title: Optimal B-cell proliferation requires phosphoinositide 3-kinase-dependent inactivation of FOXO transcription factors.
abstract: 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 (PI3K) and its downstream effector, Akt. Although PI3K activation is required for B-lymphocyte proliferation, it is not known whether PI3K-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 PI3K-dependent phosphorylation and nuclear export of FOXO1. Furthermore, forced expression of PI3K-independent variants of FOXO1 or FOXO3a in activated B cells induces partial arrest in G1 phase of the cell cycle and increases apoptosis. These findings establish that FOXO inactivation is a functionally important consequence of PI3K signaling in primary B cells.
authors.affiliation: Department of Molecular Biology and Biochemistry, University of California, Irvine, 92697-3900, USA.
authors.forename: Isharat
authors.initials: I
authors.lastname: Yusuf
authors.forename: Xiaocui
authors.initials: X
authors.lastname: Zhu
authors.forename: Michael G
authors.initials: MG
authors.lastname: Kharas
authors.forename: Jing
authors.initials: J
authors.lastname: Chen
authors.forename: David A
authors.initials: DA
authors.lastname: Fruman
mesh_terms: D000818:Animals; D001402:B-Lymphocytes / Q000166:cytology / Q000276:immunology*; D002453:Cell Cycle; D008213:Lymphocyte Activation; D051379:Mice; D008807:Mice, Inbred BALB C; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology; D014157:Transcription Factors / Q000235:genetics* / Q000276:immunology
chemical_list: D014157:Transcription Factors; D019869:Phosphatidylinositol 3-Kinases