Notch1 functions as a tumor suppressor in mouse skin.
Notch proteins are important in binary cell-fate decisions and inhibiting differentiation in many developmental systems, and aberrant Notch signaling is associated with tumorigenesis. The role of Notch signaling in mammalian skin is less well characterized and is mainly based on in vitro studies, which suggest that Notch signaling induces differentiation in mammalian skin. Conventional gene targeting is not applicable to establishing the role of Notch receptors or ligands in the skin because Notch1-/- embryos die during gestation. Therefore, we used a tissue-specific inducible gene-targeting approach to study the physiological role of the Notch1 receptor in the mouse epidermis and the corneal epithelium of adult mice. Unexpectedly, ablation of Notch1 results in epidermal and corneal hyperplasia followed by the development of skin tumors and facilitated chemical-induced skin carcinogenesis. Notch1 deficiency in skin and in primary keratinocytes results in increased and sustained expression of Gli2, causing the development of basal-cell carcinoma-like tumors. Furthermore, Notch1 inactivation in the epidermis results in derepressed beta-catenin signaling in cells that should normally undergo differentiation. Enhanced beta-catenin signaling can be reversed by re-introduction of a dominant active form of the Notch1 receptor. This leads to a reduction in the signaling-competent pool of beta-catenin, indicating that Notch1 can inhibit beta-catenin-mediated signaling. Our results indicate that Notch1 functions as a tumor-suppressor gene in mammalian skin.
Nicolas
Michael
M
Ludwig Institute for Cancer Research, Lausanne Branch, University Lausanne, 1066 Epalinges, Switzerland.
Wolfer
Anita
A
Raj
Kenneth
K
Kummer
J Alain
JA
Mill
Pleasantine
P
van Noort
Mascha
M
Hui
Chi-chung
CC
Clevers
Hans
H
Dotto
G Paolo
GP
Radtke
Freddy
F
D000818:Animals; D003598:Cytoskeletal Proteins / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism; D016147:Genes, Tumor Suppressor; D015603:Keratinocytes / Q000637:transplantation; D051741:Kruppel-Like Transcription Factors; D051821:Lymphoid Enhancer-Binding Factor 1; D008565:Membrane Proteins / Q000172:deficiency / Q000235:genetics* / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D008819:Mice, Nude; D008822:Mice, Transgenic; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051881:Receptor, Notch1; D011956:Receptors, Cell Surface; D015398:Signal Transduction; D012867:Skin / Q000378:metabolism / Q000473:pathology; D012878:Skin Neoplasms / Q000235:genetics / Q000473:pathology / Q000517:prevention & control*; D015534:Trans-Activators / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D000075746:Zinc Finger Protein Gli2; D051176:beta Catenin
C495267:CTNNB1 protein, mouse; D003598:Cytoskeletal Proteins; D004268:DNA-Binding Proteins; C000618551:Gli2 protein, mouse; D051741:Kruppel-Like Transcription Factors; D051821:Lymphoid Enhancer-Binding Factor 1; D008565:Membrane Proteins; C497762:Notch1 protein, mouse; D012333:RNA, Messenger; D051881:Receptor, Notch1; D011956:Receptors, Cell Surface; D015534:Trans-Activators; D014157:Transcription Factors; D000075746:Zinc Finger Protein Gli2; D051176:beta Catenin