NF-Y is essential for expression of the proapoptotic gene in sympathetic neurons

Jonathan Ham (1) , Rosie Hughes (1) , Mark Kristiansen (1) , Irina Lassot (1) , Solange Desagher (1) , Roberto Mantovani (1)

1 Molecular Haematology and Cancer Biology Unit

Neuronal apoptosis plays 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 expression is complex and remains incompletely understood. We report that a conserved inverted CCAAT box (ICB) in the rat promoter is bound by the heterotrimeric transcription factor NF-Y. Interestingly, NF-Y is required for 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 promoter. The amount of CBP/p300 bound to increases after NGF deprivation and inhibition of CBP/p300 activity reduces induction. Our results indicate that NF-Y cooperates with FOXO3a to recruit CBP/p300 to the promoter to form a stable multi-protein/DNA complex that activates transcription after survival factor withdrawal.

Mots clés: apoptosis; sympathetic neuron; Bim; NF-Y; CBP/p300

Jonathan Ham, Rosie Hughes, Mark Kristiansen, Irina Lassot, Solange Desagher, et al.. NF-Y is essential for expression of the proapoptotic gene in sympathetic neurons. Cell Death and Differentiation, 2010, ⟨10.1038/cdd.2010.166⟩. ⟨hal-00601171⟩