Phosphorylation of eIF2α via the general control kinase, GCN2, modulates the ability of renal medullary cells to survive high urea stress

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Abstract

The phosphorylation of the α-subunit of the eukaryotic translation initiation factor 2 (eIF2 α) occurs under many stress conditions in mammalian cells and is mediated by one of four eIF2 α kinases: PERK, PKR, GCN2, and HRI. Cells of the renal medulla are regularly exposed to fluctuating concentrations of urea and sodium, the extracellular solutes responsible for the high osmolality in the renal medulla, and thus the kidneys ability to concentrate the urine in times of dehydration. Urea stress is known to initiate molecular responses that diverge from those seen in response to hypertonic stress (NaCl). We show that urea-inducible GCN2 activation initiates the phosphorylation of eIF2 α and the downstream increase of activating transcription factor 3 (ATF3). Loss of GCN2 sensitized cells to urea stress, increasing the expression of activated caspase-3 and decreasing cell survival. Loss of GCN2 ablated urea-induced phosphorylation of eIF2 α and reduced the expression of ATF3.

Original languageEnglish (US)
JournalAmerican Journal of Physiology - Renal Physiology
Volume301
Issue number6
DOIs
StatePublished - Dec 2011

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Eukaryotic Initiation Factor-2
Eukaryotic Initiation Factors
Urea
Phosphotransferases
Phosphorylation
Kidney
Activating Transcription Factor 3
Kidney Medulla
Osmotic Pressure
Dehydration
Caspase 3
Osmolar Concentration
Cell Survival
Sodium
Urine

Keywords

  • Activating transcription factor 3
  • Collecting duct
  • Osmotic stress

ASJC Scopus subject areas

  • Physiology
  • Urology

Cite this

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title = "Phosphorylation of eIF2α via the general control kinase, GCN2, modulates the ability of renal medullary cells to survive high urea stress",
abstract = "The phosphorylation of the α-subunit of the eukaryotic translation initiation factor 2 (eIF2 α) occurs under many stress conditions in mammalian cells and is mediated by one of four eIF2 α kinases: PERK, PKR, GCN2, and HRI. Cells of the renal medulla are regularly exposed to fluctuating concentrations of urea and sodium, the extracellular solutes responsible for the high osmolality in the renal medulla, and thus the kidneys ability to concentrate the urine in times of dehydration. Urea stress is known to initiate molecular responses that diverge from those seen in response to hypertonic stress (NaCl). We show that urea-inducible GCN2 activation initiates the phosphorylation of eIF2 α and the downstream increase of activating transcription factor 3 (ATF3). Loss of GCN2 sensitized cells to urea stress, increasing the expression of activated caspase-3 and decreasing cell survival. Loss of GCN2 ablated urea-induced phosphorylation of eIF2 α and reduced the expression of ATF3.",
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T1 - Phosphorylation of eIF2α via the general control kinase, GCN2, modulates the ability of renal medullary cells to survive high urea stress

AU - Cai, Qi

AU - Brooks, Heddwen L

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N2 - The phosphorylation of the α-subunit of the eukaryotic translation initiation factor 2 (eIF2 α) occurs under many stress conditions in mammalian cells and is mediated by one of four eIF2 α kinases: PERK, PKR, GCN2, and HRI. Cells of the renal medulla are regularly exposed to fluctuating concentrations of urea and sodium, the extracellular solutes responsible for the high osmolality in the renal medulla, and thus the kidneys ability to concentrate the urine in times of dehydration. Urea stress is known to initiate molecular responses that diverge from those seen in response to hypertonic stress (NaCl). We show that urea-inducible GCN2 activation initiates the phosphorylation of eIF2 α and the downstream increase of activating transcription factor 3 (ATF3). Loss of GCN2 sensitized cells to urea stress, increasing the expression of activated caspase-3 and decreasing cell survival. Loss of GCN2 ablated urea-induced phosphorylation of eIF2 α and reduced the expression of ATF3.

AB - The phosphorylation of the α-subunit of the eukaryotic translation initiation factor 2 (eIF2 α) occurs under many stress conditions in mammalian cells and is mediated by one of four eIF2 α kinases: PERK, PKR, GCN2, and HRI. Cells of the renal medulla are regularly exposed to fluctuating concentrations of urea and sodium, the extracellular solutes responsible for the high osmolality in the renal medulla, and thus the kidneys ability to concentrate the urine in times of dehydration. Urea stress is known to initiate molecular responses that diverge from those seen in response to hypertonic stress (NaCl). We show that urea-inducible GCN2 activation initiates the phosphorylation of eIF2 α and the downstream increase of activating transcription factor 3 (ATF3). Loss of GCN2 sensitized cells to urea stress, increasing the expression of activated caspase-3 and decreasing cell survival. Loss of GCN2 ablated urea-induced phosphorylation of eIF2 α and reduced the expression of ATF3.

KW - Activating transcription factor 3

KW - Collecting duct

KW - Osmotic stress

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