Regulation of neuronal survival and death by E2F-dependent gene repression and derepression.
Neuronal death induced by a variety of means requires participation of the E2F family of transcription factors. Here, we show that E2F acts as a gene silencer in neurons and that repression of E2F-responsive genes is required for neuronal survival. Moreover, neuronal death evoked by DNA damaging agents or trophic factor withdrawal is characterized by derepression of E2F-responsive genes. Such derepression, rather than direct E2F-promoted gene activation, is required for death. Among the genes that are derepressed in neurons subjected to DNA damage or trophic factor withdrawal are the transcription factors B- and C-myb. Overexpression of B- and C-myb is sufficient to evoke neuronal death. These findings support a model in which E2F-dependent gene repression and derepression play pivotal roles in neuronal survival and death, respectively.
Liu
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Department of Pathology, Taub Center for Alzheimer's Disease Research, Columbia University College of Physicians and Surgeons, New York, NY 10032, USA. dl345@columbia.edu
Greene
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LA
D000818:Animals; D017209:Apoptosis / Q000235:genetics*; D018797:Cell Cycle Proteins; D016923:Cell Death / Q000187:drug effects / Q000235:genetics; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics; D002540:Cerebral Cortex / Q000166:cytology / Q000187:drug effects / Q000502:physiology; D004268:DNA-Binding Proteins / Q000378:metabolism; D050684:E2F Transcription Factors; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology; D020868:Gene Silencing / Q000187:drug effects / Q000502:physiology; D020570:Genes, myb / Q000502:physiology; D020932:Nerve Growth Factor / Q000008:administration & dosage; D009474:Neurons / Q000187:drug effects / Q000502:physiology*; D016716:PC12 Cells; D051381:Rats; D015534:Trans-Activators / Q000378:metabolism; D014157:Transcription Factors / Q000502:physiology*; D015533:Transcriptional Activation
D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D050684:E2F Transcription Factors; D015534:Trans-Activators; D014157:Transcription Factors; D020932:Nerve Growth Factor