B-myb and C-myb play required roles in neuronal apoptosis evoked by nerve growth factor deprivation and DNA damage.
Activation of cell cycle elements plays a required role in neuronal apoptosis associated with both development and neurodegenerative disorders. We demonstrated previously that neuron survival requires gene repression mediated by the cell cycle transcription factor E2F (E2 promoter binding factor) and that apoptotic stimuli lead to de-repression of E2F-regulated genes and consequent death. However, the downstream mediators of such death have been unclear. The transcription factors B- and C-myb are E2F-regulated genes that are induced in neurons by apoptotic stimuli. Here, we examine the role of B- and C-myb induction in neuron death. Antisense and siRNA constructs that effectively block the upregulation of B- and C-myb provide substantial protection against death of cultured neuronal PC12 cells, sympathetic neurons, and cortical neurons elicited by either NGF withdrawal or DNA damage. There is also significant protection from death induced by direct E2F-dependent gene de-repression. Our findings thus establish required roles for B- and C-myb in neuronal apoptosis.
Liu
David X
DX
Department of Pathology, Center for Neurobiology and Behavior and Taub Center for Alzheimer's Disease Research, Columbia University College of Physicians and Surgeons, New York, New York 10032, USA. dl345@columbia.edu
Biswas
Subhas C
SC
Greene
Lloyd A
LA
D000818:Animals; D016375:Antisense Elements (Genetics) / Q000494:pharmacology; D017209:Apoptosis; D018797:Cell Cycle Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D002460:Cell Line; D002470:Cell Survival; D002478:Cells, Cultured; D004249:DNA Damage; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D015536:Down-Regulation; D050684:E2F Transcription Factors; D006801:Humans; D020932:Nerve Growth Factor / Q000502:physiology; D009474:Neurons / Q000166:cytology / Q000378:metabolism*; D016716:PC12 Cells; D020598:Proto-Oncogene Proteins c-myb / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*; D034741:RNA, Small Interfering / Q000494:pharmacology; D051381:Rats; D015534:Trans-Activators / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*; D014157:Transcription Factors / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism / Q000502:physiology*
D016375:Antisense Elements (Genetics); D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D050684:E2F Transcription Factors; C064352:MYBL2 protein, human; C498883:Mybl2 protein, rat; D020598:Proto-Oncogene Proteins c-myb; D034741:RNA, Small Interfering; D015534:Trans-Activators; D014157:Transcription Factors; D020932:Nerve Growth Factor