Targeted disruption of the ubiquitous CNC-bZIP transcription factor, Nrf-1, results in anemia and embryonic lethality in mice

Chan, Jefferson Y.; Kwong, Mandy; Lu, Rongzhu; Chang, Judy C.; Wang, Brooke; Yen, T. S. Benedict; Kan, Yuet Wai

doi:10.1093/emboj/17.6.1779

Cited by 267 publications

(277 citation statements)

References 36 publications

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“…Genomic clones containing the nrf1 gene have been described (11). We generated a targeting construct containing a 5Ј loxP site inserted into the nrf1 intron-3, and a phosphoglycerate kinase 1 (PGK-1) promoter-driven neomycin resistance gene cassette flanked by a 3Ј loxP site downstream of the terminal exon.…”

Section: Methodsmentioning

confidence: 99%

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Liver-specific inactivation of the Nrf1 gene in adult mouse leads to nonalcoholic steatohepatitis and hepatic neoplasia

Chen

Leung

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

280

265

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Knockout studies have shown that the transcription factor Nrf1 is essential for embryonic development. Nrf1 has been implicated to play a role in mediating activation of oxidative stress response genes through the antioxidant response element (ARE). Because of embryonic lethality in knockout mice, analysis of this function in the adult knockout mouse was not possible. We report here that mice with somatic inactivation of nrf1 in the liver developed hepatic cancer. Before cancer development, mutant livers exhibited steatosis, apoptosis, necrosis, inflammation, and fibrosis. In addition, hepatocytes lacking Nrf1 showed oxidative stress, and gene expression analysis showed decreased expression of various ARE-containing genes, and up-regulation of CYP4A genes. These results suggest that reactive oxygen species generated from CYP4A-mediated fatty acid oxidation work synergistically with diminished expression of ARE-responsive genes to cause oxidative stress in mutant hepatocytes. Thus, Nrf1 has a protective function against oxidative stress and, potentially, a function in lipid homeostasis in the liver. Because the phenotype is similar to nonalcoholic steatohepatitis, these animals may prove useful as a model for investigating molecular mechanisms of nonalcoholic steatohepatitis and liver cancer. hepatocellular carcinoma ͉ oxidative stress ͉ knockout mouse T ranscription of many cytoprotective genes and phase-2 xenobiotic metabolizing genes is regulated through cis-active sequences known as antioxidant response elements (ARE) (1, 2). Regulation of ARE function is mediated by various basic leucine zipper (bZIP) transcription factors including members of the ''cap n collar'' (CNC)-bZIP and small-Maf family of proteins. Nrf1 and Nrf2 are CNC-bZIP proteins, and they function as obligate heterodimers by complexing with small-Maf and other bZIP proteins (3). An important role for Nrf2 in xenobiotic metabolism and oxidative stress response had been identified through knockout studies in mice (4-10). These and other studies indicate that Nrf2 is an important activator of AREs.In contrast, the function of Nrf1 is not fully understood. Mice deficient in Nrf1 function die during development (11). Analysis of nrf1 and nrf1::nrf2 mutant cells suggests that Nrf1 is also involved in the oxidative stress response (12, 13). However, the importance of Nrf1 in this function in an intact animal is not certain because early lethality precludes analysis of Nrf1-deficient animals beyond embryonic development. Chimeric mice generated with Nrf1-deficient embryonic stem cells showed widespread apoptosis in fetal livers at late gestation, demonstrating a cell autonomous role of Nrf1 in the survival of hepatocytes (14). This finding suggests that Nrf1 is required for normal function of hepatocytes. Based on these findings, we hypothesize that Nrf1 is critical to the oxidative stress response in the adult liver, and that it plays an important role in oxidative stress-induced liver disease. To bypass embryonic lethality, we used a Cre-lox system ...

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Section: Methodsmentioning

confidence: 99%

“…Mice deficient in Nrf1 function die during development (11). Analysis of nrf1 and nrf1::nrf2 mutant cells suggests that Nrf1 is also involved in the oxidative stress response (12,13).…”

mentioning

confidence: 99%

Liver-specific inactivation of the Nrf1 gene in adult mouse leads to nonalcoholic steatohepatitis and hepatic neoplasia

Chen

Leung

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

280

265

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“…Our findings also raise the intriguing question of whether Nrf proteins and SKN-1 might have similar developmental functions. Nrf2 −/− mice are viable, but Nrf1 knockouts caused either an erythroid defect, or abnormal gastrulation and lack of mesoderm (Farmer et al 1997;Itoh et al 1997;Chan et al 1998). The latter phenotype is reminiscent of the maternal skn-1 defect.…”

Section: Skn-1 and Oxidative Stress Resistance Genes And Development 1889mentioning

confidence: 99%

SKN-1 linksC. elegansmesendodermal specification to a conserved oxidative stress response

An¹,

Blackwell²

2003

Genes Dev.

672

877

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During the earliest stages of Caenorhabditis elegans embryogenesis, the transcription factor SKN-1 initiates development of the digestive system and other mesendodermal tissues. Postembryonic SKN-1 functions have not been elucidated. SKN-1 binds to DNA through a unique mechanism, but is distantly related to basic leucine-zipper proteins that orchestrate the major oxidative stress response in vertebrates and yeast. Here we show that despite its distinct mode of target gene recognition, SKN-1 functions similarly to resist oxidative stress in C. elegans. During postembryonic stages, SKN-1 regulates a key Phase II detoxification gene through constitutive and stress-inducible mechanisms in the ASI chemosensory neurons and intestine, respectively. SKN-1 is present in ASI nuclei under normal conditions, and accumulates in intestinal nuclei in response to oxidative stress. skn-1 mutants are sensitive to oxidative stress and have shortened lifespans. SKN-1 represents a connection between developmental specification of the digestive system and one of its most basic functions, resistance to oxidative and xenobiotic stress. This oxidative stress response thus appears to be both widely conserved and ancient, suggesting that the mesendodermal specification role of SKN-1 was predated by its function in these detoxification mechanisms.

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“…In 1996, Chan et al [24] showed that NRF2 is not essential in developmental processes but later this have been challenged [25][26][27]. SKN-1, the Caenorhabditis elegans ortholog of NRF2, is known to be important in the mesoderm and endoderm formation [28].…”

Section: Functional Analysis Of the Nrf2 Interactomementioning

confidence: 99%

The NRF2‐related interactome and regulome contain multifunctional proteins and fine‐tuned autoregulatory loops

et al. 2012

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a b s t r a c t NRF2 is a well-known, master transcription factor (TF) of oxidative and xenobiotic stress responses. Recent studies uncovered an even wider regulatory role of NRF2 influencing carcinogenesis, inflammation and neurodegeneration. Prompted by these advances here we present a systems-level resource for NRF2 interactome and regulome that includes 289 protein-protein, 7469 TF-DNA and 85 miRNA interactions. As systems-level examples of NRF2-related signaling we identified regulatory loops of NRF2 interacting proteins (e.g., JNK1 and CBP) and a fine-tuned regulatory system, where 35 TFs regulated by NRF2 influence 63 miRNAs that down-regulate NRF2. The presented network and the uncovered regulatory loops may facilitate the development of efficient, NRF2-based therapeutic agents.

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Targeted disruption of the ubiquitous CNC-bZIP transcription factor, Nrf-1, results in anemia and embryonic lethality in mice

Cited by 267 publications

References 36 publications

Liver-specific inactivation of the Nrf1 gene in adult mouse leads to nonalcoholic steatohepatitis and hepatic neoplasia

Liver-specific inactivation of the Nrf1 gene in adult mouse leads to nonalcoholic steatohepatitis and hepatic neoplasia

SKN-1 linksC. elegansmesendodermal specification to a conserved oxidative stress response

The NRF2‐related interactome and regulome contain multifunctional proteins and fine‐tuned autoregulatory loops

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