Phosphorylation of Nrf2 at Ser40 by Protein Kinase C in Response to Antioxidants Leads to the Release of Nrf2 from INrf2, but Is Not Required for Nrf2 Stabilization/Accumulation in the Nucleus and Transcriptional Activation of Antioxidant Response Element-mediated NAD(P)H:Quinone Oxidoreductase-1 Gene Expression

Bloom, David A.; Jaiswal, Anil K.

doi:10.1074/jbc.m307633200

Cited by 472 publications

(353 citation statements)

References 25 publications

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“…The former mechanism considers that phosphorylation of Nrf2 is required for its dissociation. This hypothesis is supported by the finding that oxidant-mediated Nrf2-Keap1 dissociation could be blocked through inhibiting Nrf2 phosphorylation, which occurs through activation of signaling pathways including those involving protein kinase C [68,69]. An alternative hypothesis of Nrf2 liberation, modification of Keap1, proposes that some reactive -SH groups on Keap1 act as oxidative stress sensors and that modification of them by ROS or electrophiles disrupts the Nrf2-Keap1 complex leading to Nrf2 dissociation.…”

Section: Discussionmentioning

confidence: 99%

“…There are reports suggesting that the signaling transduction pathways involved in EpRE activation are also in a gene-, cell-, or stimulator-specific manner. An example of this is the signaling pathways involved in the EpRE-mediated NQO-1 and GCL induction in HepG2 cells; protein kinase C (PKC) and ERK/p38MAPK were involved, respectively in their EpRE activation [66,69]. As to the signaling pathways responsible for GGT induction by HNE, recent studies from our laboratory suggest that ERK1/2 and P38MAPK mediate the induction of GGT mRNA V-2 through regulation of the activation of Nrf2 [31,87].…”

Section: Discussionmentioning

confidence: 99%

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γ-Glutamyl transpeptidase is induced by 4-hydroxynonenal via EpRE/Nrf2 signaling in rat epithelial type II cells

Zhang

Liu

Dickinson

et al. 2006

Free Radical Biology and Medicine

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Abstractγ-Glutamyl transpeptidase (GGT) plays key roles in glutathione homeostasis and metabolism of glutathione S-conjugates. Rat GGT is transcribed via five tandemly arranged promoters into seven transcripts. The transcription of mRNAV is controlled by promoter 5. Previously we found that GGT mRNAV-2 was responsible for the induction of GGT in rat alveolar epithelial cells by 4-hydroxynonenal (HNE). In the current study, the underlying mechanism was investigated. Reporter deletion and mutation analysis demonstrated that an electrophile-response element (EpRE) in the proximal region of GGT promoter 5 (GP5) was responsible for the basal-and HNE-induced promoter activity. Gel-shift assays showed an increased binding activity of GP5 EpRE after HNE exposure. The nuclear content of NF-E2-related factor 2 (Nrf2) was significantly increased by HNE. The recruitment of Nrf2 to GP5 EpRE after HNE treatment was demonstrated by supershift and chromatin immunoprecipitation assays. The tissue expression pattern of GGT mRNA V was previously unknown. Using polymerase chain reaction, we found that GGT mRNAV-2 was expressed in many tissues in rat. Taken together, GGT mRNAV-2 is widely expressed in rat tissues and its basal and HNE-induced expression is mediated through EpRE/Nrf2 signaling.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

γ-Glutamyl transpeptidase is induced by 4-hydroxynonenal via EpRE/Nrf2 signaling in rat epithelial type II cells

Zhang

Liu

Dickinson

et al. 2006

Free Radical Biology and Medicine

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“…In one of these models, Keap1 is modified by blocking agents at Cys-273 and Cys-288, which prevents it from capturing Nrf2 and targeting it for degradation (17). In the other, Nrf2 is phosphorylated by PKC or PKR-like endoplasmic reticulum-resident kinase (PERK) in response to inducing agents, thereby enabling the basic-region leucine zipper protein to either evade Keap1 or dissociate from Keap1 (23)(24)(25)(26)(27).…”

mentioning

confidence: 99%

Utility of siRNA against Keap1 as a strategy to stimulate a cancer chemopreventive phenotype

Devling

Lindsay²,

McLellan³

et al. 2005

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

117

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A duplex 21 nucleotide small interfering RNA (siRNA) against human Keap1 is described that represents a unique class of cancer chemopreventive agent. This siRNA can knockdown Keap1 mRNA and thereby relieve negative regulation of nuclear factor erythroid 2 p45-related factor 2 (Nrf2)-mediated gene expression. The siRNA lowered endogenous Keap1 mRNA to <30% of control levels between 24 and 72 h after transfection in human HaCaT keratinocyte cells and was capable of blocking ectopic expression of FLAG-tagged human Keap1 protein but not that of ectopic V5-tagged mouse Keap1 protein. Transfection of human HaCaT cells with Keap1 siRNA markedly enhanced endogenous levels of nuclear factor erythroid 2 p45-related factor 2 (Nrf2) protein and increased transcription of an antioxidant response element-driven reporter gene by 2.3-fold. Furthermore, 48 h after transfection of these cells with Keap1 siRNA, expression of aldo-keto reductase 1C1͞2 and the glutamate cysteine ligase catalytic and modifier subunits was elevated between 5-and 14-fold. A modest increase of 3-fold in NAD(P)H:quinone oxidoreductase 1 was also observed. The Keap1 siRNA produced a 1.75-fold increase in intracellular glutathione 48 h after transfection. Thus, antagonism of Keap1 by siRNA can be used to preadapt human cells to oxidative stress without the need to expose them to redox stressors.antioxidant ͉ chemoprevention ͉ glutathione ͉ nuclear factor erythroid 2 p45-related factor 2 ͉ aldo-keto reductase

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“…The PKC family of proteins comprises at least ten serine/threonine kinases (Rushworth et al, 2006). Among these, PKCα is known to phosphorylate Nrf2 at Ser 40 , resulting in translocation of Nrf2 to the nucleus, where it forms a heterodimer and activates HO-1 gene expression (Bloom and Jaiswal, 2003). In the present study, the PKCα inhibitor reduced both the expression and nuclear translocation of Nrf2, leading to HO-1 downregulation.…”

Section: Discussionmentioning

confidence: 57%

Enhancement of parthenolide-induced apoptosis by a PKC-alpha inhibition through heme oxygenase-1 blockage in cholangiocarcinoma cells

et al. 2010

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Cholangiocarcinoma (CC) is a chemoresistant intrahepatic bile duct carcinoma with a poor prognosis. The aims of this study were to identify molecular pathways that enhance sesquiterpene lactone parthenolide (PTL)-induced anticancer effects on CC cells. The effects of PTL on apoptosis and hemoxygenase-1 (HO-1) induction were examined in CC cell lines. The enhancement of PTL-mediated apoptosis by modulation of HO-1 expression and the mechanisms involved were also examined in an in vitro cell system. Low PTL concentrations (5 to 10 μM) led to Nrf2-dependent HO-1 induction, which attenuated the apoptogenic effect of PTL in Choi-CK and SCK cells. PTL-mediated apoptosis was enhanced by the protein kinase C-alpha inhibitor Ro317549 (Ro) through inhibition of expression and nuclear translocation of Nrf2, resulting in blockage of HO-1 expression. Finally, HO-1 silencing resulted in enhancement of apoptotic cell death in CC cells. The combination of PTL and Ro efficiently improved tumor growth inhibition compared to treatment with either agent alone in an in vivo subcutaneous tumor model. In conclusion, the modulation of HO-1 expression substantially improved the anticancer effect of PTL. The combination of PTL and Ro could prove to be a valuable chemotherapeutic strategy for CC.

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Cited by 472 publications

References 25 publications

γ-Glutamyl transpeptidase is induced by 4-hydroxynonenal via EpRE/Nrf2 signaling in rat epithelial type II cells

γ-Glutamyl transpeptidase is induced by 4-hydroxynonenal via EpRE/Nrf2 signaling in rat epithelial type II cells

Utility of siRNA against Keap1 as a strategy to stimulate a cancer chemopreventive phenotype

Enhancement of parthenolide-induced apoptosis by a PKC-alpha inhibition through heme oxygenase-1 blockage in cholangiocarcinoma cells

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