NF-E2-related factor 2, a key inducer of antioxidant defenses, negatively regulates the CFTR transcription

René, Céline; Lopez, Estelle; Claustres, Mireille; Taulan, Magali; Romey-Chatelain, Marie-Catherine

doi:10.1007/s00018-010-0336-4

Cited by 21 publications

(13 citation statements)

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“…These nuclear trans -acting factors play pivotal roles in airway epithelial cell differentiation during lung organogenesis [25] and are involved in the expression of lung-specific and developmentally regulated genes including SP-A and CFTR [5], [6], [7], [8], [26], [27]. We recently identified other trans -acting factors including SRF, YY1, USF2, Sp1 and Nrf2 that contribute to CFTR transcriptional activity [9], [10], [11], [28]. In addition, C/EBPβ has been previously reported to be an important accessory factor for transactivation by several other transcription factors [29].…”

Section: Discussionmentioning

confidence: 99%

Phosphorylated C/EBPβ Influences a Complex Network Involving YY1 and USF2 in Lung Epithelial Cells

et al. 2013

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The promoter of the cystic fibrosis transmembrane conductance regulator gene CFTR is tightly controlled by regulators including CCAAT/enhancer binding proteins (C/EBPs). We previously reported that the transcription factors YY1 and USF2 affect CFTR expression. We can now demonstrate that C/EBPβ, a member of the CCAAT family, binds to the CFTR promoter and contributes to its transcriptional activity. Our data reveal that C/EBPβ cooperates with USF2 and acts antagonistically to YY1 in the control of CFTR expression. Interestingly, YY1, a strong repressor, fails to repress the CFTR activation induced by USF2 through DNA binding competition. Collectively, the data strongly suggest a model by which USF2 functionally interacts with YY1 blocking its inhibitory activity, in favour of C/EBPβ transactivation. Further investigation into the interactions between these three proteins revealed that phosphorylation of C/EBPβ influences the DNA occupancy of YY1 and favours the interaction between USF2 and YY1. This phosphorylation process has several implications in the CFTR transcriptional process, thus evoking an additional layer of complexity to the mechanisms influencing CFTR gene regulation.

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Section: Discussionmentioning

confidence: 99%

Phosphorylated C/EBPβ Influences a Complex Network Involving YY1 and USF2 in Lung Epithelial Cells

et al. 2013

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“…Binding of Nrf2 to AREs usually results in the activation of gene expression, but Nrf2 also represses a few genes through as yet poorly characterized mechanisms [16][17][18][19] . We therefore speculated that some of these genes are targets of Nrf2-activated miRNAs.…”

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confidence: 99%

A novel Nrf2-miR-29-desmocollin-2 axis regulates desmosome function in keratinocytes

et al. 2014

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The Nrf2 transcription factor controls the expression of genes involved in the antioxidant defense system. Here, we identified Nrf2 as a novel regulator of desmosomes in the epidermis through the regulation of microRNAs. On Nrf2 activation, expression of miR-29a and miR-29b increases in cultured human keratinocytes and in mouse epidermis. Chromatin immunoprecipitation identified the Mir29ab1 and Mir29b2c genes as direct Nrf2 targets in keratinocytes. While binding of Nrf2 to the Mir29ab1 gene activates expression of miR-29a and -b, the Mir29b2c gene is silenced by DNA methylation. We identified desmocollin-2 (Dsc2) as a major target of Nrf2-induced miR-29s. This is functionally important, since Nrf2 activation in keratinocytes of transgenic mice causes structural alterations of epidermal desmosomes. Furthermore, the overexpression of miR-29a/b or knockdown of Dsc2 impairs the formation of hyper-adhesive desmosomes in keratinocytes, whereas Dsc2 overexpression has the opposite effect. These results demonstrate that a novel Nrf2-miR-29-Dsc2 axis controls desmosome function and cutaneous homeostasis.

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“…6). Importantly, a recent study has shown that Nrf2 negatively regulated the transcription of the fibrosis transmembrane conductance receptor gene (CFTR) through an YY1 element overlapped with an ARE (CAAA TGACA underlined) [19-25]. Although the CES1A1 YY1 element shares five nucleotides with the CFTR YY1 element, the CES1A1 YY1 element lacks the typical core nucleotides of YY1 element [19].…”

Section: Discussionmentioning

confidence: 99%

“…Although the CES1A1 YY1 element shares five nucleotides with the CFTR YY1 element, the CES1A1 YY1 element lacks the typical core nucleotides of YY1 element [19]. However, these authors detected YY1-Nrf2 complex [25], suggesting that YY1 and Nrf2 form heterodimers and bind to an YY1-Nrf2 composite site. On the other hand, Nrf2 has been established to preferably form heterodimers with small Maf proteins and confer transactivation activity [26, 27], thus dominating the repression through the YY1-Nrf2 mechanism [Fig.…”

Section: Discussionmentioning

confidence: 99%

Antioxidant sulforaphane and sensitizer trinitrobenzene sulfonate induce carboxylesterase-1 through a novel element transactivated by nuclear factor-E2 related factor-2

Chen

Shi

Yang

et al. 2012

Biochemical Pharmacology

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Carboxylesterase-1 (CES1), the most versatile human carboxylesterase, plays critical roles in drug metabolism and lipid mobilization. This enzyme is highly induced by antioxidants and sensitizers in various cell lines. These compounds are known to activate nuclear factor-E2 related factor-2 (Nrf2) by reacting to kelch-like ECH-associated protein-1 (Keap1). The aims of this study were to determine whether antioxidant sulforaphane (SFN) and sensitizer trinitrobenzene sulfonate (TNBS) target Keap1 similarly and whether they use the same element for CES1 induction. Cells over-expressing Keap1 were treated with TNBS or SFN and the formation of disulfide bonds among Keap1 molecules were determined. SFN promoted intramolecular disulfide formation whereas TNBS promoted intermolecular disulfide formation of Keap1. Two elements, sensitizing/antioxidant response element (S/ARE) and ARE4, were identified to support Nrf2 in the regulated expression of CES1A1. Both elements were bound by Nrf2, however, the S/ARE element supported, whereas the ARE4 element repressed Nrf2 transactivation. The repression required higher amounts of Nrf2, suggesting that the transactivation through the S/ARE element dominates the trans-repression through the ARE4 element under normal antioxidative condition. These findings conclude that compounds, although triggering the Keap1-Nrf2 pathway, may differ in the mode of reacting with Keap1. These findings also conclude that both positive and negative Nrf2 elements exist even within the same gene, and such opposing mechanisms provide fine-tuning in transcriptional regulation by the Keap1-Nrf2 pathway. High levels of CES1 are linked to lipid retention. Excessive induction of CES1 by antioxidants and sensitizers likely provides a mechanism for potential detrimental effect on human health.

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NF-E2-related factor 2, a key inducer of antioxidant defenses, negatively regulates the CFTR transcription

Cited by 21 publications

References 50 publications

Phosphorylated C/EBPβ Influences a Complex Network Involving YY1 and USF2 in Lung Epithelial Cells

Phosphorylated C/EBPβ Influences a Complex Network Involving YY1 and USF2 in Lung Epithelial Cells

A novel Nrf2-miR-29-desmocollin-2 axis regulates desmosome function in keratinocytes

Antioxidant sulforaphane and sensitizer trinitrobenzene sulfonate induce carboxylesterase-1 through a novel element transactivated by nuclear factor-E2 related factor-2

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