Bach1 Competes with Nrf2 Leading to Negative Regulation of the Antioxidant Response Element (ARE)-mediated NAD(P)H:Quinone Oxidoreductase 1 Gene Expression and Induction in Response to Antioxidants

Dhakshinamoorthy, Saravanakumar; Jain, Abhinav K.; Bloom, David A.; Jaiswal, Anil K.

doi:10.1074/jbc.m500166200

Cited by 361 publications

(292 citation statements)

References 35 publications

Supporting

Mentioning

283

Contrasting

Order By: Relevance

“…1A), was identified in a search of human genome sequences (chromosome 19; 19q13.3-q13.4). MARE͞ ARE combination elements (TGAG͞CTCA) are also found in the promoters of heme responsive genes such as ␤-globin (15), heme oxygenase (16), and QR (17). A search of sequences upstream of the human ferritin-H gene also revealed an MARE͞ ARE at Ϫ4.4 kb, possibly analogous to the reported murine ferritin-H gene ARE (Ϫ4.13 kb) that is regulated by the antioxidant response inducers oltipraz and TBHQ (18).…”

Section: Resultsmentioning

confidence: 86%

See 1 more Smart Citation

DNA and mRNA elements with complementary responses to hemin, antioxidant inducers, and iron control ferritin-L expression

Hintze¹,

Theil²

2005

Proc. Natl. Acad. Sci. U.S.A.

165

147

View full text Add to dashboard Cite

Ferritins, an ancient family of protein nanocages, concentrate iron in iron-oxy minerals for iron-protein biosynthesis and protection against oxy radical damage. Of the two genetic mechanisms that regulate rates of ferritin-L synthesis, DNA transcription and mRNA translation, more is known about mRNA regulation where iron targets complexes of an mRNA structure, the iron-responsive element (IRE) sequence, and ferritin IRE repressors (iron regulatory proteins 1 and 2). Neither the integration of mRNA and DNA regulation nor the ferritin-L DNA promoter are well studied. We now report the combined effects of DNA transcription and mRNA translation regulation of ferritin-L synthesis. First, the promoter of human ferritin-L, encoding the animal-specific subunit associated with human diseases, was identified, and contained an overlapping Maf recognition element (MARE) and antioxidant responsive element (ARE) that was positively regulated by tert-butylhydroquinone, sulforaphane, and hemin with responses comparable to thioredoxin reductase (ARE regulator) or quinone reductase (MARE͞ARE regulator). Iron, a poor regulator of the ferritin-L promoter, was 800 times less effective than sulforaphane. Combining the ferritin-L MARE͞ARE and IRE produced a response to hemin that was 3-fold greater than the sum of responses of the MARE͞ARE or IRE alone. Regulation of ferritin-L by a MARE͞ARE DNA sequence emphasizes the importance of ferritin-L in oxidative stress that complements the mRNA regulation in iron stress. Combining DNA and mRNA mechanisms of regulation, as for ferritin-L, illustrates the advantages of using two types of genetic targets to achieve sensitive responses to multiple signals.antioxidant responsive element ͉ Maf recognition element ͉ oxygen ͉ iron responsive element ͉ combinatorial regulation

show abstract

Section: Resultsmentioning

confidence: 86%

“…In contrast, it is known that the Bach 1͞hemin interaction relieves Bach 1 inhibition of Maf͞Nrf2 interactions with MARE͞ARE (5Ј-TGAC͞GTCA-3Ј) DNA sequences (Fig. 1 A) to enhance transcription (35), as shown for QR (17) and heme oxygenase 1 (35,37), where the hemin response is comparable to ferritin-L (Figs. 2 and 4).…”

Section: Discussionmentioning

confidence: 99%

DNA and mRNA elements with complementary responses to hemin, antioxidant inducers, and iron control ferritin-L expression

Hintze¹,

Theil²

2005

Proc. Natl. Acad. Sci. U.S.A.

165

147

View full text Add to dashboard Cite

show abstract

“…71,72,82 Bach1 is reported to be a negative regulator of Nrf2 signaling within the nuclear compartment. 82 Transient or stable binding of Bach1 to ARE in specific promoters has been shown to repress tBHQ-induced Nrf2-ARE activation. 82 An age-related increase in Bach1 binding to the ARE of the GCLC promoter competed with Nrf2-ARE binding in the liver of old mice.…”

Section: Keap1-independent Mechanismsmentioning

confidence: 99%

“…82 Transient or stable binding of Bach1 to ARE in specific promoters has been shown to repress tBHQ-induced Nrf2-ARE activation. 82 An age-related increase in Bach1 binding to the ARE of the GCLC promoter competed with Nrf2-ARE binding in the liver of old mice. 83 On the other hand, dimerization of transcriptional coactivator Mafs with Nrf2 facilitates stable Nrf2-ARE interaction and enhances the transcription of cytoprotective genes.…”

Section: Keap1-independent Mechanismsmentioning

confidence: 99%

Nuclear Factor–Erythroid-2–Related Factor 2 in Aging and Lung Fibrosis

Swamy

Rajasekaran

Thannickal

2016

The American Journal of Pathology

View full text Add to dashboard Cite

Aging and age-related diseases have been associated with elevated oxidative stress, which may be related to increased production of reactive species and/or a deficiency in antioxidant defenses. The nuclear factor-erythroid-2erelated factor 2 (Nrf2)-mediated antioxidant response pathway maintains cellular reduction-oxidation homeostasis by inducing the transcription of an array of cytoprotective genes. However, there is evidence of impaired Nrf2 response in aging contributing to age-related fibrotic diseases. Herein, we review mechanisms for the dysregulation of Nrf2 signaling in aging. This understanding will pave the way for the design of novel therapeutic strategies that restore Nrf2 signaling to reestablish cellular homeostasis in aging and age-related fibrotic diseases.

show abstract

“…Heme-regulatory motif is different from the heme pockets in heme proteins, which bind heme with higher affinity. Regulatory heme controls the mitochondrial-cytosolic distribution of ALAS (16), iron uptake (17), specific neuronal signaling pathways (18), and transcription factors (19); regulatory heme also is the precursor for heme-a. Heme-a matures via several biochemical modifications to regulatory heme (20), exists only in complex IV in the mitochondria, and is rate-limiting for its assembly (21).…”

mentioning

confidence: 99%

Amyloid-β peptide binds with heme to form a peroxidase: Relationship to the cytopathologies of Alzheimer’s disease

Atamna¹,

Boyle²

2006

Proc. Natl. Acad. Sci. U.S.A.

272

279

View full text Add to dashboard Cite

Amyloid-␤ peptide (A␤) is the toxic agent in Alzheimer's disease (AD), although the mechanism causing the neurodegeneration is not known. We previously proposed a mechanism in which excessive A␤ binds to regulatory heme, triggering functional heme deficiency (HD), causing the key cytopathologies of AD. We demonstrated that HD triggers the release of oxidants (e.g., H 2O2) from mitochondria due to the loss of complex IV, which contains heme-a. Now we add more evidence that A␤ binding to regulatory heme in vivo is the mechanism by which A␤ causes HD. Heme binds to A␤, thus preventing A␤ aggregation by forming an A␤-heme complex in a cell-free system. We suggest that this complex depletes regulatory heme, which would explain the increase in heme synthesis and iron uptake we observe in human neuroblastoma cells. The A␤-heme complex is shown to be a peroxidase, which catalyzes the oxidation of serotonin and 3,4-dihydroxyphenylalanine by H 2O2. Curcumin, which lowers oxidative damage in the brain in a mouse model for AD, inhibits this peroxidase. The binding of A␤ to heme supports a unifying mechanism by which excessive A␤ induces HD, causes oxidative damage to macromolecules, and depletes specific neurotransmitters. The relevance of the binding of regulatory heme with excessive A␤ for mitochondrial dysfunction and neurotoxicity and other cytopathologies of AD is discussed.curcumin ͉ heme deficiency ͉ mitochondria ͉ regulatory heme ͉ serotonin

show abstract

Bach1 Competes with Nrf2 Leading to Negative Regulation of the Antioxidant Response Element (ARE)-mediated NAD(P)H:Quinone Oxidoreductase 1 Gene Expression and Induction in Response to Antioxidants

Abstract: The antioxidant response element (ARE) and Nrf2 are known to regulate the expression and coordinated induction of genes encoding detoxifying enzymes including NAD(P)H:quinone oxidoreductase1 (NQO1) in response to antioxidants. In this

Cited by 361 publications

References 35 publications

DNA and mRNA elements with complementary responses to hemin, antioxidant inducers, and iron control ferritin-L expression

DNA and mRNA elements with complementary responses to hemin, antioxidant inducers, and iron control ferritin-L expression

Nuclear Factor–Erythroid-2–Related Factor 2 in Aging and Lung Fibrosis

Amyloid-β peptide binds with heme to form a peroxidase: Relationship to the cytopathologies of Alzheimer’s disease

Contact Info

Product

Resources

About