title: NF-Y is essential for expression of the proapoptotic bim gene in sympathetic neurons.
abstract: 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.
authors.affiliation: Molecular Haematology and Cancer Biology Unit, Institute of Child Health, University College London, London, UK.
authors.forename: R
authors.initials: R
authors.lastname: Hughes
authors.forename: M
authors.initials: M
authors.lastname: Kristiansen
authors.forename: I
authors.initials: I
authors.lastname: Lassot
authors.forename: S
authors.initials: S
authors.lastname: Desagher
authors.forename: R
authors.initials: R
authors.lastname: Mantovani
authors.forename: J
authors.initials: J
authors.lastname: Ham
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D051017:Apoptosis Regulatory Proteins / Q000096:biosynthesis* / Q000235:genetics; D000072224:Bcl-2-Like Protein 11; D023081:CCAAT-Binding Factor / Q000235:genetics / Q000378:metabolism*; D002478:Cells, Cultured; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation / Q000502:physiology*; D008565:Membrane Proteins / Q000096:biosynthesis* / Q000235:genetics; D020932:Nerve Growth Factor / Q000235:genetics / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D009474:Neurons / Q000166:cytology / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000096:biosynthesis* / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D020218:Response Elements / Q000502:physiology; D013564:Sympathetic Nervous System / Q000166:cytology / Q000378:metabolism*; D014158:Transcription, Genetic / Q000502:physiology; D050880:p300-CBP Transcription Factors / Q000235:genetics / Q000378:metabolism
chemical_list: D051017:Apoptosis Regulatory Proteins; D000072224:Bcl-2-Like Protein 11; C000606778:Bcl2l11 protein, rat; D023081:CCAAT-Binding Factor; C499515:FOXO3 protein, rat; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; D011518:Proto-Oncogene Proteins; D020932:Nerve Growth Factor; D050880:p300-CBP Transcription Factors