ATF4 is an oxidative stress-inducible, prodeath transcription factor in neurons in vitro and in vivo.
Oxidative stress is pathogenic in neurological diseases, including stroke. The identity of oxidative stress-inducible transcription factors and their role in propagating the death cascade are not well known. In an in vitro model of oxidative stress, the expression of the bZip transcription factor activating transcription factor 4 (ATF4) was induced by glutathione depletion and localized to the promoter of a putative death gene in neurons. Germline deletion of ATF4 resulted in a profound reduction in oxidative stress-induced gene expression and resistance to oxidative death. In neurons, ATF4 modulates an early, upstream event in the death pathway, as resistance to oxidative death by ATF4 deletion was associated with decreased consumption of the antioxidant glutathione. Forced expression of ATF4 was sufficient to promote cell death and loss of glutathione. In ATF4(-/-) neurons, restoration of ATF4 protein expression reinstated sensitivity to oxidative death. In addition, ATF4(-/-) mice experienced significantly smaller infarcts and improved behavioral recovery as compared with wild-type mice subjected to the same reductions in blood flow in a rodent model of ischemic stroke. Collectively, these findings establish ATF4 as a redox-regulated, prodeath transcriptional activator in the nervous system that propagates death responses to oxidative stress in vitro and to stroke in vivo.
Lange
Philipp S
PS
Burke Medical Research Institute, White Plains, NY 10605, USA. phl2006@med.cornell.edu
Chavez
Juan C
JC
Pinto
John T
JT
Coppola
Giovanni
G
Sun
Chiao-Wang
CW
Townes
Tim M
TM
Geschwind
Daniel H
DH
Ratan
Rajiv R
RR
D051701:Activating Transcription Factor 4 / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D000818:Animals; D016923:Cell Death; D002467:Cell Nucleus / Q000502:physiology; D002470:Cell Survival; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000196:embryology / Q000502:physiology; D002843:Chromatin / Q000502:physiology; D004247:DNA / Q000235:genetics; D016350:Leucine Zippers; D051379:Mice; D018345:Mice, Knockout; D009474:Neurons / Q000166:cytology / Q000502:physiology*; D018384:Oxidative Stress / Q000502:physiology*; D010957:Plasmids; D016133:Polymerase Chain Reaction
C081452:Atf4 protein, mouse; D002843:Chromatin; D051701:Activating Transcription Factor 4; D004247:DNA