E2F-1 regulates expression of FOXO1 and FOXO3a

Katrin Nowak, Katrin Killmer, Christine Gessner, Werner Lutz
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引用次数: 68

Abstract

E2F and FOXO transcription factors both play a role in neuronal apoptosis. In addition, both E2F-induced apoptosis and FOXO function are inhibited by the kinase Akt. We therefore tested whether FOXO is downstream of E2F-1 during neuronal apoptosis. We found that expression of endogenous FOXO1 and FOXO3a is induced by E2F-1. The presence of putative E2F binding sites in the promoters of both genes suggested that FOXO genes are direct targets of E2F-1. Indeed, a 4-hydroxytamoxifen activated E2F-1-ER fusion protein induced FOXO expression in the presence of cycloheximide. Moreover, E2F-1 activated the FOXO1 promoter in transient reporter assays, and E2F-1-ER as well as endogenous E2F bound to the FOXO1 promoter in vivo. Yet, E2F-1-mediated apoptosis of differentiated PC12 cells after withdrawal of NGF was not accompanied by changes in FOXO expression, indicating that no transcriptional induction of FOXO occurs during E2F-1-dependent neuronal apoptosis. In summary, our data identify E2F-1 as a first transcription factor regulating FOXO expression, providing a link between E2F and FOXO proteins in the control of cell fate.

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E2F-1调控FOXO1和FOXO3a的表达
E2F和FOXO转录因子均在神经元凋亡中发挥作用。此外,e2f诱导的细胞凋亡和FOXO功能均受到Akt激酶的抑制。因此,我们测试了FOXO在神经元凋亡过程中是否位于E2F-1的下游。我们发现内源性FOXO1和FOXO3a的表达受到E2F-1的诱导。在这两个基因的启动子中存在假定的E2F结合位点,这表明FOXO基因是E2F-1的直接靶点。事实上,在环己亚胺存在的情况下,4-羟基他莫昔芬激活E2F-1-ER融合蛋白诱导FOXO表达。此外,在瞬时报告基因试验中,E2F-1激活了FOXO1启动子,在体内,E2F-1- er和内源性E2F结合到FOXO1启动子上。然而,NGF停药后,e2f -1介导的分化PC12细胞凋亡不伴有FOXO表达的变化,这表明e2f -1依赖性神经元凋亡过程中不存在FOXO的转录诱导。总之,我们的数据确定E2F-1是调节FOXO表达的第一个转录因子,在控制细胞命运中提供了E2F和FOXO蛋白之间的联系。
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