title: Id2 deletion attenuates Apc-deficient ileal tumor formation.
abstract: 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) (Apc(Δ716)) mice. Genetic depletion of Id2 in Apc(Δ716) 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 Apc(Δ716) 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 Apc(Δ716) mice.
authors.affiliation: 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 biyajima@u-fukui.ac.jp.
authors.forename: Kyoko
authors.initials: K
authors.lastname: Biyajima
authors.affiliation: Department of Pharmacology, Graduate School of Medicine, Kyoto University, Yoshida Konoé-cho, Sakyo-ku, Kyoto 606-8501, Japan.
authors.forename: Fumihiko
authors.initials: F
authors.lastname: Kakizaki
authors.affiliation: 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.
authors.forename: Xiaodong
authors.initials: X
authors.lastname: Shen
authors.affiliation: 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.
authors.forename: Kentaro
authors.initials: K
authors.lastname: Mori
authors.affiliation: 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.
authors.forename: Manabu
authors.initials: M
authors.lastname: Sugai
authors.affiliation: Department of Pharmacology, Graduate School of Medicine, Kyoto University, Yoshida Konoé-cho, Sakyo-ku, Kyoto 606-8501, Japan.
authors.forename: M Mark
authors.initials: MM
authors.lastname: Taketo
authors.affiliation: 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.
authors.forename: Yoshifumi
authors.initials: Y
authors.lastname: Yokota
keywords: Apc; Id2; Ileal tumor initiation; Mxd1; c-Myc