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Heme oxygenase-1 induction by NRF2 requires inactivation of the transcriptional repressor BACH1.

Reichard JF, Motz GT, Puga A - Nucleic Acids Res. (2007)

Bottom Line: In contrast, thioredoxin reductase 1 (TXNRD1) is regulated by NRF2 but not by BACH1.By comparing the expression levels of HMOX1 with TXNRD1, we show that nuclear accumulation of NRF2 is not necessary for HMOX1 induction; rather, BACH1 inactivation permits NRF2 already present in the nucleus at low basal levels to bind the HMOX1 promoter and elicit HMOX1 induction.Thus, BACH1 confers an additional level of regulation to ARE-dependent genes that reveals a new dimension to the oxidative stress response.

View Article: PubMed Central - PubMed

Affiliation: Department of Environmental Health and Center for Environmental Genetics, University of Cincinnati, Cincinnati, OH 45267-0056, USA. john.reichard@childrens.harvard.edu

ABSTRACT
Oxidative stress activates the transcription factor NRF2, which in turn binds cis-acting antioxidant response element (ARE) enhancers and induces expression of protective antioxidant genes. In contrast, the transcriptional repressor BACH1 binds ARE-like enhancers in cells naïve to oxidative stress and antagonizes NRF2 binding until it becomes inactivated by pro-oxidants. Here, we describe the dynamic roles of BACH1 and NRF2 in the transcription of the heme oxygenase-1 (HMOX1) gene. HMOX1 induction, elicited by arsenite-mediated oxidative stress, follows inactivation of BACH1 and precedes activation of NRF2. BACH1 repression is dominant over NRF2-mediated HMOX1 transcription and inactivation of BACH1 is a prerequisite for HMOX1 induction. In contrast, thioredoxin reductase 1 (TXNRD1) is regulated by NRF2 but not by BACH1. By comparing the expression levels of HMOX1 with TXNRD1, we show that nuclear accumulation of NRF2 is not necessary for HMOX1 induction; rather, BACH1 inactivation permits NRF2 already present in the nucleus at low basal levels to bind the HMOX1 promoter and elicit HMOX1 induction. Thus, BACH1 confers an additional level of regulation to ARE-dependent genes that reveals a new dimension to the oxidative stress response.

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Time course of HMOX1 expression elicited by hemin and MG132 treatment. The time course of HMOX1 mRNA expression following treatment with 25 μM hemin or 5 μM MG132. HMOX1 mRNA was determined by quantitative real-time PCR (qRT–PCR), normalized to β-actin mRNA and expressed as percent maximum expression. Values represent at least three independent experiments quantified in triplicate ± SEM.
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Figure 5: Time course of HMOX1 expression elicited by hemin and MG132 treatment. The time course of HMOX1 mRNA expression following treatment with 25 μM hemin or 5 μM MG132. HMOX1 mRNA was determined by quantitative real-time PCR (qRT–PCR), normalized to β-actin mRNA and expressed as percent maximum expression. Values represent at least three independent experiments quantified in triplicate ± SEM.

Mentions: To confirm that RNA pol II binding is associated with gene induction by hemin but not by MG132, relative steady-state levels of HMOX1 mRNA accumulation were measured by qRT–PCR over the time course of HMOX1 protein induction. Induction of HMOX1 mRNA expression was differentially regulated by treatment with either hemin or MG132. Despite the absence of NRF2 activation, hemin triggers induction of much greater levels of HMOX1 mRNA than MG132 (Figure 5). Given that NRF2 activation is generally considered a critical event for antioxidant gene induction, it is surprising that inactivation of BACH1 by hemin produced 5-fold greater levels of HMOX1 induction than were elicited by MG132-mediated NRF2 activation.Figure 5.


Heme oxygenase-1 induction by NRF2 requires inactivation of the transcriptional repressor BACH1.

Reichard JF, Motz GT, Puga A - Nucleic Acids Res. (2007)

Time course of HMOX1 expression elicited by hemin and MG132 treatment. The time course of HMOX1 mRNA expression following treatment with 25 μM hemin or 5 μM MG132. HMOX1 mRNA was determined by quantitative real-time PCR (qRT–PCR), normalized to β-actin mRNA and expressed as percent maximum expression. Values represent at least three independent experiments quantified in triplicate ± SEM.
© Copyright Policy - creative-commons
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2175339&req=5

Figure 5: Time course of HMOX1 expression elicited by hemin and MG132 treatment. The time course of HMOX1 mRNA expression following treatment with 25 μM hemin or 5 μM MG132. HMOX1 mRNA was determined by quantitative real-time PCR (qRT–PCR), normalized to β-actin mRNA and expressed as percent maximum expression. Values represent at least three independent experiments quantified in triplicate ± SEM.
Mentions: To confirm that RNA pol II binding is associated with gene induction by hemin but not by MG132, relative steady-state levels of HMOX1 mRNA accumulation were measured by qRT–PCR over the time course of HMOX1 protein induction. Induction of HMOX1 mRNA expression was differentially regulated by treatment with either hemin or MG132. Despite the absence of NRF2 activation, hemin triggers induction of much greater levels of HMOX1 mRNA than MG132 (Figure 5). Given that NRF2 activation is generally considered a critical event for antioxidant gene induction, it is surprising that inactivation of BACH1 by hemin produced 5-fold greater levels of HMOX1 induction than were elicited by MG132-mediated NRF2 activation.Figure 5.

Bottom Line: In contrast, thioredoxin reductase 1 (TXNRD1) is regulated by NRF2 but not by BACH1.By comparing the expression levels of HMOX1 with TXNRD1, we show that nuclear accumulation of NRF2 is not necessary for HMOX1 induction; rather, BACH1 inactivation permits NRF2 already present in the nucleus at low basal levels to bind the HMOX1 promoter and elicit HMOX1 induction.Thus, BACH1 confers an additional level of regulation to ARE-dependent genes that reveals a new dimension to the oxidative stress response.

View Article: PubMed Central - PubMed

Affiliation: Department of Environmental Health and Center for Environmental Genetics, University of Cincinnati, Cincinnati, OH 45267-0056, USA. john.reichard@childrens.harvard.edu

ABSTRACT
Oxidative stress activates the transcription factor NRF2, which in turn binds cis-acting antioxidant response element (ARE) enhancers and induces expression of protective antioxidant genes. In contrast, the transcriptional repressor BACH1 binds ARE-like enhancers in cells naïve to oxidative stress and antagonizes NRF2 binding until it becomes inactivated by pro-oxidants. Here, we describe the dynamic roles of BACH1 and NRF2 in the transcription of the heme oxygenase-1 (HMOX1) gene. HMOX1 induction, elicited by arsenite-mediated oxidative stress, follows inactivation of BACH1 and precedes activation of NRF2. BACH1 repression is dominant over NRF2-mediated HMOX1 transcription and inactivation of BACH1 is a prerequisite for HMOX1 induction. In contrast, thioredoxin reductase 1 (TXNRD1) is regulated by NRF2 but not by BACH1. By comparing the expression levels of HMOX1 with TXNRD1, we show that nuclear accumulation of NRF2 is not necessary for HMOX1 induction; rather, BACH1 inactivation permits NRF2 already present in the nucleus at low basal levels to bind the HMOX1 promoter and elicit HMOX1 induction. Thus, BACH1 confers an additional level of regulation to ARE-dependent genes that reveals a new dimension to the oxidative stress response.

Show MeSH
Related in: MedlinePlus