Nrf transcription factors in keratinocytes are essential for skin tumor prevention but not for wound healing
Details
Serval ID
serval:BIB_CC08EC57DBE5
Type
Article: article from journal or magazin.
Collection
Publications
Institution
Title
Nrf transcription factors in keratinocytes are essential for skin tumor prevention but not for wound healing
Journal
Molecular and Cellular Biology
ISSN
0270-7306 (Print)
Publication state
Published
Issued date
05/2006
Volume
26
Number
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
Journal Article
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S. --- Old month value: May
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.
Keywords
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
Yes
Create date
25/01/2008 17:36
Last modification date
20/08/2019 16:46