Functional and Placental Expression Analysis of the Human NRF3 Transcription Factor

Chénais, Benoı̂t; Derjuga, Anna; Massrieh, Wael; Red-Horse, Kristy; Bellingard, Valérie; Fisher, Susan J.; Blank, Volker

doi:10.1210/me.2003-0379

Cited by 44 publications

(57 citation statements)

References 56 publications

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“…Transcriptionally Activates ARE-driven Gene Expression-Electrophoretic mobility shift assays have demonstrated that Nrf3 can bind ARE sequences as a heterodimer with sMaf proteins (1,2,23). There are however conflicting reports about whether Nrf3 activates or suppresses ARE-driven gene expression.…”

Section: Nrf3mentioning

confidence: 99%

The Nrf3 Transcription Factor Is a Membrane-bound Glycoprotein Targeted to the Endoplasmic Reticulum through Its N-terminal Homology Box 1 Sequence

Zhang

Kobayashi

Yamamoto

et al. 2009

Journal of Biological Chemistry

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Transcription factor Nrf3 (NF-E2 p45-related factor 3) is targeted to the endoplasmic reticulum (ER). Mouse Nrf3 is subject to proteolysis, Asn glycosylation, and deglycosylation reactions. It is synthesized as a ϳ96-kDa protein that is subsequently converted into isoforms of ϳ90, 80, and 70 kDa. In the ER, the ϳ90-kDa glycoprotein is predominant and gives rise to ϳ80-and ϳ70-kDa isoforms. The ϳ90-and ϳ80-kDa polypeptides were observed in the nuclear envelope, whereas the ϳ70-kDa isoform was detected primarily in the nucleoplasm. Our experiments showed the N-terminal homology box 1 (NHB1, residues 12-31) is part of a tripartite signal peptide sequence, comprising n, h, and c regions. The h region (residues 12-23) was demonstrated to target Nrf3 to the ER and is necessary for its Asn glycosylation. The n region (residues 1-11) controlled the abundance of the ϳ90-kDa glycoprotein. The c region (residues 24 -39) was found to contain a signal peptidase cleavage site that is responsible for production of the ϳ90-kDa mature Nrf3 glycoprotein from a ϳ96-kDa precursor. We have found that Nrf3 is activated by the ER stressors tunicamycin and brefeldin A, and that NHB1 is required for this response. Amino acids between the c region and NHB2 (residues 76 -100) controlled the proteolytic processing of mouse Nrf3 into cleavage products of ϳ80-kDa (glycated) and ϳ70-kDa (non-glycated); by contrast, human Nrf3 lacked a signal peptidase cleavage site between its c region and NHB2. Lastly, data are presented suggesting that the NHB2 sequence in mouse Nrf3 may regulate the topology of the transcription factor within the ER membrane.Nuclear factor-erythroid 2 p45-related factor 3 (Nrf3) 2 is a member of the cap "n" collar (CNC) subfamily of basic-region leucine zipper (bZIP) transcription factors (1, 2), which also includes Nrf1, Nrf2, and the NF-E2 p45 subunit. Like other members of the CNC bZIP family, Nrf3 can bind to the antioxidant response element (ARE, with a core consensus sequence 5Ј-TGA(C/G)nnnGC-3Ј) (1-5) and is therefore presumably involved in the regulation of antioxidant and detoxification genes, such as those for the glutamate cysteine ligase catalytic and modifier subunits, glutathione S-transferase (GST) isoenzymes and NAD(P)H:quinone oxidoreductase 1 (NQO1).The physiological functions of Nrf3 remain elusive. It is expressed in the liver and a wide variety of other tissues, but is particularly abundant in the placenta (1, 6, 7). As Nrf3 Ϫ/Ϫ mice have no obvious phenotype (8), it is possible that its loss can be compensated by Nrf1 and/or Nrf2. Interestingly, it has been found that the expression of Gclc, Gclm, and Nqo1 genes is not completely abolished in double Nrf1 Ϫ/Ϫ ::Nrf2 Ϫ/Ϫ knockout mice (9), suggesting that the residual transcriptional activation may be mediated by Nrf3. This hypothesis is supported by the observation that Nrf3 mRNA levels were elevated between 4-and 5-fold in skin from Nrf2 Ϫ/Ϫ mice, when compared with that in wild-type mice (10).We and others have used bioinformatics to gain an insight ...

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Section: Nrf3mentioning

confidence: 99%

The Nrf3 Transcription Factor Is a Membrane-bound Glycoprotein Targeted to the Endoplasmic Reticulum through Its N-terminal Homology Box 1 Sequence

Zhang

Kobayashi

Yamamoto

et al. 2009

Journal of Biological Chemistry

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“…16 Nrf3 heterodimerizes with MafK and MafG and this complex binds to the ␤-globin enhancer. 17,18 Nrf3 is able to represses antioxidant responsive elementmediated gene expression of antioxidant enzymes, such as the NAD(P)H:quinone oxidoreductase1 (NQO1) 19 and peroxiredoxin 6. 20 Recently we have shown that reactive oxygen species (ROS) are also involved in ESC differentiation toward SMCs.…”

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confidence: 99%

Crucial Role of Nrf3 in Smooth Muscle Cell Differentiation From Stem Cells

Pepe

Xiao²,

Zampetaki³

et al. 2010

Circulation Research

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Rationale: Nuclear factor erythroid 2-related factor (Nrf)3, a member of the cap 'N' collar family of transcription factors that bind to the DNA-antioxidant responsive elements, is involved in reactive oxygen species balancing and in muscle precursor migration during early embryo development. Objective: To investigate the functional role of Nrf3 in smooth muscle cell (SMC) differentiation in vitro and in vivo. Methods and Results: Nrf3 was upregulated significantly following 1 to 8 days of SMC differentiation. Knockdown of Nrf3 resulted in downregulation of smooth muscle specific markers expression, whereas enforced expression of Nrf3 enhanced SMC differentiation in a dose-dependent manner. SMC-specific transcription factor myocardin, but not serum response factor, was significantly upregulated by Nrf3 overexpression. Strikingly, the binding of SRF and myocardin to the promoter of smooth muscle differentiation genes was dramatically increased by Nrf3 overexpression, and Nrf3 can directly bind to the promoters of SMC differentiation genes as demonstrated by chromatin immunoprecipitation assay. Moreover, NADPH-derived reactive oxygen species production during SMC differentiation was further enhanced by Nrf3 overexpression through upregulation of NADPH oxidase and inhibition of antioxidant signaling pathway. In addition, Nrf3 was involved in the endoplasmic reticulum stressor induced SMC differentiation. (SMCs). [1][2][3] Our previous studies showed that growth factor stimulation, 2 mechanical force or extracellular matrix 4 can be used to drive ESC differentiation toward the vascular lineage. We have established an in vitro model for ESC differentiation into SMCs, 3 which involves the choice of extracellular matrix protein collagen IV, 3,5,6 to investigate SMC differentiation more closely. In the adult organism, SMCs have the main physiological function of contracting and controlling the blood vessel tone, diameter, blood pressure and blood flow. In response to vascular injury, SMCs dramatically increase their rate of proliferation, migration and synthetic capacity. 7,8 Atherosclerosis and postangioplasty restenosis, for example, are characterized by the development of an enlarged neointima. 9 The cells responsible for the neointima formation have been identified as not only SMC migrating from the tunica media, 10 but also vascular progenitors that originate from the circulation and the perivascular adventitia, which differentiate into vascular SMCs in the lesion. 11-14 However, the mechanisms involved in SMC differentiation in vitro and in vivo is still poorly understood.In a microarray screen for factors involved in vascular progenitor differentiation, we identified nuclear factor erythroid 2-related factor (Nrf)3 expression to be constantly modulated. Nrf3 is the most recently identified member of the Nrf family and contains a domain homologous to the cap 'N' collar (CNC) transcription factors. 15 The CNC domain is a unique, conserved region, located at the amino-terminus of the bZIP domain. 16 Nrf3 heterodim...

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“…TFAP2C and IRF1 are not expressed in uterine microvascular endothelial cells in vivo (45)(46)(47). NFE2L3 has been suggested to play a potential role in placental gene expression and development (48). Interestingly, a previous study demonstrated that NFE2L3 is a negative regulator of NAD(P)H dehydrogenase NQO1 (49).…”

Section: Discussionmentioning

confidence: 99%

Genes regulated by interferon-γ in human uterine microvascular endothelial cells

Kitaya¹,

Yasuo²,

Yamaguchi³

et al. 2007

Int J Mol Med

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Abstract. Interferon (IFN)-γ plays a critical role in murine uterine spiral artery remodeling for successful pregnancy. The effect of IFN-γ on human uterine microvasculature, however, remains poorly understood. The aim of this study was to identify the genes regulated by IFN-γ in human uterine microvascular endothelial cells. The effect of IFN-γ on the gene expression profile in human uterine microvascular endothelial cells was evaluated by cDNA microarray analysis and quantitative real-time reverse transcriptase-polymerase chain reaction for the selected genes of interest. In vivo expression of the protein encoded by some of these genes in human uterine microvascular endothelial cells was evaluated by Western blotting and immunohistochemistry. Treatment with 10 ng/ml IFN-γ for 4 h induced a significant ≥2-fold change in 29 genes in pooled human uterine microvascular endothelial cells; a total of 20 genes were up-regulated, whereas nine genes were down-regulated. The genes significantly up-regulated included chemokines (CXCL9, CXCL10, CCL8, IL15RA, and CCL5), enzymes (GBP5, TAP1, CYP27B1, SOD2, MX1, CASP1, and PTGES), and transcription factors (TFAP2C, IRF1, NFE2L3). The genes significantly down-regulated following IFN-γ treatment included cytokines/cytokine receptors (CSF2, IL1R2, and SPP1), and insulin-like growth factor binding proteins (WISP2 and IGFBP3). The results of the cDNA microarray analysis were confirmed by quantitative real-time reverse transcriptase-polymerase chain reaction for the selected 17 genes of interest. The immunoreactivity for the proteins encoded by IL15RA, IFI30, and MX1 was detected in human uterine microvascular endothelial cells in vivo, whereas the immunoreactivity for CCNA1 and NQO1 was not detectable. These results suggest that IFN-γ regulates the gene expression involved in natural killer cell recruitment, embryo and trophoblast migration, endometrial decidualization, angiogenesis, angiostasis, and anti-viral infection in human uterine microvascular endothelial cells.

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Functional and Placental Expression Analysis of the Human NRF3 Transcription Factor

Cited by 44 publications

References 56 publications

The Nrf3 Transcription Factor Is a Membrane-bound Glycoprotein Targeted to the Endoplasmic Reticulum through Its N-terminal Homology Box 1 Sequence

The Nrf3 Transcription Factor Is a Membrane-bound Glycoprotein Targeted to the Endoplasmic Reticulum through Its N-terminal Homology Box 1 Sequence

Crucial Role of Nrf3 in Smooth Muscle Cell Differentiation From Stem Cells

Genes regulated by interferon-γ in human uterine microvascular endothelial cells

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