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PMID: 17313370 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't

Nrf2 Neh5 domain is differentially utilized in the transactivation of cytoprotective genes.

The Biochemical journal ·Vol. 404 ·No. 3 ·2007-06-15 ·Pages 459-66

Zhang J, Hosoya T, Maruyama A, Nishikawa K, Maher JM, Ohta T, Motohashi H, Fukamizu A, Shibahara S, Itoh K, Yamamoto M

Abstract

The transcription factor Nrf2 (nuclear factor erythroid 2-related factor 2) contains two transcription activation domains, Neh4 (Nrf2 ECH homology 4) and Neh5, which co-ordinately regulate transactivation of cytoprotective genes. In the present study we aimed to clarify the role of the Neh5 domain in Nrf2-mediated gene regulation. Deletion of the complete Neh5 domain reduces expression of endogenous Nrf2 target genes, such as HO-1 (haem oxygenase 1), NQO1 [NAD(P)H:quinone oxidoreductase 1] and GCLM (glutamate cysteine ligase modulatory subunit), in human kidney epithelial cells. Furthermore, the deletion of Neh5 markedly repressed CBP [CREB (cAMP-response-element-binding protein)-binding protein] and BRG1 (Brahma-related gene 1) from associating with Nrf2, diminishing their co-operative enhancement of HO-1 promoter activity. Mutational analysis of the Neh5 domain revealed a motif that shares significant homology with beta-actin and ARP1 (actin-related protein 1). Mutagenesis of this motif selectively decreased HO-1, but not NQO1 and GCLM, expression. Taken together, these results indicate that the Neh5 domain has the ability to regulate Nrf2 target gene transcription, yet the role of the Neh5 domain in transcription varies from gene to gene.

MeSH Terms
Amino Acid Sequence Animals CREB-Binding Protein/genetics,metabolism Cell Line Cytoprotection/genetics DNA Helicases/genetics,metabolism Genes, Reporter Heme Oxygenase-1/genetics,metabolism Humans Mice Molecular Sequence Data NF-E2-Related Factor 2/chemistry,genetics,metabolism Nuclear Proteins/genetics,metabolism Promoter Regions, Genetic Protein Structure, Tertiary Sequence Alignment Transcription Factors/genetics,metabolism Transcriptional Activation
Chemicals
NF-E2-Related Factor 2 Nfe2l2 protein, mouse Nuclear Proteins Transcription Factors HMOX1 protein, human Heme Oxygenase-1 CREB-Binding Protein Smarca4 protein, mouse DNA Helicases
Authors & Affiliations
11 authors, click to expand affiliations / ORCID
Zhang Jianyong
Graduate School of Comprehensive Human Sciences, Center for Tsukuba Advanced Research Alliance, University of Tsukuba, 1-1-1 Tennoudai, Tsukuba 305-8577, Japan.
Hosoya Tomonori
Maruyama Atsushi
Nishikawa Keizo
Maher Jonathan M
Ohta Tsutomu
Motohashi Hozumi
Fukamizu Akiyoshi
Shibahara Shigeki
Itoh Ken
Yamamoto Masayuki
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Article Info
Journal
The Biochemical journal
Abbr.
Biochem J
ISSN
1470-8728
DOI
10.1042/BJ20061611
Published
2007-06-15
Pages
459-66
Language
English
Region
England
NLM ID
2984726R
PMCID
PMC1896277
Subset
IM
External Links
PubMed source DOI: 10.1042/BJ20061611 PMC Full Text View journal details
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