Hemin-induced Activation of the Thioredoxin Gene by Nrf2

Kim, Yong Chul; Masutani, Hiroshi; Yamaguchi, Yoshimi; Itoh, Ken; Yamamoto, Masayuki; Yodoi, Junji

doi:10.1074/jbc.m100103200

Cited by 275 publications

(70 citation statements)

References 52 publications

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“…EpREs have been found in the promoter regions of various genes, e.g. those encoding glutathione S-transferase, NADPH: quinone oxidoreductase, the heavy and light subunits of ␥-GCS, ferritin L subunit, metallothionein-1, and thioredoxin (9,10,(22)(23)(24)(25). The common function of these proteins is for cell defense against xenobiotics and oxidants.…”

Section: Discussionmentioning

confidence: 99%

Electrophile Response Element-mediated Induction of the Cystine/Glutamate Exchange Transporter Gene Expression

Sasaki¹,

Sato²,

Kuriyama-Matsumura³

et al. 2002

Journal of Biological Chemistry

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465

332

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In mammalian cultured cells, the cystine/glutamate exchange transport mediated by system x c ؊ is important to maintain intracellular GSH levels. System x c ؊ consists of two protein components, xCT and the heavy chain of 4F2 antigen. The activity of system x c ؊ is induced by various stimuli, including electrophilic agents like diethyl maleate. In the present study, we have investigated the mechanism of the transcriptional regulation of xCT mRNA by diethyl maleate. The xCT gene consisted of twelve exons and sequence analysis identified four electrophile response element (EpRE)-like sequences between ؊230 and ؊1 in the 5-flanking region, designated EpRE-1 to EpRE-4. To identify sequences mediating the constitutive and induced expression of xCT, a series of 5-deletion mutants created from the 5-flanking region were cloned into a luciferase reproter vector and transfected into BHK21 cells. The 5-deletion analysis revealed that the sequence between ؊116 and ؊82 is essential for the basal expression and the sequence between ؊226 and ؊116 containing EpRE-1 is essential in response to diethyl maleate. Mutational analysis demonstrated that EpRE-1 is critically involved in the response to diethyl maleate. Other stress agents like arsenite, cadmium, and hydroquinone seemed to induce system x c ؊ activity via the same sequence. Furthermore, the experiments using the mouse embryonic fibroblasts derived from the Nrf2-deficient mice revealed that the induction of xCT gene by electrophilic agents is mediated by Nrf2. EpRE occurs in a broad spectrum of genes for the proteins that are involved in the defense against xenobiotics and regulates their expression. The present results have demonstrated that xCT is a novel member of this protein family.

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Section: Discussionmentioning

confidence: 99%

Electrophile Response Element-mediated Induction of the Cystine/Glutamate Exchange Transporter Gene Expression

Sasaki¹,

Sato²,

Kuriyama-Matsumura³

et al. 2002

Journal of Biological Chemistry

Self Cite

465

332

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“…Furthermore, we demonstrated that heme deficiency shows a selective decrease in mitochondrial complex IV that leads to oxidative stress and corruption of Ca 2ϩ homeostasis (9). Heme functions in hemoglobin and enzymes, and it regulates the activity of proteins and gene expression through the heme regulatory motifs (HRMs) in several proteins (10)(11)(12). Also, a role of heme in promoting neurite outgrowth and neurogenesis has been known for some time (13).…”

mentioning

confidence: 99%

Heme deficiency may be a factor in the mitochondrial and neuronal decay of aging

Atamna¹,

Killilea²,

Killilea³

et al. 2002

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

197

150

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Heme, a major functional form of iron in the cell, is synthesized in the mitochondria by ferrochelatase inserting ferrous iron into protoporphyrin IX. Heme deficiency was induced with N-methylprotoporphyrin IX, a selective inhibitor of ferrochelatase, in two human brain cell lines, SHSY5Y (neuroblastoma) and U373 (astrocytoma), as well as in rat primary hippocampal neurons. Heme deficiency in brain cells decreases mitochondrial complex IV, activates nitric oxide synthase, alters amyloid precursor protein, and corrupts iron and zinc homeostasis. The metabolic consequences resulting from heme deficiency seem similar to dysfunctional neurons in patients with Alzheimer's disease. Heme-deficient SHSY5Y or U373 cells die when induced to differentiate or to proliferate, respectively. The role of heme in these observations could result from its interaction with heme regulatory motifs in specific proteins or secondary to the compromised mitochondria. Common causes of heme deficiency include aging, deficiency of iron and vitamin B6, and exposure to toxic metals such as aluminum. Iron and B6 deficiencies are especially important because they are widespread, but they are also preventable with supplementation. Thus, heme deficiency or dysregulation may be an important and preventable component of the neurodegenerative process.iron ͉ complex IV ͉ amyloid precursor protein (APP) ͉ nitric oxide synthase ͉ oxidative stress

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“…In addition, an antioxidant-responsive element (ARE) sequence was reported in the mouse ferritin-L and -H genes (7). The ARE mediates transcriptional response to oxidative stress by increasing expression of a diverse set of proteins involved in redox homeostasis such as thioredoxin reductase (TRR), thioredoxin, quinone reductase (QR), heme oxygenase, and glutathione (8)(9)(10). The ARE is in the family of AP-1 response sequences that bind leucine zipper ''cap n' collar'' transcription factors such as Nrf2 to increase transcription (8).…”

mentioning

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

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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

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Hemin-induced Activation of the Thioredoxin Gene by Nrf2

Cited by 275 publications

References 52 publications

Electrophile Response Element-mediated Induction of the Cystine/Glutamate Exchange Transporter Gene Expression

Electrophile Response Element-mediated Induction of the Cystine/Glutamate Exchange Transporter Gene Expression

Heme deficiency may be a factor in the mitochondrial and neuronal decay of aging

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

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