ATF4 is an oxidative stress–inducible, prodeath transcription factor in neurons in vitro and in vivo

Burke Medical Research Institute, White Plains, NY 10605, USA.
Journal of Experimental Medicine (Impact Factor: 13.91). 06/2008; 205(5):1227-42. DOI: 10.1084/jem.20071460
Source: PubMed

ABSTRACT 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.

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    • "Many novel ER stress-inducible factors have been rapidly identified and characterized because ER stress has been implicated in the onset and progression of diseases, such as neurodegenerative and inflammations (Lange et al. 2008; Woo et al. 2009). Although several ER stress-inducible secretory factors, including CRELD2 (Maslen et al. 2006; Ortiz et al. 2005; Oh-hashi et al. 2011), mesencephalic astrocyte-derived neurotrophic factor (Mizobuchi et al. 2007) and nucleobindin 1 (Tsukumo et al. 2007), have been identified, the regulation of their intracellular transportation and secretion as well as their precise functions have not been elucidated well. "
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    Cell Biology and Toxicology 04/2014; 30(3). DOI:10.1007/s10565-014-9274-5 · 1.97 Impact Factor
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    • "Nevertheless, numerous reports also describe a pro-death role for ATF4 in neurons (Carracedo et al., 2006; Lange et al., 2008; Ohoka et al., 2005). In contrast to fibroblasts, ATF4 is a pro-apoptotic factor in neurons both in vitro and in vivo (Lange et al., 2008). A subset of ATF4-regulated genes, including TRB3 (Ohoka et al., 2005), promote neuronal apoptosis, suggesting that context-dependent ATF4 regulation may account for the divergent phenotypes observed. "
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    • "However, if overstressed, the failed recovery from ER stress turns on the UPR-activated cell death. Indeed, the contribution of UPR-activated cell death has been reported in ischemic stroke (Lange et al., 2008), multiple sclerosis (Lin et al., 2006), and Alzheimer's disease (Milhavet et al., 2002). One of the components of ER stress-mediated apoptotic pathway is the transcription factor, C/EBP (CCAAT enhancer binding protein) homologous protein (CHOP). "
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