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PMID:14978030

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Citation

Cullinan, SB and Diehl, JA (2004) PERK-dependent activation of Nrf2 contributes to redox homeostasis and cell survival following endoplasmic reticulum stress. J. Biol. Chem. 279:20108-17

Abstract

The accumulation of unfolded proteins elicits a cellular response that triggers both pro-survival and pro-apoptotic signaling events. PERK-dependent activation of NF-E2-related factor-2 (Nrf2) is critical for survival signaling during this response; however, the mechanism whereby Nrf2 confers a protective advantage to stressed cells remains to be defined. We now demonstrate that Nrf2 activation contributes to the maintenance of glutathione levels, which in turn functions as a buffer for the accumulation of reactive oxygen species during the unfolded protein response. The deleterious effects of Nrf2 or PERK deficiencies could be attenuated by the restoration of cellular glutathione levels or Nrf2 activity. In addition, the inhibition of reactive oxygen species production attenuated apoptotic induction following endoplasmic reticulum stress. Our data suggest that perturbations in cellular redox status sensitize cells to the harmful effects of endoplasmic reticulum stress, but that other factors are essential for apoptotic commitment.

Links

PubMed Online version:10.1074/jbc.M314219200

Keywords

Animals; Apoptosis; Blotting, Northern; Blotting, Southern; Cell Survival; Cells, Cultured; Culture Techniques; DNA-Binding Proteins/metabolism; Electrophoresis, Polyacrylamide Gel; Endoplasmic Reticulum/metabolism; Fibroblasts/metabolism; Glucose/metabolism; Glutathione/metabolism; Immunoblotting; Mice; Microscopy, Fluorescence; NF-E2-Related Factor 2; Oxidation-Reduction; Oxidative Stress; Plasmids/metabolism; Precipitin Tests; Protein Folding; Reactive Oxygen Species; Signal Transduction; Subcellular Fractions; Time Factors; Trans-Activators/metabolism; Transfection; eIF-2 Kinase/metabolism

Significance

Annotations

Gene product Qualifier GO Term Evidence Code with/from Aspect Extension Notes Status

MOUSE:MAFG

involved_in

GO:0010628: positive regulation of gene expression

ECO:0000316: genetic interaction evidence used in manual assertion

UniProtKB:Q60795

P

  • has_input:(UniProtKB:P35639)

Seeded From UniProt

complete

MOUSE:MAFG

part_of

GO:0005667: transcription regulator complex

ECO:0000304: author statement supported by traceable reference used in manual assertion

C

Seeded From UniProt

complete

MOUSE:NF2L2

located_in

GO:0005634: nucleus

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

MOUSE:NF2L2

located_in

GO:0005737: cytoplasm

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

MOUSE:NF2L2

involved_in

GO:0010628: positive regulation of gene expression

ECO:0000316: genetic interaction evidence used in manual assertion

UniProtKB:O54790

P

  • has_input:(UniProtKB:P35639)

Seeded From UniProt

complete

MOUSE:NF2L2

part_of

GO:0005667: transcription regulator complex

ECO:0000304: author statement supported by traceable reference used in manual assertion

C

Seeded From UniProt

complete

MOUSE:NF2L2

involved_in

GO:0045944: positive regulation of transcription by RNA polymerase II

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:NF2L2

involved_in

GO:0045454: cell redox homeostasis

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:E2AK3

involved_in

GO:0034976: response to endoplasmic reticulum stress

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:E2AK3

involved_in

GO:1903788: positive regulation of glutathione biosynthetic process

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:E2AK3

involved_in

GO:1900182: positive regulation of protein localization to nucleus

ECO:0000315: mutant phenotype evidence used in manual assertion

P

  • has_input:(UniProtKB:Q60795)

Seeded From UniProt

complete

MOUSE:NF2L2

involved_in

GO:0045454: cell redox homeostasis

ECO:0000315: mutant phenotype evidence used in manual assertion

P

part_of:(GO:0034976)

Seeded From UniProt

complete

MOUSE:NF2L2

involved_in

GO:0034976: response to endoplasmic reticulum stress

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:NF2L2

involved_in

GO:1903788: positive regulation of glutathione biosynthetic process

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:NF2L2

involved_in

GO:0042149: cellular response to glucose starvation

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:NF2L2

involved_in

GO:0045944: positive regulation of transcription by RNA polymerase II

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:NF2L2

part_of

GO:0005634: nucleus

ECO:0000314: direct assay evidence used in manual assertion

C

exists_during:(GO:0042149)

Seeded From UniProt

complete

MOUSE:NF2L2

part_of

GO:0005737: cytoplasm

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

MOUSE:NF2L2

involved_in

GO:0010628: positive regulation of gene expression

ECO:0000316: genetic interaction evidence used in manual assertion

UniProtKB:O54790

P

has_regulation_target:(UniProtKB:P35639)

Seeded From UniProt

complete

MOUSE:NF2L2

enables

GO:0046982: protein heterodimerization activity

ECO:0000304: author statement supported by traceable reference used in manual assertion

F

has_direct_input:(UniProtKB:O54790)

Seeded From UniProt

complete

Notes

See also

References

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