Loss of Presenilin 1 is Associated with Enhanced β-Catenin Signaling and Skin Tumorigenesis

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 98; no. 19; pp. 10863 - 10868
• Main Authors: Xia, Xuefeng, Qian, Su, Soriano, Salvador, Wu, Ying, Fletcher, Anthony M., Wang, Xiao-Jing, Koo, Edward H., Wu, Xiangwei, Zheng, Hui
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 11.09.2001; National Acad Sciences; The National Academy of Sciences
• Subjects: Animals; b-catenin; beta Catenin; Biological Sciences; Cell cycle; Cells, Cultured; cyclin D1; Cyclin D1 - metabolism; Cyclins; Cytoskeletal Proteins - metabolism; Cytosol - metabolism; DNA-Binding Proteins - metabolism; Epidermal cells; Epidermis; G1 Phase; Humans; Keratinocytes; Keratinocytes - cytology; Keratinocytes - metabolism; Lymphoid Enhancer-Binding Factor 1; Membrane Proteins - genetics; Membrane Proteins - physiology; Mice; Mice, Knockout; Molecules; Phenotypes; Presenilin-1; Proteins; S Phase; Signal Transduction; Skin; Skin cancer; Skin cancers; Skin Neoplasms - metabolism; Skin Neoplasms - pathology; Tissues; Trans-Activators; Transcription Factors - metabolism; Tumors
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.191284198

Presenilin 1 (PS1) is required for the proteolytic processing of Notch and the β-amyloid precursor protein (APP), molecules that play pivotal roles in cell-fate determination during development and Alzheimer's disease pathogenesis, respectively. In addition, PS1 interacts with β-catenin and promotes its turnover through independent mechanisms. Consistent with this activity, we report here that PS1 is important in controlling epidermal cell proliferation in vivo. PS1 knockout mice that are rescued through neuronal expression of human PS1 transgene develop spontaneous skin cancers. PS1-null keratinocytes exhibit higher cytosolic β-catenin and β-catenin/lymphoid enhancer factor-1/T cell factor (β-catenin/LEF)-mediated signaling. This effect can be reversed by reintroducing wild-type PS1, but not a PS1 mutant active in Notch processing but defective in β-catenin binding. Nuclear β-catenin protein can be detected in tumors. Elevated β-catenin/LEF signaling is correlated with activation of its downstream target cyclin D1 and accelerated entry from G1into S phase of the cell cycle. This report demonstrates a function of PS1 in adult tissues, and our analysis suggests that deregulation of β-catenin pathway contributes to the skin tumor phenotype.