF treatment further elevated Mcl-1 levels by an mTOR-independent pathway, while consuming p100. Accordingly, Mcl-1 induction by BAFF is abrogated in Nfkb2-/- B cells. We propose that the cumulative effects of the BCR and BAFF-R signaling pathways increase Mcl-1 levels beyond the threshold required for B cell survival.
authors.affiliation: Gene Regulation Section, Laboratory of Molecular Biology and Immunology, National Institute on Aging, National Institutes of Health, Baltimore, Maryland, United States of America.
authors.forename: Mary
authors.initials: M
authors.lastname: Kaileh
authors.affiliation: Laboratory of Molecular Immunology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, United States of America.
authors.forename: Estefania
authors.initials: E
authors.lastname: Vazquez
authors.affiliation: Fox Chase Cancer Center, Division of Basic Science, Institute for Cancer Research, Philadelphia, Pennsylvania, United States of America.
authors.forename: Alexander W
authors.initials: AW
authors.lastname: MacFarlane
authors.affiliation: Fox Chase Cancer Center, Division of Basic Science, Institute for Cancer Research, Philadelphia, Pennsylvania, United States of America.
authors.forename: Kerry
authors.initials: K
authors.lastname: Campbell
authors.affiliation: Laboratory of Lymphocyte Differentiation, WPI Immunology Frontier Research Center, Osaka University, Suita, Osaka, Japan.
authors.forename: Tomohiro
authors.initials: T
authors.lastname: Kurosaki
authors.affiliation: Laboratory of Molecular Immunology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, United States of America.
authors.forename: Ulrich
authors.initials: U
authors.lastname: Siebenlist
authors.affiliation: Gene Regulation Section, Laboratory of Molecular Biology and Immunology, National Institute on Aging, National Institutes of Health, Baltimore, Maryland, United States of America.
authors.forename: Ranjan
authors.initials: R
authors.lastname: Sen
mesh_terms: D000818:Animals; D053264:B-Cell Activating Factor / Q000494:pharmacology; D053265:B-Cell Activation Factor Receptor / Q000378:metabolism; D001402:B-Lymphocytes / Q000166:cytology* / Q000378:metabolism; D002470:Cell Survival; D002478:Cells, Cultured; D051379:Mice; D064549:Myeloid Cell Leukemia Sequence 1 Protein / Q000235:genetics*; D052003:NF-kappa B p52 Subunit / Q000235:genetics*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D051562:Proto-Oncogene Proteins c-bcr / Q000378:metabolism; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*
chemical_list: D053264:B-Cell Activating Factor; D053265:B-Cell Activation Factor Receptor; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D052003:NF-kappa B p52 Subunit; D019869:Phosphatidylinositol 3-Kinases; D051562:Proto-Oncogene Proteins c-bcr; D058570:TOR Serine-Threonine Kinases; C579094:Mcl1 protein, mouse; C498207:Nfkb2 protein, mouse; C486662:Tnfrsf13c protein, mouse; C546843:mTOR protein, mouse; C496614:Bcr protein, mouse