Nrf transcription factors in keratinocytes are essential for skin tumor prevention but not for wound healing.
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.
auf dem Keller
Ulrich
U
Institute of Cell Biology, Department of Biology, ETH Zurich, Honggerberg, HPM D42, CH-8093 Zurich, Switzerland.
Huber
Marcel
M
Beyer
Tobias A
TA
Kümin
Angelika
A
Siemes
Christina
C
Braun
Susanne
S
Bugnon
Philippe
P
Mitropoulos
Varvara
V
Johnson
Delinda A
DA
Johnson
Jeffrey A
JA
Hohl
Daniel
D
Werner
Sabine
S
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
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