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

被引:117
作者
Yusuf, I [1 ]
Zhu, XC [1 ]
Kharas, MG [1 ]
Chen, J [1 ]
Fruman, DA [1 ]
机构
[1] Univ Calif Irvine, Dept Mol Biol & Biochem, Irvine, CA 92697 USA
关键词
D O I
10.1182/blood-2003-09-3071
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
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.
引用
收藏
页码:784 / 787
页数:4
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