Transcription factor Nrf2 mediates an adaptive response to sulforaphane that protects fibroblasts in vitro against the cytotoxic effects of electrophiles, peroxides and redox-cycling agents

Higgins, Larry G.; Kelleher, Michael O.; Eggleston, Ian M.; Itoh, Ken; Yamamoto, Masayuki; Hayes, John D.

doi:10.1016/j.taap.2009.03.005

Cited by 153 publications

(150 citation statements)

References 62 publications

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“…We employed menadione, CDNB, and BITC, which are well-established stressors for testing the roles played by Nrf2 in the stress response (30). Consistent with the reduced expression of Nqo1 and Gstm1 in Nrf2 heterozy- gous macrophages, the cells appeared to be more susceptible to menadione, CDNB, and BITC than the wild-type cells but less susceptible to the insult than Nrf2-null macrophages ( Fig.…”

Section: Reflection Ofmentioning

confidence: 70%

Regulatory Nexus of Synthesis and Degradation Deciphers Cellular Nrf2 Expression Levels

Suzuki

Shibata²,

Takaya

et al. 2013

Molecular and Cellular Biology

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103

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f Transcription factor Nrf2 (NF-E2-related factor 2) is essential for oxidative and electrophilic stress responses. While it has been well characterized that Nrf2 activity is tightly regulated at the protein level through proteasomal degradation via Keap1 (Kelchlike ECH-associated protein 1)-mediated ubiquitination, not much attention has been paid to the supply side of Nrf2, especially regulation of Nrf2 gene transcription. Here we report that manipulation of Nrf2 transcription is effective in changing the final Nrf2 protein level and activity of cellular defense against oxidative stress even in the presence of Keap1 and under efficient Nrf2 degradation, determined using genetically engineered mouse models. In excellent agreement with this finding, we found that minor A/A homozygotes of a single nucleotide polymorphism (SNP) in the human NRF2 upstream promoter region (rs6721961) exhibited significantly diminished NRF2 gene expression and, consequently, an increased risk of lung cancer, especially those who had ever smoked. Our results support the notion that in addition to control over proteasomal degradation and derepression from degradation/repression, the transcriptional level of the Nrf2 gene acts as another important regulatory point to define cellular Nrf2 levels. These results thus verify the critical importance of human SNPs that influence the levels of transcription of the NRF2 gene for future personalized medicine.

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Section: Reflection Ofmentioning

confidence: 70%

Regulatory Nexus of Synthesis and Degradation Deciphers Cellular Nrf2 Expression Levels

Suzuki

Shibata²,

Takaya

et al. 2013

Molecular and Cellular Biology

Self Cite

103

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“…Electrophiles in foods have attracted great attention because of their protection against toxicity and many chronic pathological conditions (Nakamura and Miyoshi, 2010). Numerous studies have found that dietary electrophiles can activate transcription factor nuclear factor-E2-related factor 2 (Nrf2) through modifying cysteine residues in Kelch-like ECH-associated protein 1 (KEAP1) and therefore stimulating the overproduction of GSH to detoxify electrophiles as well as carcinogens (Juge et al, 2007;Higgins et al, 2009;MacLeod et al, 2009;Nakamura and Miyoshi, 2010). It has been reported that the level of GSH in mouse embryonic fibroblast cells were reduced to approximately 25% of the basal level, returned to the basal level, and rose between 1.75-and 1.9-fold higher than the basal level at 2 to 4, 8 to 12, and 18 and 24 h after treatment with 3 M SFN, respectively .…”

Section: Discussionmentioning

confidence: 99%

Metabolism of [6]-Shogaol in Mice and in Cancer Cells

Chen

Lv²,

Soroka³

et al. 2012

Drug Metab Dispos

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ABSTRACT:Ginger has received extensive attention because of its antioxidant, antiinflammatory, and antitumor activities. However, the metabolic fate of its major components is still unclear. In the present study, the metabolism of [6]-shogaol, one of the major active components in ginger, was examined for the first time in mice and in cancer cells. Thirteen metabolites were detected and identified, seven of which were purified from fecal samples collected from

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“…BHA is the first agent identified to date that activates CYP2J2 gene expression in human cells. Alternate agents, such as sulforaphane, that also activate bZIP factor expression have been found to exert protective effects in cells and in in vivo models of experimental injury (Yoon et al, 2008;Higgins et al, 2009). In view of the proliferative and mitogenic actions of EETs, it is now of interest to evaluate the specific role of CYP2J2 in the overall cytoprotective actions of such agents.…”

Section: Discussionmentioning

confidence: 99%

Up-Regulation of Human CYP2J2 in HepG2 Cells by Butylated Hydroxyanisole Is Mediated by c-Jun and Nrf2

Lee

Murray²

2010

Mol Pharmacol

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Transcription factor Nrf2 mediates an adaptive response to sulforaphane that protects fibroblasts in vitro against the cytotoxic effects of electrophiles, peroxides and redox-cycling agents

Cited by 153 publications

References 62 publications

Regulatory Nexus of Synthesis and Degradation Deciphers Cellular Nrf2 Expression Levels

Regulatory Nexus of Synthesis and Degradation Deciphers Cellular Nrf2 Expression Levels

Metabolism of [6]-Shogaol in Mice and in Cancer Cells

Up-Regulation of Human CYP2J2 in HepG2 Cells by Butylated Hydroxyanisole Is Mediated by c-Jun and Nrf2

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