Nrf transcription factors in keratinocytes are essential for skin tumor prevention but not for wound healing

Détails

ID Serval
serval:BIB_CC08EC57DBE5
Type
Article: article d'un périodique ou d'un magazine.
Collection
Publications
Titre
Nrf transcription factors in keratinocytes are essential for skin tumor prevention but not for wound healing
Périodique
Molecular and Cellular Biology
Auteur(s)
auf dem Keller  U., Huber  M., Beyer  T. A., Kumin  A., Siemes  C., Braun  S., Bugnon  P., Mitropoulos  V., Johnson  D. A., Johnson  J. A., Hohl  D., Werner  S.
ISSN
0270-7306 (Print)
Statut éditorial
Publié
Date de publication
05/2006
Volume
26
Numéro
10
Pages
3773-84
Notes
Comparative Study
Journal Article
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S. --- Old month value: May
Résumé
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.
Mots-clé
9,10-Dimethyl-1,2-benzanthracene/pharmacology Alkaline Phosphatase/metabolism Animals Blotting, Western COS Cells Carcinogenicity Tests Carcinogens/pharmacology Cell Culture Techniques Cells, Cultured Cercopithecus aethiops Eosine Yellowish-(YS)/metabolism Female Fluorescent Antibody Technique *Gene Expression Regulation, Neoplastic Hematoxylin/metabolism Histocytochemistry Hydroquinones/pharmacology Keratinocytes/cytology/drug effects/*metabolism/pathology Mice Mice, Transgenic Microscopy, Fluorescence Models, Biological NF-E2-Related Factor 2/genetics/*metabolism Skin Neoplasms/chemically induced/*prevention & control Tetradecanoylphorbol Acetate/pharmacology *Wound Healing
Pubmed
Web of science
Open Access
Oui
Création de la notice
25/01/2008 17:36
Dernière modification de la notice
09/05/2019 1:19
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