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Molecular and Cellular Biology, July 2003, p. 4673-4686, Vol. 23, No. 13
0270-7306/03/$08.00+0     DOI: 10.1128/MCB.23.13.4673-4686.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

Nrf1 Is Critical for Redox Balance and Survival of Liver Cells during Development

Linyun Chen,1,{dagger} Mandy Kwong,1,{ddagger} Ronghua Lu,1 David Ginzinger,2 Candy Lee,3 Laura Leung,3 and Jefferson Y. Chan1,3*

Department of Laboratory Medicine,1 Cancer Genetics Program and Genome Analysis Core Facility, University of California, San Francisco, San Francisco, California 94143,2 Department of Pathology, University of California, Irvine, Irvine, California 926973

Received 4 November 2002/ Returned for modification 21 January 2003/ Accepted 8 April 2003

The Nrf1 transcription factor belongs to the CNC subfamily of basic leucine zipper proteins. Knockout of Nrf1 is lethal in mouse embryos, but nothing is known about the cell types that absolutely require its function during development. We show by chimera analysis that Nrf1 is essential for the hepatocyte lineage. Mouse embryonic stem cells lacking Nrf1 developed normally and contributed to most tissues in adult chimeras where Nrf1 is normally expressed. Nrf1-deficient cells contributed to fetal, but not adult, liver cells. Loss of Nrf1 function resulted in liver cell apoptosis in late-gestation chimeric fetuses. Fetal livers from mutant embryos exhibited increased oxidative stress and impaired expression of antioxidant genes, and primary cultures of nrf1-/- fetal hepatocytes were sensitive to tert-butyl hydroperoxide-induced cell death, suggesting that impaired antioxidant defense may be responsible for the apoptosis observed in the livers of chimeric mice. In addition, cells deficient in Nrf1 were sensitized to the cytotoxic effects of tumor necrosis factor (TNF). Our results provide in vivo evidence demonstrating an essential role of Nrf1 in the survival of hepatocytes during development. Our results also suggest that Nrf1 may promote cell survival by maintaining redox balance and protecting embryonic hepatocytes from TNF-mediated apoptosis during development.

* Corresponding author. Present address: Department of Pathology, University of California, Irvine, D440 Medical Sciences, Irvine, CA 92697. Phone: (949) 824-9605. Fax: (949) 824-2160. E-mail: jchan{at}uci.edu.

{dagger} Present address: Department of Internal Medicine, Carney Hospital, Dorchester, MA 02124.

{ddagger} Present address: Genentech, South San Francisco, CA 94080.

Molecular and Cellular Biology, July 2003, p. 4673-4686, Vol. 23, No. 13
0022-538X/03/$08.00+0     DOI: 10.1128/MCB.23.13.4673-4686.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.



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