Notch1 functions as a tumor suppressor in mouse skin

• Published in: Nature genetics Vol. 33; no. 3; pp. 416 - 421
• Main Authors: Wolfer, Anita, Radtke, Freddy, Nicolas, Michael, Dotto, G. Paolo, Kummer, J. Alain, Mill, Pleasantine, Clevers, Hans, van Noort, Mascha, Hui, Chi-chung, Raj, Kenneth
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01.03.2003; Nature Publishing Group
• Subjects: Agriculture; Animal Genetics and Genomics; Animals; beta Catenin; Biological and medical sciences; Biomedical and Life Sciences; Biomedicine; Cancer cells; Cancer Research; Carcinogenesis; Cellular signal transduction; Classical genetics, quantitative genetics, hybrids; Cytoskeletal Proteins - metabolism; DNA-Binding Proteins - metabolism; Embryos; Epidermis; Fundamental and applied biological sciences. Psychology; Gene Function; Genes, Tumor Suppressor; Genetic aspects; Genetics of eukaryotes. Biological and molecular evolution; Human Genetics; Inactivation; Keratinocytes - transplantation; Kruppel-Like Transcription Factors; letter; Lymphoid Enhancer-Binding Factor 1; Mammals; Membrane Proteins - deficiency; Membrane Proteins - genetics; Membrane Proteins - physiology; Mice; Mice, Knockout; Mice, Nude; Mice, Transgenic; Physiological aspects; Physiology; Receptor, Notch1; Receptors, Cell Surface; RNA, Messenger - genetics; RNA, Messenger - metabolism; Signal Transduction; Skin; Skin - metabolism; Skin - pathology; Skin Neoplasms - genetics; Skin Neoplasms - pathology; Skin Neoplasms - prevention & control; Trans-Activators - metabolism; Transcription Factors - genetics; Transcription Factors - metabolism; Tumor suppressor genes; Tumors; Vertebrata; Zinc Finger Protein Gli2; United States; Vertebrata; Mammalia; Mouse; Rodentia; Suppressor; Tumor; Skin
• ISSN: 1061-4036; 1546-1718
• DOI: 10.1038/ng1099

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 β-catenin signaling in cells that should normally undergo differentiation. Enhanced β-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 β-catenin, indicating that Notch1 can inhibit β-catenin-mediated signaling. Our results indicate that Notch1 functions as a tumor-suppressor gene in mammalian skin.