Bim is a direct target of a neuronal E2F-dependent apoptotic pathway.
The inappropriate expression/activation of cell-cycle-related molecules is associated with neuron death in many experimental paradigms and human neuropathologic conditions. However, the means whereby this links to the core apoptotic machinery in neurons have been unclear. Here, we show that the pro-apoptotic Bcl-2 homology 3 domain-only molecule Bcl-2 interacting mediator of cell death (Bim) is a target of a cell-cycle-related apoptotic pathway in neuronal cells. Induction of Bim in NGF-deprived cells requires expression and activity of cyclin-dependent kinase 4 (cdk4) and consequent de-repression of E2 promoter binding factor (E2F)-regulated genes including members of the myb transcription factor family. The Bim promoter contains two myb binding sites, mutation of which abolishes induction of a Bim promoter-driven reporter by NGF deprivation or E2F-dependent gene de-repression. NGF deprivation significantly increases endogenous levels of C-myb and its occupancy of the endogenous Bim promoter. These findings support a model in which apoptotic stimuli lead to cdk4 activation, consequent de-repression of E2F-regulated mybs, and induction of pro-apoptotic Bim.
Biswas
Subhas C
SC
Department of Pathology, Center for Neurobiology and Behavior, Taub Center for Alzheimer's Disease Research, Columbia University College of Physicians and Surgeons, New York, New York 10032, USA. scb34@columbia.edu
Liu
David X
DX
Greene
Lloyd A
LA
D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D051017:Apoptosis Regulatory Proteins / Q000235:genetics*; D000072224:Bcl-2-Like Protein 11; D017931:DNA Primers; D050684:E2F Transcription Factors / Q000502:physiology*; D049452:Green Fluorescent Proteins / Q000235:genetics; D008565:Membrane Proteins / Q000235:genetics*; D009414:Nerve Growth Factors / Q000172:deficiency / Q000502:physiology; D009474:Neurons / Q000166:cytology* / Q000502:physiology*; D016716:PC12 Cells; D016133:Polymerase Chain Reaction; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D034741:RNA, Small Interfering / Q000235:genetics; D051381:Rats; D014162:Transfection
D051017:Apoptosis Regulatory Proteins; C000606775:BCL2L11 protein, human; D000072224:Bcl-2-Like Protein 11; C000606778:Bcl2l11 protein, rat; D017931:DNA Primers; D050684:E2F Transcription Factors; D008565:Membrane Proteins; D009414:Nerve Growth Factors; D011518:Proto-Oncogene Proteins; D034741:RNA, Small Interfering; D049452:Green Fluorescent Proteins