title: Nrf transcription factors in keratinocytes are essential for skin tumor prevention but not for wound healing.
abstract: The Nrf2 transcription factor is a key player in the cellular stress response through its regulation of cytoprotective genes. In this study we determined the role of Nrf2-mediated gene expression in keratinocytes for skin development, wound repair, and skin carcinogenesis. To overcome compensation by the related Nrf1 and Nrf3 proteins, we expressed a dominant-negative Nrf2 mutant (dnNrf2) in the epidermis of transgenic mice. The functionality of the transgene product was verified in vivo using mice doubly transgenic for dnNrf2 and an Nrf2-responsive reporter gene. Surprisingly, no abnormalities of the epidermis were observed in dnNrf2-transgenic mice, and even full-thickness skin wounds healed normally. However, the onset, incidence, and multiplicity of chemically induced skin papillomas were strikingly enhanced, whereas the progression to squamous cell carcinomas was unaltered. We provide evidence that the enhanced tumorigenesis results from reduced basal expression of cytoprotective Nrf target genes, leading to accumulation of oxidative damage and reduced carcinogen detoxification. Our results reveal a crucial role of Nrf-mediated gene expression in keratinocytes in the prevention of skin tumors and suggest that activation of Nrf2 in keratinocytes is a promising strategy to prevent carcinogenesis of this highly exposed organ.
authors.affiliation: Institute of Cell Biology, Department of Biology, ETH Zurich, Honggerberg, HPM D42, CH-8093 Zurich, Switzerland.
authors.forename: Ulrich
authors.initials: U
authors.lastname: auf dem Keller
authors.forename: Marcel
authors.initials: M
authors.lastname: Huber
authors.forename: Tobias A
authors.initials: TA
authors.lastname: Beyer
authors.forename: Angelika
authors.initials: A
authors.lastname: Kümin
authors.forename: Christina
authors.initials: C
authors.lastname: Siemes
authors.forename: Susanne
authors.initials: S
authors.lastname: Braun
authors.forename: Philippe
authors.initials: P
authors.lastname: Bugnon
authors.forename: Varvara
authors.initials: V
authors.lastname: Mitropoulos
authors.forename: Delinda A
authors.initials: DA
authors.lastname: Johnson
authors.forename: Jeffrey A
authors.initials: JA
authors.lastname: Johnson
authors.forename: Daniel
authors.initials: D
authors.lastname: Hohl
authors.forename: Sabine
authors.initials: S
authors.lastname: Werner
mesh_terms: D015127:9,10-Dimethyl-1,2-benzanthracene / Q000494:pharmacology; D000469:Alkaline Phosphatase / Q000378:metabolism; D000818:Animals; D015153:Blotting, Western; D019556:COS Cells; D015197:Carcinogenicity Tests; D002273:Carcinogens / Q000494:pharmacology; D018929:Cell Culture Techniques; D002478:Cells, Cultured; D002522:Chlorocebus aethiops; D004801:Eosine Yellowish-(YS) / Q000378:metabolism; D005260:Female; D005455:Fluorescent Antibody Technique; D015972:Gene Expression Regulation, Neoplastic; D006416:Hematoxylin / Q000378:metabolism; D006651:Histocytochemistry; D006873:Hydroquinones / Q000494:pharmacology; D015603:Keratinocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D008856:Microscopy, Fluorescence; D008954:Models, Biological; D051267:NF-E2-Related Factor 2 / Q000235:genetics / Q000378:metabolism*; D012878:Skin Neoplasms / Q000139:chemically induced / Q000517:prevention & control*; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D014945:Wound Healing
chemical_list: D002273:Carcinogens; D006873:Hydroquinones; D051267:NF-E2-Related Factor 2; D015127:9,10-Dimethyl-1,2-benzanthracene; C018855:2-tert-butylhydroquinone; D000469:Alkaline Phosphatase; D013755:Tetradecanoylphorbol Acetate; D004801:Eosine Yellowish-(YS); D006416:Hematoxylin