抄録
β-Catenin is a downstream effector of the Wnt signalling pathway and exerts its oncogenic activity by transactivating the target genes of TCF4 (T-cell factor-4). The aberrant transactivation of these TCF4-regulated genes by β-catenin plays a crucial role in early colorectal carcinogenesis. Recently, we identified that splicing factor-1 (SF1) was one of the proteins whose expression is regulated by the β-catenin / TCF4 complex using quantitative differential proteomics analysis (isotope-coded affinity tagging and mass spectrometry). SF1 negatively regulates β-catenin-evoked gene transactivation and cell proliferation. In addition, we found that SF1 was essential for the induction of alternative splicing by the β-catenin / TCF4 complex, and induced known cancer-related alternative by spliced variants, such as Wnt-induced secreted protein-1v and fibroblast growth factor receptor-3-ATII. In intestinal tissues, the expression of SF1 was found to be correlated with the differentiation status of intestinal epithelial cells and inversely correlated with tumorigenesis. To analyze the biological involvement of SF1 in the process of carcinogenesis in vivo, we developed SF1-deficient mice by gene trapping. Azoxymethane (AOM), a known carcinogen organotropic to the colon, was administered into SF1+/+ and SF1+/− mice. The average number and volume of colon tumors per mouse were significantly greater in SF1+/− than in SF1+/+ mice. The enhanced susceptibility of SF1 haploinsufficiency to AOM-induced colon tumorigenesis may be attributable to the suppressive role of SF1 in the Wnt signalling pathway.
