Optimal B-cell proliferation requires phosphoinositide 3-kinase-dependent inactivation of FOXO transcription factors

Transcription factors of the Forkhead Box, class O (FOXO) family promote cell-cycle arrest and/or apoptosis in a variety of cell types. Mitogenic stimuli inactivate FOXO function by way of an evolutionarily conserved pathway involving the activation of phosphoinositide 3-kinase (Pl3K) and its downstream effector, Akt. Although Pl3K activation is required for B-lympho-cyte proliferation, it is not known whether Pl3K-dependent inactivation of FOXO proteins is important for cell-cycle progression and survival of these cells. Here, we show that B-cell receptor (BCR) engagement triggers Pl3K-dependent phosphorylation and nuclear export of FOXO1. Furthermore, forced expression of Pl3K-independent variants of FOXO1 or FOXO3a in activated B cells induces partial arrest in G, phase of the cell cycle and increases apoptosis. These findings establish that FOXO inactivation is a functionally important consequence of Pl3K signaling in primary B cells.