Abstract
While small Maf proteins have been suggested to be essential for the Nrf2-mediated activation of antioxidant response element (ARE)-dependent genes, the extent of their requirement remains to be fully documented. To address this issue, we generated mafG::mafF double-mutant mice possessing MafK as the single available small Maf. Induction of the NAD(P)H:quinone oxidoreductase 1 (NQO1) gene was significantly impaired in double-mutant mice treated with butylated hydroxyanisole, while other ARE-dependent genes were less affected. Similarly, in a keap1-null background, where many of the ARE-dependent genes are constitutively activated in an Nrf2-dependent manner, only a subset of ARE-dependent genes, including NQO1, were sensitive to a simultaneous deficiency in MafG and MafF. Examination of single and double small maf mutant cells revealed that MafK also contributes to the induction of ARE-dependent genes. To obtain decisive evidence, we established mafG::mafK::mafF triple-mutant fibroblasts that completely lack small Mafs and turned out to be highly susceptible to oxidative stress. We found that induction in response to diethyl maleate was abolished in a wider range of ARE-dependent genes in the triple-mutant cells. These data explicitly demonstrate that small Mafs play critical roles in the inducible expression of a significant portion of ARE-dependent genes.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Adaptor Proteins, Signal Transducing / genetics
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Animals
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Antioxidants / metabolism*
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Cytoskeletal Proteins / genetics
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DNA-Binding Proteins / genetics
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DNA-Binding Proteins / physiology*
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Embryo, Mammalian / cytology
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Erythroid-Specific DNA-Binding Factors
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Fibroblasts / metabolism
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Gene Expression Regulation*
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Kelch-Like ECH-Associated Protein 1
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MafF Transcription Factor
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MafG Transcription Factor
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MafK Transcription Factor
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Maleates / pharmacology
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Mice
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Mice, Mutant Strains
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NAD(P)H Dehydrogenase (Quinone)
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NADPH Dehydrogenase / genetics
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Nuclear Proteins / genetics
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Nuclear Proteins / physiology*
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Oligonucleotide Array Sequence Analysis
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Oxidative Stress / genetics
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Repressor Proteins / genetics
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Repressor Proteins / physiology*
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Response Elements / drug effects
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Response Elements / genetics*
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Transcription Factors / genetics
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Transcription Factors / physiology*
Substances
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Adaptor Proteins, Signal Transducing
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Antioxidants
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Cytoskeletal Proteins
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DNA-Binding Proteins
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Erythroid-Specific DNA-Binding Factors
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Keap1 protein, mouse
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Kelch-Like ECH-Associated Protein 1
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MafF Transcription Factor
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MafG Transcription Factor
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MafK Transcription Factor
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Maff protein, mouse
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Mafg protein, mouse
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Mafk protein, mouse
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Maleates
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Nuclear Proteins
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Repressor Proteins
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Transcription Factors
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NAD(P)H Dehydrogenase (Quinone)
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Nqo1 protein, mouse
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NADPH Dehydrogenase