Nrf1 (nuclear factor-erythroid 2 p45 subunit-related factor 1) and Nrf2 regulate ARE (antioxidant response element)-driven genes. At its N-terminal end, Nrf1 contains 155 additional amino acids that are absent from Nrf2. This 155-amino-acid polypeptide includes the N-terminal domain (NTD, amino acids 1–124) and a region (amino acids 125–155) that is part of acidic domain 1 (amino acids 125–295). Within acidic domain 1, residues 156–242 share 43% identity with the Neh2 (Nrf2-ECH homology 2) degron of Nrf2 that serves to destabilize this latter transcription factor through an interaction with Keap1 (Kelch-like ECH-associated protein 1). We have examined the function of the 155-amino-acid N-terminal polypeptide in Nrf1, along with its adjacent Neh2-like subdomain. Activation of ARE-driven genes by Nrf1 was negatively controlled by the NTD (N-terminal domain) through its ability to direct Nrf1 to the endoplasmic reticulum. Ectopic expression of wild-type Nrf1 and mutants lacking either the NTD or portions of its Neh2-like subdomain into wild-type and mutant mouse embryonic fibroblasts indicated that Keap1 controls neither the activity of Nrf1 nor its subcellular distribution. Immunocytochemistry showed that whereas Nrf1 gave primarily cytoplasmic staining that was co-incident with that of an endoplasmic-reticulum marker, Nrf2 gave primarily nuclear staining. Attachment of the NTD from Nrf1 to the N-terminus of Nrf2 produced a fusion protein that was redirected from the nucleus to the endoplasmic reticulum. Although this NTD–Nrf2 fusion protein exhibited less transactivation activity than wild-type Nrf2, it was nevertheless still negatively regulated by Keap1. Thus Nrf1 and Nrf2 are targeted to different subcellular compartments and are negatively regulated by distinct mechanisms.
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Research Article|
October 13 2006
Negative regulation of the Nrf1 transcription factor by its N-terminal domain is independent of Keap1: Nrf1, but not Nrf2, is targeted to the endoplasmic reticulum
Yiguo Zhang;
Yiguo Zhang
1
*Biomedical Research Centre, Ninewells Hospital and Medical School, University of Dundee, Dundee DD1 9SY, Scotland, U.K.
1Correspondence may be addressed to either of these authors (email y.z.zhang@dundee.ac.uk or john.hayes@cancer.org.uk).
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Dorothy H. Crouch;
Dorothy H. Crouch
*Biomedical Research Centre, Ninewells Hospital and Medical School, University of Dundee, Dundee DD1 9SY, Scotland, U.K.
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Masayuki Yamamoto;
Masayuki Yamamoto
†Center for Tsukuba Advanced Research Alliance and Institute of Basic Medical Sciences, University of Tsukuba, Tsukuba 305-8577, Japan
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John D. Hayes
John D. Hayes
1
*Biomedical Research Centre, Ninewells Hospital and Medical School, University of Dundee, Dundee DD1 9SY, Scotland, U.K.
1Correspondence may be addressed to either of these authors (email y.z.zhang@dundee.ac.uk or john.hayes@cancer.org.uk).
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Publisher: Portland Press Ltd
Received:
May 16 2006
Revision Received:
July 19 2006
Accepted:
July 27 2006
Accepted Manuscript online:
July 27 2006
Online ISSN: 1470-8728
Print ISSN: 0264-6021
The Biochemical Society, London
2006
Biochem J (2006) 399 (3): 373–385.
Article history
Received:
May 16 2006
Revision Received:
July 19 2006
Accepted:
July 27 2006
Accepted Manuscript online:
July 27 2006
Citation
Yiguo Zhang, Dorothy H. Crouch, Masayuki Yamamoto, John D. Hayes; Negative regulation of the Nrf1 transcription factor by its N-terminal domain is independent of Keap1: Nrf1, but not Nrf2, is targeted to the endoplasmic reticulum. Biochem J 1 November 2006; 399 (3): 373–385. doi: https://doi.org/10.1042/BJ20060725
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