Bim regulates BCR-induced entry of B cells into the cell cycle.

BH3-only Bcl-2 homologs are key regulators of the intrinsic apoptotic pathway. In particular, Bim, is critical for mediating apoptosis of hematopoietic cells including B cells. While studies using Bcl-2 Tg mice have defined an important role for Bcl-2 in cell cycle control, the role of BH3-only proteins is less clear. Using Bim KO mice, we show that Bim is required for B cells to enter the cell cycle normally. Bim KO B cells had reduced cell division compared to WT B cells in response to BCR, TLR3 or TLR4 signaling, whereas Bim deficiency did not affect TLR9-induced B cell division. Cell cycle progression in BCR- and LPS-stimulated Bim KO B cells was blocked at the G0-G1 stage. BCR-induced p130 degradation and pRb hyperphosphorylation on Ser807/811, which are critical for G1 entry, were reduced in Bim KO compared to WT B cells. Likewise, BCR-induced p27(Kip1) degradation was decreased in Bim KO compared to WT B cells. These defects in BCR-induced cell cycle entry correlated with a proximal defect in BCR-mediated intracellular calcium release in Bim KO B cells. Our results suggest that the balance of pro- and anti-apoptotic Bcl-2 family proteins is critical for controlling both cell cycle progression and apoptosis in B cells.