Amino Acid Deprivation Induces the Transcription Rate of the Human Asparagine Synthetase Gene through a Timed Program of Expression and Promoter Binding of Nutrient-responsive Basic Region/Leucine Zipper Transcription Factors as Well as Localized Histone Acetylation

Chen, Hong; Pan, Yuan Xiang; Dudenhausen, Elizabeth E.; Kilberg, Michael S.

doi:10.1074/jbc.m409173200

Cited by 176 publications

(270 citation statements)

References 37 publications

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“…Although we do not provide direct evidence for the activation IRE-1α signaling, c/EBP-β harbors an Xbp-1 response element in the genomic region corresponding to its 3′UTR, which induces c/EBP-β expression following amino acid starvation (Chen et al, 2004a). c/EBP-β also activates the asparagine synthetase (ASNS) promoter linking c/EBP-β with ER pathways controlling amino acid metabolism (Chen et al, 2004b). These reports suggest several potential mechanisms responsible for the observed induction of c/EBP-β in cortical neurons after hypoxic stress.…”

Section: Discussionmentioning

confidence: 59%

Loss of c/EBP-β activity promotes the adaptive to apoptotic switch in hypoxic cortical neurons

Halterman

Jesus

Rempe

et al. 2008

Molecular and Cellular Neuroscience

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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-β activity and was associated with markers of ER-stress including transient eIF2α phosphorylation, and the delayed induction of the bZIP proteins ATF4 and CHOP-10. Pretreatment with the eIF2α 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-β 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-β-mediated survival signals and activation of pro-death pathways originating from the endoplasmic reticulum.

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Section: Discussionmentioning

confidence: 59%

Loss of c/EBP-β activity promotes the adaptive to apoptotic switch in hypoxic cortical neurons

Halterman

Jesus

Rempe

et al. 2008

Molecular and Cellular Neuroscience

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“…To monitor ATF4 binding to the parkin gene, a ChIP assay was performed as previously described. 39 The ATF4 antibody was a rabbit polycolonal antibody. Enrichment of DNA at the parkin promoter region that contains the potential ATF4 binding site was analyzed with quantitative real-time PCR.…”

Section: Discussionmentioning

confidence: 99%

Parkin is transcriptionally regulated by ATF4: evidence for an interconnection between mitochondrial stress and ER stress

et al. 2010

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Loss of parkin function is responsible for the majority of autosomal recessive parkinsonism. Here, we show that parkin is not only a stress-protective, but also a stress-inducible protein. Both mitochondrial and endoplasmic reticulum (ER) stress induce an increase in parkin-specific mRNA and protein levels. The stress-induced upregulation of parkin is mediated by ATF4, a transcription factor of the unfolded protein response (UPR) that binds to a specific CREB/ATF site within the parkin promoter. Interestingly, c-Jun can bind to the same site, but acts as a transcriptional repressor of parkin gene expression. We also present evidence that mitochondrial damage can induce ER stress, leading to the activation of the UPR, and thereby to an upregulation of parkin expression. Vice versa, ER stress results in mitochondrial damage, which can be prevented by parkin. Notably, the activity of parkin to protect cells from stress-induced cell death is independent of the proteasome, indicating that proteasomal degradation of parkin substrates cannot explain the cytoprotective activity of parkin. Our study supports the notion that parkin has a role in the interorganellar crosstalk between the ER and mitochondria to promote cell survival under stress, suggesting that both ER and mitochondrial stress can contribute to the pathogenesis of Parkinson's disease.

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“…Chromatin Immunoprecipitation (ChIP)-The ChIP assay was performed according to our previously published protocol (12). The ATF4 antibody was the same as used for immunoblotting, whereas other antibodies were from Santa Cruz Biotechnology (Santa Cruz, CA) as follows: ATF3 (sc-188); C/EBP␤ (sc-150); RNA polymerase II (sc-899); TFIID (TBP) (sc-204); TFIIB (sc-274); normal rabbit IgG (sc-2027).…”

Section: Rna Isolation and Quantitative Rt-pcr-totalmentioning

confidence: 99%

“…Several ATF4 target genes have been identi-fied that contain a genomic sequence comprised of a half-site for C/EBP family members and a half-site for ATF members and will be referred to as a C/EBP-ATF response element (CARE) (11). Using the AAR as a model system to activate ATF4 synthesis, Chen et al (12) have proposed a self-limiting model that consists of two stages. During the first stage, increased ATF4 synthesis leads to enhanced binding to the CARE composite sites.…”

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confidence: 99%

Elevated ATF4 Expression, in the Absence of Other Signals, Is Sufficient for Transcriptional Induction via CCAAT Enhancer-binding Protein-activating Transcription Factor Response Elements

Shan

Örd

et al. 2009

Journal of Biological Chemistry

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Protein limitation in vivo or amino acid deprivation of cells in culture causes a signal transduction cascade consisting of activation of the kinase GCN2 (general control nonderepressible 2), phosphorylation of eukaryotic initiation factor 2, and increased synthesis of activating transcription factor (ATF) 4 by a translational control mechanism. In a self-limiting transcriptional program, ATF4 transiently activates a wide range of downstream target genes involved in transport, cellular metabolism, and other cell functions. Simultaneous activation of other signal transduction pathways by amino acid deprivation led to the question of whether or not the increased abundance of ATF4 alone was sufficient to trigger the transcriptional control mechanisms. Using 293 cells that ectopically express ATF4 in a tetracycline-inducible manner showed that ATF4 target genes were activated in the absence of amino acid deprivation. Ectopic expression of ATF4 alone resulted in effective recruitment of the general transcription machinery, but some reduction in histone modification was observed. These data document that ATF4 alone is sufficient to trigger the amino acid-responsive transcriptional control program. However, the absolute amount of ectopic ATF4 required to achieve the same degree of transcriptional activation observed after amino acid limitation was greater, suggesting that other factors may serve to enhance ATF4 function.

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Amino Acid Deprivation Induces the Transcription Rate of the Human Asparagine Synthetase Gene through a Timed Program of Expression and Promoter Binding of Nutrient-responsive Basic Region/Leucine Zipper Transcription Factors as Well as Localized Histone Acetylation

Cited by 176 publications

References 37 publications

Loss of c/EBP-β activity promotes the adaptive to apoptotic switch in hypoxic cortical neurons

Loss of c/EBP-β activity promotes the adaptive to apoptotic switch in hypoxic cortical neurons

Parkin is transcriptionally regulated by ATF4: evidence for an interconnection between mitochondrial stress and ER stress

Elevated ATF4 Expression, in the Absence of Other Signals, Is Sufficient for Transcriptional Induction via CCAAT Enhancer-binding Protein-activating Transcription Factor Response Elements

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