Gilley Jonathan, Coffer Paul J, Ham Jonathan
Molecular Haematology and Cancer Biology Unit, Camelia Botnar Laboratories, Institute of Child Health, University College London, 30 Guilford St., London WC1N 1EH, UK.
J Cell Biol. 2003 Aug 18;162(4):613-22. doi: 10.1083/jcb.200303026. Epub 2003 Aug 11.
Developing sympathetic neurons die by apoptosis when deprived of NGF. BIM, a BH3-only member of the BCL-2 family, is induced after NGF withdrawal in these cells and contributes to NGF withdrawal-induced death. Here, we have investigated the involvement of the Forkhead box, class O (FOXO) subfamily of Forkhead transcription factors in the regulation of BIM expression by NGF. We find that overexpression of FOXO transcription factors induces BIM expression and promotes death of sympathetic neurons in a BIM-dependent manner. In addition, we find that FKHRL1 (FOXO3a) directly activates the bim promoter via two conserved FOXO binding sites and that mutation of these sites abolishes bim promoter activation after NGF withdrawal. Finally, we show that FOXO activity contributes to the NGF deprivation-induced death of sympathetic neurons.
当被剥夺神经生长因子（NGF）时，发育中的交感神经元会通过凋亡死亡。BIM是BCL-2家族中仅含BH3结构域的成员，在这些细胞中NGF撤除后被诱导表达，并促使因NGF撤除引起的细胞死亡。在此，我们研究了叉头转录因子O类（FOXO）亚家族在NGF对BIM表达调控中的作用。我们发现，FOXO转录因子的过表达以BIM依赖的方式诱导BIM表达并促进交感神经元死亡。此外，我们发现FKHRL1（FOXO3a）通过两个保守的FOXO结合位点直接激活bim启动子，且这些位点的突变会消除NGF撤除后bim启动子的激活。最后，我们表明FOXO活性促使了因NGF剥夺引起的交感神经元死亡。
