Loss of c/EBP-beta activity promotes the adaptive to apoptotic switch in hypoxic cortical neurons.
Understanding the mechanisms governing the switch between hypoxia-induced adaptive and pathological transcription may reveal novel therapeutic targets for stroke. Using an in vitro hypoxia model that temporally separates these divergent responses, we found apoptotic signaling was preceded by a decline in c/EBP-beta activity and was associated with markers of ER-stress including transient eIF2alpha phosphorylation, and the delayed induction of the bZIP proteins ATF4 and CHOP-10. Pretreatment with the eIF2alpha phosphatase inhibitor salubrinal blocked the activation of caspase-3, indicating that ER-related stress responses are integral to this transition. Delivery of either full-length, or a transcriptionally inactive form of c/EBP-beta protected cultures from hypoxic challenge, in part by inducing levels of the anti-apoptotic protein Bcl-2. These data indicate that the pathologic response in cortical neurons induced by hypoxia involves both the loss of c/EBP-beta-mediated survival signals and activation of pro-death pathways originating from the endoplasmic reticulum.
Halterman
Marc W
MW
Department of Neurology, University of Rochester School of Medicine and Dentistry, Rochester, NY 14642, USA. marc_halterman@urmc.rochester.edu
De Jesus
Christopher
C
Rempe
David A
DA
Schor
Nina F
NF
Federoff
Howard J
HJ
D051701:Activating Transcription Factor 4 / Q000235:genetics / Q000378:metabolism; D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D050976:Basic-Leucine Zipper Transcription Factors / Q000235:genetics / Q000378:metabolism; D022782:CCAAT-Enhancer-Binding Protein-beta / Q000235:genetics* / Q000378:metabolism*; D015687:Cell Hypoxia / Q000502:physiology; D002470:Cell Survival / Q000502:physiology; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology; D004721:Endoplasmic Reticulum / Q000502:physiology; D020869:Gene Expression Profiling; D002534:Hypoxia, Brain / Q000378:metabolism / Q000503:physiopathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D009474:Neurons / Q000166:cytology* / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology; D051742:Transcription Factor CHOP / Q000235:genetics / Q000378:metabolism; D014158:Transcription, Genetic / Q000502:physiology
C081452:Atf4 protein, mouse; D050976:Basic-Leucine Zipper Transcription Factors; D022782:CCAAT-Enhancer-Binding Protein-beta; C497250:Ddit3 protein, mouse; D051701:Activating Transcription Factor 4; D051742:Transcription Factor CHOP