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B Signaling Pathways Are Required for B Cell Antigen Receptor-Mediated Cyclin D2 Induction in Mature B Cells1
* Departments of Microbiology and Medicine, Boston University School of Medicine, Boston Medical Center, Boston, MA 02118; and
Department of Biology, Boston College, Chestnut Hill, MA 02467
Phosphatidylinositol 3-kinase (PI-3K) has been linked to promitogenic responses in splenic B cells following B cell Ag receptor (BCR) cross-linking; however identification of the signaling intermediates that link PI-3K activity to the cell cycle remains incomplete. We show that cyclin D2 induction is blocked by the PI-3K inhibitors wortmannin and LY294002, which coincides with impaired BCR-mediated mitogen-activated protein/extracellular signal-related kinase kinase (MEK)1/2 and p42/44ERK phosphorylation on activation residues. Cyclin D2 induction is virtually absent in B lymphocytes from mice deficient in the class IA PI-3K p85
regulatory subunit. In contrast to studies with PI-3K inhibitors, which inhibit all classes of PI-3Ks, the p85 regulatory subunit is not required for BCR-induced MEK1/2 and p42/44ERK phosphorylation, suggesting the contribution of another PI-3K family members in MEK1/2 and p42/44ERK activation. However, p85-/- splenic B cells are defective in BCR-induced I
B kinase 
and IB phosphorylation. We demonstrate that NF-B signaling is required for cyclin D2 induction via the BCR in normal B cells, implicating a possible link with the defective IB kinase and IB phosphorylation in p85-/- splenic B cells and their ability to induce cyclin D2. These results indicate that MEK1/2-p42/44ERK and NF-B pathways link PI-3K activity to Ag receptor-mediated cyclin D2 induction in splenic B cells.
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