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PMID: 16135796 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, P.H.S.

Genetic evidence that small maf proteins are essential for the activation of antioxidant response element-dependent genes.

Molecular and cellular biology ·Vol. 25 ·No. 18 ·2005-09-00 ·Pages 8044-51

Katsuoka F, Motohashi H, Ishii T, Aburatani H, Engel JD, Yamamoto M

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.

MeSH Terms
Adaptor Proteins, Signal Transducing/genetics Animals Antioxidants/metabolism Cytoskeletal Proteins/genetics DNA-Binding Proteins/genetics,physiology Embryo, Mammalian/cytology Erythroid-Specific DNA-Binding Factors Fibroblasts/metabolism Gene Expression Regulation Kelch-Like ECH-Associated Protein 1 MafF Transcription Factor MafG Transcription Factor MafK Transcription Factor Maleates/pharmacology Mice Mice, Mutant Strains NAD(P)H Dehydrogenase (Quinone) NADPH Dehydrogenase/genetics Nuclear Proteins/genetics,physiology Oligonucleotide Array Sequence Analysis Oxidative Stress/genetics Repressor Proteins/genetics,physiology Response Elements/drug effects,genetics Transcription Factors/genetics,physiology
Chemicals
Adaptor Proteins, Signal Transducing Antioxidants Cytoskeletal Proteins DNA-Binding Proteins Erythroid-Specific DNA-Binding Factors Keap1 protein, mouse Kelch-Like ECH-Associated Protein 1 MafF Transcription Factor MafG Transcription Factor MafK Transcription Factor Maff protein, mouse Mafg protein, mouse Mafk protein, mouse Maleates Nuclear Proteins Repressor Proteins Transcription Factors NAD(P)H Dehydrogenase (Quinone) Nqo1 protein, mouse NADPH Dehydrogenase
Authors & Affiliations
6 authors, click to expand affiliations / ORCID
Katsuoka Fumiki
Center for TARA, University of Tsukuba, 1-1-1 Tennoudai, Tsukuba 305-8577, Japan.
Motohashi Hozumi
Ishii Tetsuro
Aburatani Hiroyuki
Engel James Douglas
Yamamoto Masayuki
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43 references, click to expand
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Article Info
Journal
Molecular and cellular biology
Abbr.
Mol Cell Biol
ISSN
0270-7306
DOI
10.1128/MCB.25.18.8044-8051.2005
Published
2005-09-00
Pages
8044-51
Language
English
Region
United States
NLM ID
8109087
PMCID
PMC1234339
Subset
IM
Grants
NCI NIH HHS · R01 CA080088 · United States
NIGMS NIH HHS · R01 GM028896 · United States
NCI NIH HHS · CA80088 · United States
NIGMS NIH HHS · GM28896 · United States
External Links
PubMed source DOI: 10.1128/MCB.25.18.8044-8051.2005 PMC Full Text View journal details
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