Protein Kinase C Modulates Aryl Hydrocarbon Receptor Nuclear Translocator Protein-mediated Transactivation Potential in a Dimer Context

Long, William P.; Chen, Xi; Perdew, Gary H.

doi:10.1074/jbc.274.18.12391

Cited by 44 publications

(21 citation statements)

References 34 publications

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“…Therefore PKC phosphorylation does not appear to play a role in either the association of Nrf2/MafK heterodimer with the ARE sequence or dimerization of Nrf2 with MafK. PKC has also been implicated in the aryl hydrocarbon receptor-mediated transcriptional regulation (26,27). Although PKC action in that pathway appears to involve a nuclear event, it does not impact the DNA-binding activity of the transcription factor (26).…”

Section: Phosphorylation Of Nrf2 By Pkc Promotes Its Dissociation Fromentioning

confidence: 99%

Phosphorylation of Nrf2 at Ser-40 by Protein Kinase C Regulates Antioxidant Response Element-mediated Transcription

Huang¹,

Nguyen²,

Pickett³

2002

Journal of Biological Chemistry

938

645

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Nrf2, a basic leucine zipper transcription factor, is an essential activator of the coordinated transcription of genes encoding antioxidant enzymes and phase II detoxifying enzymes through the regulatory sequence termed antioxidant response element (ARE). Recently we reported evidence for the involvement of protein kinase C (PKC) in phosphorylating Nrf2 and triggering its nuclear translocation in response to oxidative stress. We show here that phosphorylation of purified rat Nrf2 by the catalytic subunit of PKC was blocked by a synthetic peptide mimicking one of the potential PKC sites. Accordingly, Nrf2 bearing a Ser to Ala mutation at amino acid 40 (S40A) could not be phosphorylated by PKC. The S40A mutation did not affect in vitro binding of Nrf2/ MafK to the ARE. However, it partially impaired Nrf2 activation of ARE-driven transcription in a reporter gene assay when Keap1 was overexpressed. In vitro transcribed/translated Keap1 could be coimmunoprecipitated with Nrf2. Phosphorylation of wild-type Nrf2 by PKC promoted its dissociation from Keap1, whereas the Nrf2-S40A mutant remained associated. These findings together with our prior studies suggest that the PKC-catalyzed phosphorylation of Nrf2 at Ser-40 is a critical signaling event leading to ARE-mediated cellular antioxidant response. The antioxidant response element (ARE)1 is a regulatory sequence involved in the coordinated transcriptional activation of genes coding for a number of antioxidant enzymes and phase II detoxifying enzymes (1-6). Reactive oxygen species and electrophiles are potent activators of genes containing an ARE, mediated by the basic leucine zipper (bZIP) transcription factor Nrf2 (NF-E2-related factor 2) (7-9). Accumulated evidence from studies of nrf2-null mice has established that Nrf2 is an essential ARE-binding factor involved in both constitutive and inducible gene expression via the ARE (9 -11). An important regulatory step leading to ARE activation is the oxidative stress-induced nuclear translocation of Nrf2, which normally appears to be sequestered in the cytoplasm by the cytoskeletonbinding Keap1 protein (12-14). However, the precise mechanism by which ARE-activating signals reach Nrf2 and cause dissociation of the putative inhibitory Nrf2-Keap1 complex remains unclear.Several protein kinase pathways have been implicated in transducing oxidative stress signals to gene expression mediated through the ARE. A number of reports have addressed a possible role for extracellular signal-regulated kinase (ERK1/2) in ARE activation. The findings have however remained controversial: ERK1/2 has been found to regulate the ARE positively in certain hepatoma cells (15-17) but negatively in others (18). Similarly, p38 MAP (mitogen-activated protein) kinase has also been shown to affect ARE activity, either positively (17,19,20) or negatively (16,21). More recently, phosphatidylinositol 3-kinase and its downstream target Akt/PKB (protein kinase B) have been linked to activation of the ARE in hepatoma (18, 19) and neuroblastoma (22) cell lin...

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Section: Phosphorylation Of Nrf2 By Pkc Promotes Its Dissociation Fromentioning

confidence: 99%

Phosphorylation of Nrf2 at Ser-40 by Protein Kinase C Regulates Antioxidant Response Element-mediated Transcription

Huang¹,

Nguyen²,

Pickett³

2002

Journal of Biological Chemistry

938

645

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“…The AhR signaling pathway has been shown to be influenced by several protein kinases, including mitogen-activated protein kinases (MAPKs) and protein kinases A and C (Long et al, 1999;Du et al, 2005;Henklová et al, 2008). In addition, the Ca 2ϩ /calmodulindependent protein kinase (CaMK) I␣ has been recently recognized as a contributing factor to AhR-mediated genomic response (Monteiro et al, 2008).…”

mentioning

confidence: 99%

Activation of the Aryl Hydrocarbon Receptor by the Calcium/Calmodulin-Dependent Protein Kinase Kinase Inhibitor 7-Oxo-7H-benzimidazo[2,1-a ]benz[de]isoquinoline-3-carboxylic Acid (STO-609)

Monteiro

Gilot²,

Langouët³

et al. 2008

Drug Metabolism and Disposition

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“…First, a hARNT consensus binding sequence is present in the Snn promoter region (Dejneka et al, 1998). Second, hARNT has been shown to be regulated by PKC (Long et al, 1999); this attribute provides a mechanism whereby Snn expression would be induced by PKC. Third, hARNT is active in endothelial cells and Jurkat cells (Adelman et al, 1999;Nagai et al, 2002).…”

Section: Discussionmentioning

confidence: 99%

Protein Kinase Cϵ Regulates Tumor Necrosis Factor-α-Induced Stannin Gene Expression

Reese

Davidson

Billingsley³

et al. 2005

The Journal of Pharmacology and Experimental Therapeutics

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Stannin (Snn) is a highly conserved vertebrate protein that has been closely linked to trimethyltin (TMT) toxicity. We have previously demonstrated that Snn is required for TMT-induced cell death. Others have shown that TMT exposure results in tumor necrosis factor-␣ (TNF␣) production and that TNF␣ treatment induces Snn gene expression in human umbilical vein endothelial cells (HUVECs). In this study, we investigated a signaling mechanism by which Snn gene expression is regulated by TMT and demonstrated that TNF␣ stimulates Snn gene expression in a protein kinase C⑀-dependent manner in HUVECs in response to TMT exposure. Supporting this, we show that TMTinduced toxicity is significantly blocked by pretreatment with an anti-TNF␣ antibody in HUVECs. Using a quantitative real-time polymerase chain reaction assay, we also show that the level of Snn gene expression is significantly increased in HUVECs in response to either TMT or TNF␣ treatment. This TNF␣-induced Snn gene expression is blocked when HUVECs were pretreated with bisindolylmaleimide I, an inhibitor of protein kinase C (PKC). In contrast, when HUVECs were treated with phorbol 12-myristate 13-acetate, a PKC activator, we observed a significant increase in Snn gene expression. Using isotypespecific siRNA against PKC, we further show that knockdown of PKC⑀, but not PKC␦ or PKC, significantly blocked TNF␣-induced Snn gene expression. Together, these results indicate that TNF␣-induced, PKC⑀-dependent Snn expression may be a critical factor in TMT-induced cytotoxicity.

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Protein Kinase C Modulates Aryl Hydrocarbon Receptor Nuclear Translocator Protein-mediated Transactivation Potential in a Dimer Context

Abstract: The ARNT 1 protein is a member of the bHLH-PAS family of transcription factors and is the central dimerization partner (Fig.

Cited by 44 publications

References 34 publications

Phosphorylation of Nrf2 at Ser-40 by Protein Kinase C Regulates Antioxidant Response Element-mediated Transcription

Phosphorylation of Nrf2 at Ser-40 by Protein Kinase C Regulates Antioxidant Response Element-mediated Transcription

Activation of the Aryl Hydrocarbon Receptor by the Calcium/Calmodulin-Dependent Protein Kinase Kinase Inhibitor 7-Oxo-7H-benzimidazo[2,1-a ]benz[de]isoquinoline-3-carboxylic Acid (STO-609)

Protein Kinase Cϵ Regulates Tumor Necrosis Factor-α-Induced Stannin Gene Expression

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