Journal
CELL DEATH AND DIFFERENTIATION
Volume 18, Issue 6, Pages 937-947Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/cdd.2010.166
Keywords
apoptosis; sympathetic neuron; Bim; NF-Y; CBP/p300
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Funding
- Wellcome Trust [057700]
- Associazione Italiana Ricerca Cancro (AIRC)
- Centre National de la Recherche Scientifique (CNSR)
- Institut National de la Sante et de la Recherche Medicale (INSERM)
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Neuronal apoptosis has a major role during development and aberrant apoptosis contributes to the pathology of certain neurological conditions. Studies with nerve growth factor (NGF)-dependent sympathetic neurons have provided important insights into the molecular mechanisms of neuronal apoptosis and the signalling pathways that regulate the cell death programme in neurons. The BH3-only protein Bim is a critical mediator of apoptosis in many cell types and in sympathetic neurons is required for NGF withdrawal-induced death. However, regulation of bim expression is complex and remains incompletely understood. We report that a conserved inverted CCAAT box (ICB) in the rat bim promoter is bound by the heterotrimeric transcription factor NF-Y. Interestingly, NF-Y is required for bim promoter activity and its induction following NGF withdrawal. We demonstrate that NF-Y activity is essential for endogenous Bim expression and contributes to NGF withdrawal-induced death. Furthermore, we find that the transcriptional coactivators CBP and p300 interact with NF-Y and FOXO3a and bind to this region of the bim promoter. The amount of CBP/p300 bound to bim increases after NGF deprivation and inhibition of CBP/p300 activity reduces bim induction. Our results indicate that NF-Y cooperates with FOXO3a to recruit CBP/p300 to the bim promoter to form a stable multi-protein/DNA complex that activates bim transcription after survival factor withdrawal. Cell Death and Differentiation (2011) 18, 937-947; doi:10.1038/cdd.2010.166; published online 17 December 2010
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