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PMID:17015834

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Citation

Clements, CM, McNally, RS, Conti, BJ, Mak, TW and Ting, JP (2006) DJ-1, a cancer- and Parkinson's disease-associated protein, stabilizes the antioxidant transcriptional master regulator Nrf2. Proc. Natl. Acad. Sci. U.S.A. 103:15091-6

Abstract

DJ-1/PARK7, a cancer- and Parkinson's disease (PD)-associated protein, protects cells from toxic stresses. However, the functional basis of this protection has remained elusive. We found that loss of DJ-1 leads to deficits in NQO1 [NAD(P)H quinone oxidoreductase 1], a detoxification enzyme. This deficit is attributed to a loss of Nrf2 (nuclear factor erythroid 2-related factor), a master regulator of antioxidant transcriptional responses. DJ-1 stabilizes Nrf2 by preventing association with its inhibitor protein, Keap1, and Nrf2's subsequent ubiquitination. Without intact DJ-1, Nrf2 protein is unstable, and transcriptional responses are thereby decreased both basally and after induction. This effect of DJ-1 on Nrf2 is present in both transformed lines and primary cells across human and mouse species. DJ-1's effect on Nrf2 and subsequent effects on antioxidant responses may explain how DJ-1 affects the etiology of both cancer and PD, which are seemingly disparate disorders. Furthermore, this DJ-1/Nrf2 functional axis presents a therapeutic target in cancer treatment and justifies DJ-1 as a tumor biomarker.

Links

PubMed PMC1586179 Online version:10.1073/pnas.0607260103

Keywords

Animals; Antioxidants/metabolism; Antioxidants/physiology; Cell Line, Tumor; Embryo, Mammalian; Fibroblasts/chemistry; Fibroblasts/physiology; Humans; Intracellular Signaling Peptides and Proteins/genetics; Intracellular Signaling Peptides and Proteins/metabolism; Intracellular Signaling Peptides and Proteins/physiology; Mice; Mice, Inbred C57BL; Mice, Knockout; NF-E2-Related Factor 2/antagonists & inhibitors; NF-E2-Related Factor 2/metabolism; Neoplasm Proteins/metabolism; Neoplasm Proteins/physiology; Oncogene Proteins/genetics; Oncogene Proteins/physiology; Parkinson Disease/etiology; Parkinson Disease/metabolism; Ubiquitin/metabolism

Significance

Annotations

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

HUMAN:KEAP1

located_in

GO:0005829: cytosol

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

C

Seeded From UniProt

complete

HUMAN:KEAP1

involved_in

GO:0032436: positive regulation of proteasomal ubiquitin-dependent protein catabolic process

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

P

  • has_input:(UniProtKB:Q16236)

Seeded From UniProt

complete

HUMAN:KEAP1

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:Q16236

F

Seeded From UniProt

complete

HUMAN:NF2L2

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:Q14145

F

Seeded From UniProt

complete

HUMAN:NF2L2

enables

GO:0000976: transcription cis-regulatory region binding

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

F

  • has_input:(UniProtKB:P15559)

Seeded From UniProt

complete

HUMAN:NF2L2

enables

GO:0003700: DNA-binding transcription factor activity

ECO:0000314: direct assay evidence used in manual assertion

F

  • has_input:(UniProtKB:P15559)

Seeded From UniProt

complete

HUMAN:NF2L2

involved_in

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

ECO:0000314: direct assay evidence used in manual assertion

P

  • has_input:(UniProtKB:P15559)

Seeded From UniProt

complete

HUMAN:PARK7

involved_in

GO:0032435: negative regulation of proteasomal ubiquitin-dependent protein catabolic process

ECO:0000314: direct assay evidence used in manual assertion

P

  • has_input:(UniProtKB:Q16236)

Seeded From UniProt

complete

HUMAN:PARK7

involved_in

GO:0032091: negative regulation of protein binding

ECO:0000314: direct assay evidence used in manual assertion

P

  • has_input:(UniProtKB:Q14145)
  • has_input:(UniProtKB:Q16236)

Seeded From UniProt

complete

HUMAN:PARK7

involved_in

GO:0031397: negative regulation of protein ubiquitination

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:PARK7

involved_in

GO:0051091: positive regulation of DNA-binding transcription factor activity

ECO:0000315: mutant phenotype evidence used in manual assertion

P

  • has_input:(UniProtKB:Q16236)

Seeded From UniProt

complete

HUMAN:PARK7

involved_in

GO:0050821: protein stabilization

ECO:0000315: mutant phenotype evidence used in manual assertion

P

  • has_input:(UniProtKB:Q16236)

Seeded From UniProt

complete

HUMAN:PARK7

involved_in

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

ECO:0000316: genetic interaction evidence used in manual assertion

UniProtKB:Q16236

P

  • has_input:(UniProtKB:P15559)

Seeded From UniProt

complete

MOUSE:PARK7

involved_in

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

ECO:0000315: mutant phenotype evidence used in manual assertion

P

  • has_input:(UniProtKB:Q64669)
  • has_input:(UniProtKB:O09172)

Seeded From UniProt

complete

HUMAN:PARK7

involved_in

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

ECO:0000316: genetic interaction evidence used in manual assertion

UniProtKB:Q16236

P

has_regulation_target:(UniProtKB:P15559)

Seeded From UniProt

complete

HUMAN:PARK7

involved_in

GO:0032435: negative regulation of proteasomal ubiquitin-dependent protein catabolic process

ECO:0000314: direct assay evidence used in manual assertion

P

has_regulation_target:(UniProtKB:Q16236)

Seeded From UniProt

complete

HUMAN:PARK7

involved_in

GO:0032091: negative regulation of protein binding

ECO:0000314: direct assay evidence used in manual assertion

P

  • has_regulation_target:(UniProtKB:Q14145)
  • has_regulation_target:(UniProtKB:Q16236)

Seeded From UniProt

complete

HUMAN:PARK7

involved_in

GO:0031397: negative regulation of protein ubiquitination

ECO:0000314: direct assay evidence used in manual assertion

P

  • has_regulation_target:(UniProtKB:Q16236)
  • part_of:(GO:0032435)

Seeded From UniProt

complete

HUMAN:PARK7

involved_in

GO:0051091: positive regulation of DNA-binding transcription factor activity

ECO:0000315: mutant phenotype evidence used in manual assertion

P

has_regulation_target:(UniProtKB:Q16236)

Seeded From UniProt

complete

HUMAN:PARK7

involved_in

GO:0050821: protein stabilization

ECO:0000315: mutant phenotype evidence used in manual assertion

P

stabilizes:(UniProtKB:Q16236)

Seeded From UniProt

complete

HUMAN:PARK7

involved_in

GO:0050821: protein stabilization

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:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:PARK7

involved_in

GO:0050821: protein stabilization

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:PARK7

involved_in

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

ECO:0000315: mutant phenotype evidence used in manual assertion

P

  • has_regulation_target:(UniProtKB:Q64669)
  • has_regulation_target:(UniProtKB:O09172)

Seeded From UniProt

complete

HUMAN:KEAP1

enables

GO:0008134: transcription factor binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:Q16236

F

Seeded From UniProt

complete

HUMAN:KEAP1

involved_in

GO:0032436: positive regulation of proteasomal ubiquitin-dependent protein catabolic process

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

P

has_regulation_target:(UniProtKB:Q16236)

Seeded From UniProt

complete

HUMAN:KEAP1

involved_in

GO:0043433: negative regulation of DNA-binding transcription factor activity

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

P

Seeded From UniProt

complete

HUMAN:NF2L2

enables

GO:0003700: DNA-binding transcription factor activity

ECO:0000314: direct assay evidence used in manual assertion

F

has_regulation_target:(UniProtKB:P15559)

Seeded From UniProt

complete

HUMAN:NF2L2

enables

GO:0044212: transcription regulatory region DNA binding

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

F

has_input:(UniProtKB:P15559)

Seeded From UniProt

complete

HUMAN:NF2L2

involved_in

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

ECO:0000314: direct assay evidence used in manual assertion

P

has_regulation_target:(UniProtKB:P15559)

Seeded From UniProt

complete


See also

References

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