Syk Is Required for p38 Activation and G2/M Arrest in B Cells Exposed to Oxidative Stress

Abstract

Syk has been demonstrated to play a crucial role in oxidative stress signaling in B cells. In this study, we have investigated the role of Syk in p38 activation and the regulation of cell-cycle progression upon oxidative stress. In B cells, p38 is activated by hydrogen peroxide (H₂O₂) stimulation. Syk is required for p38 activation following stimulation with 10-100 μM H₂O₂, but not with 1 mM H₂O₂. H₂O₂-induced p38 activation is abrogated in phospholipase C-γ2 (PLC-γ2)-deficient as well as Syk-deficient cells, suggesting that Syk activates p38 through PLC-γ2 upon H₂O₂ stimulation. Although stimulation with 20-100 μM H₂O₂ induces cellular apoptosis in B cells, pretreatment with SB203580, a p38-specific inhibitor, has no effect on H₂O₂-induced apoptosis. Flow cytometric analysis reveals that B cells exposed to 10-20 μM H₂O₂ exhibit cell-cycle profile of G2/M arrest, and pretreatment with SB203580 inhibits only a little H₂O₂-induced G2/M arrest. On the other hand, Syk-deficient cells show no induction of G2/M arrest following H₂O₂ stimulation. These findings indicate that Syk plays a role in the regulation of cell-cycle progression in G2/M phase via p38-dependent and -independent pathways after oxidative stress.