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Molecular and Cellular Biology, August 2002, p. 5492-5505, Vol. 22, No. 15
0270-7306/02/$04.00+0     DOI: 10.1128/MCB.22.15.5492-5505.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

Nrf2 Transcription Factor, a Novel Target of Keratinocyte Growth Factor Action Which Regulates Gene Expression and Inflammation in the Healing Skin Wound

Susanne Braun,1 Christine Hanselmann,1,2 Marcus G. Gassmann,2 Ulrich auf dem Keller,1 Christiane Born-Berclaz,1 Kaimin Chan,3 Yuet Wai Kan,3,4 and Sabine Werner1,2*

Institute of Cell Biology, Department of Biology, ETH Zürich, CH-8093 Zürich, Switzerland,1 Max Planck Institute of Biochemistry, D-82152 Martinsried, Germany,2 Cardiovascular Research Institute,3 Department of Laboratory Medicine and Howard Hughes Medical Institute, University of California, San Francisco, California 94143-07934

Received 18 April 2002/ Accepted 29 April 2002

Keratinocyte growth factor (KGF) is a potent mitogen for epithelial cells, and it promotes survival of these cells under stress conditions. In a search for KGF-regulated genes in keratinocytes, we identified the gene encoding the transcription factor NF-E2-related factor 2 (Nrf2). Nrf2 is a key player in the cellular stress response. This might be of particular importance during wound healing, where large amounts of reactive oxygen species are produced as a defense against invading bacteria. Therefore, we studied the wound repair process in Nrf2 knockout mice. Interestingly, the expression of various key players involved in wound healing was significantly reduced in early wounds of the Nrf2 knockout animals, and the late phase of repair was characterized by prolonged inflammation. However, these differences in gene expression were not reflected by obvious histological abnormalities. The normal healing rate appears to be at least partially due to an up-regulation of the related transcription factor Nrf3, which was also identified as a target of KGF and which was coexpressed with Nrf2 in the healing skin wound. Taken together, our results reveal novel roles of the KGF-regulated transcription factors Nrf2 and possibly Nrf3 in the control of gene expression and inflammation during cutaneous wound repair.

* Corresponding author. Mailing address: Institute of Cell Biology, ETH Zürich, Hönggerberg, 8093 Zürich, Switzerland. Phone: 41 1 633 3941. Fax: 41 1 633 1174. E-mail: Sabine.werner{at}cell.biol.ethz.ch.

Molecular and Cellular Biology, August 2002, p. 5492-5505, Vol. 22, No. 15
0022-538X/02/$04.00+0     DOI: 10.1128/MCB.22.15.5492-5505.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.



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