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Article ; Online: Retraction: Antioxidant-induced INrf2 (Keap1) tyrosine 85 phosphorylation controls the nuclear export and degradation of the INrf2-Cul3-Rbx1 complex to allow normal Nrf2 activation and repression.

Kaspar, James W / Niture, Suryakant K / Jaiswal, Anil K

2017 Volume 130, Issue 4, Page(s) 814

Language	English
Publishing date	2017-02-15
Publishing country	England
Document type	Journal Article ; Retraction of Publication
ZDB-ID	2993-2
ISSN	1477-9137 ; 0021-9533
ISSN (online)	1477-9137
ISSN	0021-9533
DOI	10.1242/jcs.201947
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Zs.MG 14: Show issues

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Article: Engineering of a Peptide α-N-Methyltransferase to Methylate Non-Proteinogenic Amino Acids.

Song, Haigang / Burton, Antony J / Shirran, Sally L / Fahrig-Kamarauskaitė, Jūratė / Kaspar, Hannelore / Muir, Tom W / Künzler, Markus / Naismith, James H

Angewandte Chemie (Weinheim an der Bergstrasse, Germany)

2021 Volume 133, Issue 26, Page(s) 14440–14444

Abstract: Introduction of α-N-methylated non-proteinogenic amino acids into peptides can improve their biological activities, membrane permeability and proteolytic stability. This is commonly achieved, in nature and in the lab, by assembling pre-methylated amino ... ...

Abstract	Introduction of α-N-methylated non-proteinogenic amino acids into peptides can improve their biological activities, membrane permeability and proteolytic stability. This is commonly achieved, in nature and in the lab, by assembling pre-methylated amino acids. The more appealing route of methylating amide bonds is challenging. Biology has evolved an α-N-automethylating enzyme, OphMA, which acts on the amide bonds of peptides fused to its C-terminus. Due to the ribosomal biosynthesis of its substrate, the activity of this enzyme towards peptides with non-proteinogenic amino acids has not been addressed. An engineered OphMA, intein-mediated protein ligation and solid-phase peptide synthesis have allowed us to demonstrate the methylation of amide bonds in the context of non-natural amides. This approach may have application in the biotechnological production of therapeutic peptides.
Language	English
Publishing date	2021-05-17
Publishing country	Germany
Document type	Journal Article
ZDB-ID	506609-8
ISSN	1521-3757 ; 0044-8249 ; 0932-2140
ISSN (online)	1521-3757
ISSN	0044-8249 ; 0932-2140
DOI	10.1002/ange.202100818
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Article ; Online: Engineering of a Peptide α-N-Methyltransferase to Methylate Non-Proteinogenic Amino Acids.

Song, Haigang / Burton, Antony J / Shirran, Sally L / Fahrig-Kamarauskaitė, Jūratė / Kaspar, Hannelore / Muir, Tom W / Künzler, Markus / Naismith, James H

Angewandte Chemie (International ed. in English)

2021 Volume 60, Issue 26, Page(s) 14319–14323

Abstract	Introduction of α-N-methylated non-proteinogenic amino acids into peptides can improve their biological activities, membrane permeability and proteolytic stability. This is commonly achieved, in nature and in the lab, by assembling pre-methylated amino acids. The more appealing route of methylating amide bonds is challenging. Biology has evolved an α-N-automethylating enzyme, OphMA, which acts on the amide bonds of peptides fused to its C-terminus. Due to the ribosomal biosynthesis of its substrate, the activity of this enzyme towards peptides with non-proteinogenic amino acids has not been addressed. An engineered OphMA, intein-mediated protein ligation and solid-phase peptide synthesis have allowed us to demonstrate the methylation of amide bonds in the context of non-natural amides. This approach may have application in the biotechnological production of therapeutic peptides.
MeSH term(s)	Amides/chemistry ; Amides/metabolism ; Amino Acids/chemistry ; Amino Acids/metabolism ; Methylation ; Methyltransferases/chemistry ; Methyltransferases/metabolism ; Peptides/chemistry ; Peptides/metabolism ; Protein Conformation ; Protein Engineering
Chemical Substances	Amides ; Amino Acids ; Peptides ; Methyltransferases (EC 2.1.1.-)
Language	English
Publishing date	2021-05-17
Publishing country	Germany
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2011836-3
ISSN	1521-3773 ; 1433-7851
ISSN (online)	1521-3773
ISSN	1433-7851
DOI	10.1002/anie.202100818
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Article ; Online: An autoregulatory loop between Nrf2 and Cul3-Rbx1 controls their cellular abundance.

Kaspar, James W / Jaiswal, Anil K

The Journal of biological chemistry

2010 Volume 285, Issue 28, Page(s) 21349–21358

Abstract: The INrf2 (Keap1)/Cul3-Rbx1 complex constantly degrades Nrf2 under normal conditions. When a cell encounters oxidative or electrophilic stress, Nrf2 dissociates from the INrf2/Cul3-Rbx1 complex and translocates into the nucleus. In the nucleus, Nrf2 ... ...

Abstract	The INrf2 (Keap1)/Cul3-Rbx1 complex constantly degrades Nrf2 under normal conditions. When a cell encounters oxidative or electrophilic stress, Nrf2 dissociates from the INrf2/Cul3-Rbx1 complex and translocates into the nucleus. In the nucleus, Nrf2 activates a myriad of antioxidant and defensive genes that protect cells. Nrf2 is then exported out of the nucleus and degraded. INrf2 serves as a substrate adaptor to link Nrf2 to Cul3 and Rbx1. Cul3 and Rbx1 make up the ubiquitin ligase complex that is responsible for the ubiquitination and degradation of Nrf2. Previously we have shown a feedback autoregulatory loop between Nrf2 and INrf2 indicating that Nrf2 regulates INrf2 by controlling its transcription. Here we are extending this research by demonstrating the presence of another feedback autoregulatory loop between Cul3-Rbx1 and Nrf2. Experiments using Hepa-1 and HepG2 cells indicate that Nrf2 controls its own degradation by regulating expression and induction of Cul3-Rbx1 genes. Treatment with the antioxidant tert-Butylhydroquinone (t-BHQ) leads to induction of Cul3-Rbx1 genes. Mutagenesis and transfection experiments identified an antioxidant response element in the forward and reverse strands of the proximal Cul3 and Rbx1 promoters, respectively, that Nrf2 binds and regulates expression and antioxidant induction of the Cul3-Rbx1 genes. In addition, short interfering RNA inhibition and overexpression of Nrf2 led to a respective decrease and increase in Cul3-Rbx1 gene expression. The increase in Cul3-Rbx1 leads to ubiquitination and degradation of Nrf2. These data suggest that Nrf2 regulates Cul3-Rbx1 by controlling regulation of expression and induction of Cul3-Rbx1. The induction of Cul3-Rbx1 control Nrf2 by increasing degradation.
MeSH term(s)	Animals ; Antioxidants/metabolism ; Carrier Proteins/metabolism ; Cell Line, Tumor ; Cullin Proteins/metabolism ; Gene Expression Regulation ; Humans ; Mice ; Models, Biological ; NF-E2-Related Factor 2/metabolism ; Transcription, Genetic ; Ubiquitin/metabolism
Chemical Substances	Antioxidants ; CUL3 protein, human ; Carrier Proteins ; Cul3 protein, mouse ; Cullin Proteins ; NF-E2-Related Factor 2 ; NFE2L2 protein, human ; Nfe2l2 protein, mouse ; RBX1 protein, human ; RBX1 protein, mouse ; Ubiquitin
Language	English
Publishing date	2010-05-07
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	2997-x
ISSN	1083-351X ; 0021-9258
ISSN (online)	1083-351X
ISSN	0021-9258
DOI	10.1074/jbc.M110.121863
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Article ; Online: Tyrosine phosphorylation controls nuclear export of Fyn, allowing Nrf2 activation of cytoprotective gene expression.

Kaspar, James W / Jaiswal, Anil K

FASEB journal : official publication of the Federation of American Societies for Experimental Biology

2010 Volume 25, Issue 3, Page(s) 1076–1087

Abstract: Fyn, an Src kinase family member, acts as a negative regulator of NF-E2-related factor 2 (Nrf2). Under stressful conditions, Nrf2 translocates into the nucleus and binds to the antioxidant response element (ARE), activating defensive gene expression. ... ...

Abstract	Fyn, an Src kinase family member, acts as a negative regulator of NF-E2-related factor 2 (Nrf2). Under stressful conditions, Nrf2 translocates into the nucleus and binds to the antioxidant response element (ARE), activating defensive gene expression. Once Nrf2 completes activation, Fyn phosphorylates tyrosine 568 of Nrf2, resulting in the nuclear export and degradation of Nrf2. The present studies demonstrate that within 0.5 h of antioxidant treatment in human hepatoblastoma (HepG2) cells, Fyn exports out of the nucleus, allowing Nrf2 unimpeded movement to the ARE. Mutation of tyrosine 213 of Fyn stymied nuclear export, suggesting that tyrosine phosphorylation controls nuclear export. Mass spectrometry confirmed tyrosine 213 as the site of phosphorylation. ChIP and real-time PCR assays revealed that FynY213A mutant caused decreased binding of Nrf2 to the promoter of defensive gene NAD(P)H:quinone oxidoreductase 1 (NQO1) and decreased NQO1 expression by 5-fold (P<0.0001) compared to wild-type Fyn. In addition, a putative nuclear export signal (NES) was identified, and mutation of it also inhibited nuclear export of Fyn. Furthermore, FynY213A caused an increased susceptibility to cell death following treatment with etoposide in mouse hepatoma (Hepa-1) cells. The preinduction regulation of Nrf2 is controlled by the nuclear export of Fyn, allowing for activation of defensive gene expression.
MeSH term(s)	Active Transport, Cell Nucleus/physiology ; Adaptor Proteins, Signal Transducing/metabolism ; Animals ; Antioxidants/pharmacology ; Carcinoma, Hepatocellular ; Cell Death/physiology ; Cell Nucleus/metabolism ; Cell Survival/physiology ; Cytoskeletal Proteins/metabolism ; Genistein/pharmacology ; Hep G2 Cells ; Humans ; Karyopherins/antagonists & inhibitors ; Kelch-Like ECH-Associated Protein 1 ; Mice ; NF-E2-Related Factor 2/metabolism ; Oxidative Stress/physiology ; Phosphorylation/physiology ; Proteasome Endopeptidase Complex/metabolism ; Proteasome Inhibitors ; Protein Kinase Inhibitors/pharmacology ; Proto-Oncogene Proteins c-fyn/genetics ; Proto-Oncogene Proteins c-fyn/metabolism ; Receptors, Cytoplasmic and Nuclear/antagonists & inhibitors ; Tyrosine/genetics ; Tyrosine/metabolism ; Exportin 1 Protein
Chemical Substances	Adaptor Proteins, Signal Transducing ; Antioxidants ; Cytoskeletal Proteins ; Karyopherins ; Keap1 protein, mouse ; Kelch-Like ECH-Associated Protein 1 ; NF-E2-Related Factor 2 ; Nfe2l2 protein, mouse ; Proteasome Inhibitors ; Protein Kinase Inhibitors ; Receptors, Cytoplasmic and Nuclear ; Tyrosine (42HK56048U) ; Genistein (DH2M523P0H) ; Fyn protein, mouse (EC 2.7.10.2) ; Proto-Oncogene Proteins c-fyn (EC 2.7.10.2) ; Proteasome Endopeptidase Complex (EC 3.4.25.1)
Language	English
Publishing date	2010-11-19
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	639186-2
ISSN	1530-6860 ; 0892-6638
ISSN (online)	1530-6860
ISSN	0892-6638
DOI	10.1096/fj.10-171553
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Zs.A 2266: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular Jg. 1995 - 2021: Lesesall (1.OG) ab Jg. 2022: Lesesaal (EG)
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Article ; Online: Antioxidant-induced phosphorylation of tyrosine 486 leads to rapid nuclear export of Bach1 that allows Nrf2 to bind to the antioxidant response element and activate defensive gene expression.

Kaspar, James W / Jaiswal, Anil K

The Journal of biological chemistry

2009 Volume 285, Issue 1, Page(s) 153–162

Abstract: Antioxidants cause stabilization and nuclear translocation of NF-E2-related factor 2 (Nrf2), where it binds to the antioxidant response element (ARE) and induces up-regulation of defensive genes that protect cells against oxidative and electrophilic ... ...

Abstract	Antioxidants cause stabilization and nuclear translocation of NF-E2-related factor 2 (Nrf2), where it binds to the antioxidant response element (ARE) and induces up-regulation of defensive genes that protect cells against oxidative and electrophilic stress. Bach1, the negative regulator of Nrf2, competes with Nrf2 for binding to the ARE in the human NQO1 promoter. In this study, we demonstrate that Bach1 exits the nucleus within 1-2 h upon antioxidant treatment. Genistein, an inhibitor of tyrosine kinases, blocked nuclear export of Bach1. Site-directed mutagenesis and immunoprecipitation assays identified tyrosine 486 that was phosphorylated in response to the antioxidant and was essential for nuclear export of Bach1. Chromatin immunoprecipitation assays revealed a competitive interplay between Bach1 and Nrf2 at 1-2 and 4 h for binding to the human NQO1 ARE. Luciferase and real time PCR assays showed a significant decrease in antioxidant induction of reporter activity and mRNA levels in cells transfected with mutant Bach1 compared with wild type. This decrease was due to the absence of nuclear export of the mutant protein. Bach1 levels inside the nucleus returned to normal at 4 h after antioxidant treatment in the absence but not in the presence of protein synthesis inhibitor cycloheximide. In addition, antioxidant treatment increased the transcription of Bach1 as shown by pulse chase and real time PCR experiments. Taken together, these results indicate that increased synthesis of Bach1 restored its nuclear levels to normal at 4 h. In conclusion, antioxidant-induced tyrosine 486 phosphorylation leads to nuclear exit of Bach1, thus allowing Nrf2 access to the ARE.
MeSH term(s)	Active Transport, Cell Nucleus/drug effects ; Animals ; Antioxidants/pharmacology ; Basic-Leucine Zipper Transcription Factors/chemistry ; Basic-Leucine Zipper Transcription Factors/genetics ; Basic-Leucine Zipper Transcription Factors/metabolism ; Cadmium/pharmacology ; Cell Nucleus/drug effects ; Cell Nucleus/metabolism ; Cycloheximide/pharmacology ; Fanconi Anemia Complementation Group Proteins/chemistry ; Fanconi Anemia Complementation Group Proteins/genetics ; Fanconi Anemia Complementation Group Proteins/metabolism ; Gene Expression Regulation/drug effects ; Hep G2 Cells ; Humans ; Hydroquinones/pharmacology ; Karyopherins/metabolism ; Mice ; Mutant Proteins ; Mutation/genetics ; NAD(P)H Dehydrogenase (Quinone)/metabolism ; NF-E2-Related Factor 2/metabolism ; Phosphorylation/drug effects ; Phosphotyrosine/metabolism ; Protein Binding/drug effects ; Protein Kinase Inhibitors/pharmacology ; Protein Structure, Tertiary ; RNA, Messenger/genetics ; RNA, Messenger/metabolism ; Receptors, Cytoplasmic and Nuclear/metabolism ; Response Elements/genetics ; Exportin 1 Protein
Chemical Substances	Antioxidants ; BACH1 protein, human ; Bach1 protein, mouse ; Basic-Leucine Zipper Transcription Factors ; Fanconi Anemia Complementation Group Proteins ; Hydroquinones ; Karyopherins ; Mutant Proteins ; NF-E2-Related Factor 2 ; Protein Kinase Inhibitors ; RNA, Messenger ; Receptors, Cytoplasmic and Nuclear ; Cadmium (00BH33GNGH) ; Phosphotyrosine (21820-51-9) ; Cycloheximide (98600C0908) ; 2-tert-butylhydroquinone (C12674942B) ; NAD(P)H Dehydrogenase (Quinone) (EC 1.6.5.2) ; NQO1 protein, human (EC 1.6.5.2)
Language	English
Publishing date	2009-11-06
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	2997-x
ISSN	1083-351X ; 0021-9258
ISSN (online)	1083-351X
ISSN	0021-9258
DOI	10.1074/jbc.M109.040022
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Article ; Online: Antioxidant-induced INrf2 (Keap1) tyrosine 85 phosphorylation controls the nuclear export and degradation of the INrf2-Cul3-Rbx1 complex to allow normal Nrf2 activation and repression.

Kaspar, James W / Niture, Suryakant K / Jaiswal, Anil K

publication RETRACTED

Journal of cell science

2012 Volume 125, Issue Pt 4, Page(s) 1027–1038

Abstract: INrf2 (Keap1) serves as a negative regulator of the cytoprotective transcription factor Nrf2. At basal levels, INrf2 functions as a substrate adaptor to sequester Nrf2 into the Cul3-Rbx1 E3 ligase complex for ubiquitylation and proteasomal degradation. ... ...

Abstract	INrf2 (Keap1) serves as a negative regulator of the cytoprotective transcription factor Nrf2. At basal levels, INrf2 functions as a substrate adaptor to sequester Nrf2 into the Cul3-Rbx1 E3 ligase complex for ubiquitylation and proteasomal degradation. In response to antioxidants, Nrf2 is released from the INrf2-Cul3-Rbx1 complex and translocates into the nucleus, where it activates ARE-mediated cytoprotective gene expression. The present studies demonstrate that INrf2, Cul3 and Rbx1 export out of the nucleus and are degraded during the early or pre-induction response to antioxidants. Mutation of Tyr85 in INrf2 stymied the nuclear export of INrf2, suggesting that tyrosine phosphorylation controls the pre-induction nuclear export and degradation in response to antioxidants. The nuclear export of Cul3-Rbx1 were also blocked when INrf2Tyr85 was mutated, suggesting that INrf2-Cul3-Rbx1 undergo nuclear export as a complex. INrf2 siRNA also inhibited the nuclear export of Cul3-Rbx1, confirming that Cul3-Rbx1 requires INrf2 for nuclear export. Newly synthesized INrf2-Cul3-Rbx1 is imported back into the nucleus during the post-induction period to ubiquitylate and degrade Nrf2. Mutation of INrf2Tyr85 had no effect on activation of Nrf2 but led to nuclear accumulation of Nrf2 during the post-induction period owing to reduced export and degradation of Nrf2. Our results also showed that nuclear export and degradation followed by the new synthesis of INrf2-Cul3-Rbx1 controls the cellular abundance of the proteins during different phases of antioxidant responses. In conclusion, the early or pre-induction nuclear export of INrf2 in response to antioxidants is controlled by tyrosine phosphorylation, whereas the nuclear export of Cul3 and Rbx1 is controlled by INrf2, allowing normal activation or repression of Nrf2.
MeSH term(s)	Active Transport, Cell Nucleus/drug effects ; Adaptor Proteins, Signal Transducing/chemistry ; Adaptor Proteins, Signal Transducing/genetics ; Adaptor Proteins, Signal Transducing/metabolism ; Animals ; Antioxidants/pharmacology ; Carrier Proteins/chemistry ; Carrier Proteins/genetics ; Carrier Proteins/metabolism ; Cell Line, Tumor ; Cell Nucleus/drug effects ; Cell Nucleus/metabolism ; Cullin Proteins/chemistry ; Cullin Proteins/metabolism ; Cytoskeletal Proteins/chemistry ; Cytoskeletal Proteins/genetics ; Cytoskeletal Proteins/metabolism ; Cytosol/drug effects ; Cytosol/metabolism ; Humans ; Immunoprecipitation ; Intracellular Signaling Peptides and Proteins/chemistry ; Intracellular Signaling Peptides and Proteins/genetics ; Intracellular Signaling Peptides and Proteins/metabolism ; Karyopherins/antagonists & inhibitors ; Kelch-Like ECH-Associated Protein 1 ; Mutant Proteins/chemistry ; Mutant Proteins/genetics ; Mutant Proteins/metabolism ; Mutation ; NF-E2-Related Factor 2/metabolism ; Phosphorylation ; Phosphotyrosine/genetics ; Phosphotyrosine/metabolism ; Protein Binding ; Protein Kinase Inhibitors/pharmacology ; Receptors, Cytoplasmic and Nuclear/antagonists & inhibitors ; Exportin 1 Protein
Chemical Substances	Adaptor Proteins, Signal Transducing ; Antioxidants ; CUL3 protein, human ; Carrier Proteins ; Cul3 protein, mouse ; Cullin Proteins ; Cytoskeletal Proteins ; Intracellular Signaling Peptides and Proteins ; KEAP1 protein, human ; Karyopherins ; Keap1 protein, mouse ; Kelch-Like ECH-Associated Protein 1 ; Mutant Proteins ; NF-E2-Related Factor 2 ; NFE2L2 protein, human ; Protein Kinase Inhibitors ; RBX1 protein, human ; RBX1 protein, mouse ; Receptors, Cytoplasmic and Nuclear ; Phosphotyrosine (21820-51-9)
Language	English
Publishing date	2012-03-24
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Retracted Publication
ZDB-ID	2993-2
ISSN	1477-9137 ; 0021-9533
ISSN (online)	1477-9137
ISSN	0021-9533
DOI	10.1242/jcs.097295
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Article: Plasma Hydrogen Sulfide Is Positively Associated With Post-operative Survival in Patients Undergoing Surgical Revascularization.

Longchamp, Alban / MacArthur, Michael R / Trocha, Kaspar / Ganahl, Janine / Mann, Charlotte G / Kip, Peter / King, William W / Sharma, Gaurav / Tao, Ming / Mitchell, Sarah J / Ditrói, Tamás / Yang, Jie / Nagy, Péter / Ozaki, C Keith / Hine, Christopher / Mitchell, James R

Frontiers in cardiovascular medicine

2021 Volume 8, Page(s) 750926

Abstract: Objective: ...

Abstract	Objective:
Language	English
Publishing date	2021-10-25
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2781496-8
ISSN	2297-055X
ISSN	2297-055X
DOI	10.3389/fcvm.2021.750926
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Article: Tyrosine phosphorylation controls nuclear export of Fyn, allowing Nrf2 activation of cytoprotective gene expression

Kaspar, James W / Jaiswal, Anil K

FASEB journal. 2011 Mar., v. 25, no. 3

2011

Abstract: ... allowing for activation of defensive gene expression.--Kaspar, J. W., Jaiswal, A. K. Tyrosine ...

Abstract	Fyn, an Src kinase family member, acts as a negative regulator of NF-E2-related factor 2 (Nrf2). Under stressful conditions, Nrf2 translocates into the nucleus and binds to the antioxidant response element (ARE), activating defensive gene expression. Once Nrf2 completes activation, Fyn phosphorylates tyrosine 568 of Nrf2, resulting in the nuclear export and degradation of Nrf2. The present studies demonstrate that within 0.5 h of antioxidant treatment in human hepatoblastoma (HepG2) cells, Fyn exports out of the nucleus, allowing Nrf2 unimpeded movement to the ARE. Mutation of tyrosine 213 of Fyn stymied nuclear export, suggesting that tyrosine phosphorylation controls nuclear export. Mass spectrometry confirmed tyrosine 213 as the site of phosphorylation. ChIP and real-time PCR assays revealed that FynY213A mutant caused decreased binding of Nrf2 to the promoter of defensive gene NAD(P)H:quinone oxidoreductase 1 (NQO1) and decreased NQO1 expression by 5-fold (P<0.0001) compared to wild-type Fyn. In addition, a putative nuclear export signal (NES) was identified, and mutation of it also inhibited nuclear export of Fyn. Furthermore, FynY213A caused an increased susceptibility to cell death following treatment with etoposide in mouse hepatoma (Hepa-1) cells. The preinduction regulation of Nrf2 is controlled by the nuclear export of Fyn, allowing for activation of defensive gene expression.--Kaspar, J. W., Jaiswal, A. K. Tyrosine phosphorylation controls nuclear export of Fyn, allowing Nrf2 activation of cytoprotective gene expression.
Language	English
Dates of publication	2011-03
Size	p. 1076-1087.
Publishing place	The Federation of American Societies for Experimental Biology
Document type	Article
ZDB-ID	639186-2
ISSN	1530-6860 ; 0892-6638
ISSN (online)	1530-6860
ISSN	0892-6638
Database	NAL-Catalogue (AGRICOLA)

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Article: Antioxidant-induced Phosphorylation of Tyrosine 486 Leads to Rapid Nuclear Export of Bach1 That Allows Nrf2 to Bind to the Antioxidant Response Element and Activate Defensive Gene Expression

Kaspar, James W / Jaiswal, Anil K

Journal of biological chemistry. 2010 Jan. 1, v. 285, no. 1

2010

Abstract	Antioxidants cause stabilization and nuclear translocation of NF-E2-related factor 2 (Nrf2), where it binds to the antioxidant response element (ARE) and induces up-regulation of defensive genes that protect cells against oxidative and electrophilic stress. Bach1, the negative regulator of Nrf2, competes with Nrf2 for binding to the ARE in the human NQO1 promoter. In this study, we demonstrate that Bach1 exits the nucleus within 1-2 h upon antioxidant treatment. Genistein, an inhibitor of tyrosine kinases, blocked nuclear export of Bach1. Site-directed mutagenesis and immunoprecipitation assays identified tyrosine 486 that was phosphorylated in response to the antioxidant and was essential for nuclear export of Bach1. Chromatin immunoprecipitation assays revealed a competitive interplay between Bach1 and Nrf2 at 1-2 and 4 h for binding to the human NQO1 ARE. Luciferase and real time PCR assays showed a significant decrease in antioxidant induction of reporter activity and mRNA levels in cells transfected with mutant Bach1 compared with wild type. This decrease was due to the absence of nuclear export of the mutant protein. Bach1 levels inside the nucleus returned to normal at 4 h after antioxidant treatment in the absence but not in the presence of protein synthesis inhibitor cycloheximide. In addition, antioxidant treatment increased the transcription of Bach1 as shown by pulse chase and real time PCR experiments. Taken together, these results indicate that increased synthesis of Bach1 restored its nuclear levels to normal at 4 h. In conclusion, antioxidant-induced tyrosine 486 phosphorylation leads to nuclear exit of Bach1, thus allowing Nrf2 access to the ARE.
Language	English
Dates of publication	2010-0101
Size	p. 153-162.
Publishing place	American Society for Biochemistry and Molecular Biology
Document type	Article
ZDB-ID	2997-x
ISSN	1083-351X ; 0021-9258
ISSN (online)	1083-351X
ISSN	0021-9258
Database	NAL-Catalogue (AGRICOLA)

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