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Published online 11 August 2003. doi:10.1083/jcb.200303026
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© The Rockefeller University Press, 0021-9525/2003/8/613 $5.00
The Journal of Cell Biology, Volume 162, Number 4, 613-622

Article

FOXO transcription factors directly activate bim gene expression and promote apoptosis in sympathetic neurons



Jonathan Gilley1, Paul J. Coffer2 and Jonathan Ham1

1 Molecular Haematology and Cancer Biology Unit, Camelia Botnar Laboratories, Institute of Child Health, University College London, London WC1N 1EH, UK
2 Department of Pulmonary Diseases, University Medical Center, 3584 CX Utrecht, Netherlands

Address correspondence to Jonathan Ham, Molecular Haematology and Cancer Biology Unit, Camelia Botnar Laboratories, Institute of Child Health, University College London, 30 Guilford St., London WC1N 1EH, UK. Tel.: 020-7905-2294. Fax: 020-7813-8100. email: J.Ham{at}ich.ucl.ac.uk

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.

Key Words: sympathetic neurons; NGF; promoter; BH3-only proteins; Forkhead transcription factors

Abbreviations used in this paper: DBD, DNA-binding domain; FasL, Fas ligand; FOXO, Forkhead box, class O; JNK, c-Jun NH2-terminal kinase; PAC, P1 artificial chromosome; PCD, programmed cell death; PI3-K, phosphatidylinositol 3-kinase; SCG, superior cervical ganglia; SGK, serum and glucocorticoid–induced kinase.


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