scholarly journals Amino Acid Deprivation and Endoplasmic Reticulum Stress Induce Expression of Multiple Activating Transcription Factor-3 mRNA Species That, When Overexpressed in HepG2 Cells, Modulate Transcription by the Human Asparagine Synthetase Promoter

2003 ◽  
Vol 278 (40) ◽  
pp. 38402-38412 ◽  
Author(s):  
YuanXiang Pan ◽  
Hong Chen ◽  
Fai Siu ◽  
Michael S. Kilberg
Keyword(s):  
Endoplasmic Reticulum ◽  
Transcription Factor ◽  
Amino Acid ◽  
Endoplasmic Reticulum Stress ◽  
Hepg2 Cells ◽  
Asparagine Synthetase ◽  
Activating Transcription Factor 3 ◽  
Amino Acid Deprivation ◽  
Mrna Species ◽  
Activating Transcription Factor

scholarly journals Activating Transcription Factor 3 Is Integral to the Eukaryotic Initiation Factor 2 Kinase Stress Response

2004 ◽  
Vol 24 (3) ◽  
pp. 1365-1377 ◽  
Author(s):  
Hao-Yuan Jiang ◽  
Sheree A. Wek ◽  
Barbara C. McGrath ◽  
Dan Lu ◽  
Tsonwin Hai ◽  
...  
Keyword(s):  
Gene Expression ◽  
Transcription Factor ◽  
Amino Acid ◽  
Stress Response ◽  
Amino Acid Starvation ◽  
Initiation Factor ◽  
Activating Transcription Factor 3 ◽  
Eukaryotic Initiation Factor ◽  
Initiation Factor 2 ◽  
Activating Transcription Factor

ABSTRACT In response to environmental stress, cells induce a program of gene expression designed to remedy cellular damage or, alternatively, induce apoptosis. In this report, we explore the role of a family of protein kinases that phosphorylate eukaryotic initiation factor 2 (eIF2) in coordinating stress gene responses. We find that expression of activating transcription factor 3 (ATF3), a member of the ATF/CREB subfamily of basic-region leucine zipper (bZIP) proteins, is induced in response to endoplasmic reticulum (ER) stress or amino acid starvation by a mechanism requiring eIF2 kinases PEK (Perk or EIF2AK3) and GCN2 (EIF2AK4), respectively. Increased expression of ATF3 protein occurs early in response to stress by a mechanism requiring the related bZIP transcriptional regulator ATF4. ATF3 contributes to induction of the CHOP transcriptional factor in response to amino acid starvation, and loss of ATF3 function significantly lowers stress-induced expression of GADD34, an eIF2 protein phosphatase regulatory subunit implicated in feedback control of the eIF2 kinase stress response. Overexpression of ATF3 in mouse embryo fibroblasts partially bypasses the requirement for PEK for induction of GADD34 in response to ER stress, further supporting the idea that ATF3 functions directly or indirectly as a transcriptional activator of genes targeted by the eIF2 kinase stress pathway. These results indicate that ATF3 has an integral role in the coordinate gene expression induced by eIF2 kinases. Given that ATF3 is induced by a very large number of environmental insults, this study supports involvement of eIF2 kinases in the coordination of gene expression in response to a more diverse set of stress conditions than previously proposed.

FGF19 (fibroblast growth factor 19) as a novel target gene for activating transcription factor 4 in response to endoplasmic reticulum stress

2013 ◽  
Vol 450 (1) ◽  
pp. 221-229 ◽  
Author(s):  
Makoto Shimizu ◽  
Juan Li ◽  
Ryuto Maruyama ◽  
Jun Inoue ◽  
Ryuichiro Sato
Keyword(s):  
Endoplasmic Reticulum ◽  
Transcription Factor ◽  
Growth Factor ◽  
Endoplasmic Reticulum Stress ◽  
Fibroblast Growth ◽  
Activating Transcription Factor 4 ◽  
Fgf19 Expression ◽  
Activating Transcription Factor ◽  
Fibroblast Growth Factor 19 ◽  
Transcription Factor 4

FGF19 (fibroblast growth factor 19), expressed in the small intestine, acts as an enterohepatic hormone by mediating inhibitory effects on the bile acid synthetic pathway and regulating carbohydrate and lipid metabolism. In an attempt to identify novel agents other than bile acids that induce increased FGF19 expression, we found that some ER (endoplasmic reticulum) stress inducers were effective. When intestinal epithelial Caco-2 cells were incubated with thapsigargin, marked increases were observed in the mRNA and secreted protein levels of FGF19. This was not associated with the farnesoid X receptor. Reporter gene analyses using the 5′-promoter region of FGF19 revealed that a functional AARE (amino-acid-response element) was localized in this region, and this site was responsible for inducing its transcription through ATF4 (activating transcription factor 4), which is activated in response to ER stress. EMSAs (electrophoretic mobility-shift assays) and ChIP (chromatin immunoprecipitation) assays showed that ATF4 bound to this site and enhanced FGF19 expression. Overexpression of ATF4 in Caco-2 cells induced increased FGF19 mRNA expression, whereas shRNA (short hairpin RNA)-mediated depletion of ATF4 significantly attenuated a thapsigargin-induced increase in FGF19 mRNA.

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