Division of Molecular Genetics, Department of Biochemistry and Bioinformative Sciences, School of Medicine, Faculty of Medical Sciences, University of Fukui, 23-3 Matsuoka-Shimoaizuki, Eiheiji-cho, Yoshida-gun, Fukui 910-1193, Japan
Fumihiko Kakizaki
Department of Pharmacology, Graduate School of Medicine, Kyoto University, Yoshida Konoé-cho, Sakyo-ku, Kyoto 606-8501, Japan
Xiaodong Shen
Division of Molecular Genetics, Department of Biochemistry and Bioinformative Sciences, School of Medicine, Faculty of Medical Sciences, University of Fukui, 23-3 Matsuoka-Shimoaizuki, Eiheiji-cho, Yoshida-gun, Fukui 910-1193, Japan
Kentaro Mori
Division of Molecular Genetics, Department of Biochemistry and Bioinformative Sciences, School of Medicine, Faculty of Medical Sciences, University of Fukui, 23-3 Matsuoka-Shimoaizuki, Eiheiji-cho, Yoshida-gun, Fukui 910-1193, Japan
Manabu Sugai
Division of Molecular Genetics, Department of Biochemistry and Bioinformative Sciences, School of Medicine, Faculty of Medical Sciences, University of Fukui, 23-3 Matsuoka-Shimoaizuki, Eiheiji-cho, Yoshida-gun, Fukui 910-1193, Japan
M. Mark Taketo
Department of Pharmacology, Graduate School of Medicine, Kyoto University, Yoshida Konoé-cho, Sakyo-ku, Kyoto 606-8501, Japan
Yoshifumi Yokota
Division of Molecular Genetics, Department of Biochemistry and Bioinformative Sciences, School of Medicine, Faculty of Medical Sciences, University of Fukui, 23-3 Matsuoka-Shimoaizuki, Eiheiji-cho, Yoshida-gun, Fukui 910-1193, Japan
The expression level of inhibitor of DNA binding 2 (Id2) is increased in colorectal carcinomas and is positively correlated with poor prognosis. However, the functional significance of Id2 in intestinal tumorigenesis has not been fully defined using genetic approaches. Here, we show that Id2 promotes ileal tumor initiation in Apc-deficient mice. Expression of Id2 was stimulated by Wnt signaling through the enhancer region of the Id2 promoter at the early stage of tumorigenesis in Apc+/Δ716 (ApcΔ716) mice. Genetic depletion of Id2 in ApcΔ716 mice caused ∼80% reduction in the number of ileal polyps, but had little effect on tumor size. Notably, the lack of Id2 increased the number of apoptotic cells in the normal crypt epithelium of the mice. Furthermore, DNA microarray analysis revealed that the expression level of Max dimerization protein 1 (Mxd1), known as a c-Myc antagonist, was specifically increased by Id2 deletion in the ileal intestinal epithelium of ApcΔ716 mice. In contrast, the protein level of c-Myc, but not the mRNA level, was decreased by loss of Id2 in these mice. These results indicate that loss of Id2 inhibits tumor initiation by up-regulation of Mxd1 and down-regulation of c-Myc in ApcΔ716 mice.
