RGD Reference Report - Redox regulation by nuclear factor erythroid 2-related factor 2: gatekeeping for the basal and diabetes-induced expression of thioredoxin-interacting protein.

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Redox regulation by nuclear factor erythroid 2-related factor 2: gatekeeping for the basal and diabetes-induced expression of thioredoxin-interacting protein.
Authors:	He, X Ma, Q
Citation:	He X and Ma Q, Mol Pharmacol. 2012 Nov;82(5):887-97. doi: 10.1124/mol.112.081133. Epub 2012 Aug 6.
RGD ID:	10412694
Pubmed:	PMID:22869588 (View Abstract at PubMed)
PMCID:	PMC4678870 (View Article at PubMed Central)
DOI:	DOI:10.1124/mol.112.081133 (Journal Full-text)
Nuclear factor erythroid 2-related factor 2 (Nrf2) is a transcription factor activated by a range of oxidants and electrophiles. The transcriptional response to endogenous oxidative cues by Nrf2 plays an important role in mammalian redox physiology and oxidative pathology. Hyperglycemia induces oxidative stress in the heart where it leads to apoptosis and ultimately cardiomyopathy. Here we investigated the mechanism by which Nrf2 suppresses oxidative stress in diabetic mouse heart. Knockout (KO) of Nrf2 induced oxidative stress and apoptosis in KO heart; diabetes further increased oxidative damage. A pathway-focused gene array revealed that Nrf2 controls the expression of 24 genes in the heart, including the gene encoding thioredoxin-interacting protein (TXNIP). Nrf2 suppressed the basal expression of Txnip in the heart and blocked induction of Txnip by high glucose by binding to an antioxidant response element (ARE) (-1286 to -1276) of the Txnip promoter. Binding of Nrf2 to ARE also suppressed the binding of MondoA to the carbohydrate response element with or without high glucose. TXNIP promoted reactive oxygen species production and apoptosis by inhibiting thioredoxin. On the other hand, Nrf2 boosted thioredoxin activity by inhibiting Txnip. The findings revealed, for the first time, that Nrf2 is a key gatekeeper of Txnip transcription, suppressing both its basal expression and MondoA-driven induction to control the thioredoxin redox signaling in diabetes.

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Object Symbol	Species	Term	Qualifier	Evidence	With	Notes	Source	Original Reference(s)
NFE2L2	Human	Experimental Diabetes Mellitus		ISO	Nfe2l2 (Mus musculus)		RGD
Nfe2l2	Rat	Experimental Diabetes Mellitus		ISO	Nfe2l2 (Mus musculus)		RGD
Nfe2l2	Mouse	Experimental Diabetes Mellitus		IMP			RGD

Objects Annotated

Genes (Rattus norvegicus)

Nfe2l2 (NFE2 like bZIP transcription factor 2)

Genes (Mus musculus)

Nfe2l2 (nuclear factor, erythroid derived 2, like 2)

Genes (Homo sapiens)

NFE2L2 (NFE2 like bZIP transcription factor 2)

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Redox regulation by nuclear factor erythroid 2-related factor 2: gatekeeping for the basal and diabetes-induced expression of thioredoxin-interacting protein.