TY - JOUR
T1 - Induction of REDD1 gene expression in the liver in response to endoplasmic reticulum stress is mediated through a PERK, eIF2α phosphorylation, ATF4-dependent cascade
AU - Kimball, Scot R.
AU - Jefferson, Leonard S.
N1 - Funding Information:
The authors wish to thank Lydia Kutzler and Gina Dieter for help in performing the studies described herein. The studies were supported by NIH grants GM39277 (SRK) and DK13499 (LSJ). The funding agencies had no role in the design of the study, in the collection, analysis, or interpretation of the data, in the writing of the report, or in the decision to submit the article for publication.
PY - 2012/10/26
Y1 - 2012/10/26
N2 - Since the endoplasmic reticulum (ER) plays a vital role in hepatocyte function, it is not surprising that a variety of liver-related diseases are associated with ER stress. As in other tissues, ER stress in the liver leads to generation of the unfolded-protein response resulting in activation of a transcriptional program that promotes restoration of homeostasis within the lumen of the ER. Previous studies using cells in culture demonstrated that ER stress induces expression of REDD1 (regulated in development and DNA damage responses), a potent repressor of signaling through the protein kinase referred to as the mechanistic target of rapamycin in complex 1 (mTORC1). In the present study, the results from the cell culture experiments were extended to show that tunicamycin-mediated ER stress in the liver in vivo also induces REDD1 gene expression. Moreover, the induction of REDD1 gene expression was shown to require the protein kinase PERK and enhanced phosphorylation of its substrate, the α-subunit of eukaryotic initiation factor 2.
AB - Since the endoplasmic reticulum (ER) plays a vital role in hepatocyte function, it is not surprising that a variety of liver-related diseases are associated with ER stress. As in other tissues, ER stress in the liver leads to generation of the unfolded-protein response resulting in activation of a transcriptional program that promotes restoration of homeostasis within the lumen of the ER. Previous studies using cells in culture demonstrated that ER stress induces expression of REDD1 (regulated in development and DNA damage responses), a potent repressor of signaling through the protein kinase referred to as the mechanistic target of rapamycin in complex 1 (mTORC1). In the present study, the results from the cell culture experiments were extended to show that tunicamycin-mediated ER stress in the liver in vivo also induces REDD1 gene expression. Moreover, the induction of REDD1 gene expression was shown to require the protein kinase PERK and enhanced phosphorylation of its substrate, the α-subunit of eukaryotic initiation factor 2.
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U2 - 10.1016/j.bbrc.2012.09.074
DO - 10.1016/j.bbrc.2012.09.074
M3 - Article
C2 - 23000413
AN - SCOPUS:84867852387
SN - 0006-291X
VL - 427
SP - 485
EP - 489
JO - Biochemical and Biophysical Research Communications
JF - Biochemical and Biophysical Research Communications
IS - 3
ER -