Induction of REDD1 gene expression in the liver in response to endoplasmic reticulum stress is mediated through a PERK, eIF2α phosphorylation, ATF4-dependent cascade

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Abstract

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.

Original languageEnglish (US)
Pages (from-to)485-489
Number of pages5
JournalBiochemical and Biophysical Research Communications
Volume427
Issue number3
DOIs
StatePublished - Oct 26 2012

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Phosphorylation
Endoplasmic Reticulum Stress
Gene expression
Liver
Gene Expression
Endoplasmic Reticulum
Protein Kinases
Cell Culture Techniques
Eukaryotic Initiation Factor-2
Unfolded Protein Response
Tunicamycin
Sirolimus
Cell culture
Transcriptional Activation
DNA Damage
Restoration
Liver Diseases
Hepatocytes
Homeostasis
Chemical activation

All Science Journal Classification (ASJC) codes

  • Biophysics
  • Biochemistry
  • Molecular Biology
  • Cell Biology

Cite this

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title = "Induction of REDD1 gene expression in the liver in response to endoplasmic reticulum stress is mediated through a PERK, eIF2α phosphorylation, ATF4-dependent cascade",
abstract = "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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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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