Regulation of B‐cell entry into the cell cycle

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Abstract
Summary:B cells are induced to enter the cell cycle by stimuli including ligation of the B‐cell receptor (BCR) complex and Toll‐like receptor (TLR) agonists. This review discusses the contribution of several molecules, which act at distinct steps in B‐cell activation. The adapter molecule Bam32 (B‐lymphocyte adapter of 32 kDa) helps promote BCR‐induced cell cycle entry, while the secondary messenger superoxide has the opposite effect. Bam32 and superoxide may fine tune BCR‐induced activation by competing for the same limited resources, namely Rac1 and the plasma membrane phospholipid PI(3,4)P2. The co‐receptor CD22 can inhibit BCR‐induced proliferation by binding to novel CD22 ligands. Finally, regulators of B‐cell survival and death also play roles in B‐cell transit through the cell cycle. Caspase 6 negatively regulates CD40‐ and TLR‐dependent G1entry, while acting later in the cell cycle to promote S‐phase entry. Caspase 6 deficiency predisposes B cells to differentiate rather than proliferate after stimulation. Bim, a pro‐apoptotic Bcl‐2 family member, exerts a positive regulatory effect on cell cycle entry, which is opposed by Bcl‐2. New insights into what regulates B‐cell transit through the cell cycle may lead to thoughtful design of highly selective drugs that target pathogenic B cells.