title: Identification of BMP and activin membrane-bound inhibitor (BAMBI), an inhibitor of transforming growth factor-beta signaling, as a target of the beta-catenin pathway in colorectal tumor cells.
abstract: The Wnt signaling pathway is activated in most human colorectal tumors. Mutational inactivation in the tumor suppressor adenomatous polyposis coli (APC), as well as activation of beta-catenin, causes the accumulation of beta-catenin, which in turn associates with the T cell factor/lymphoid enhancer factor (TCF/LEF) family of transcription factors and activates transcription of their target genes. Here we show that beta-catenin activates transcription of the BMP and activin membrane-bound inhibitor (BAMBI)/NMA gene. The expression level of BAMBI was found to be aberrantly elevated in most colorectal and hepatocellular carcinomas relative to the corresponding non-cancerous tissues. Expression of BAMBI in colorectal tumor cell lines was repressed by a dominant-negative mutant of TCF-4 or by an inhibitor of beta-catenin-TCF interaction, suggesting that beta-catenin is responsible for the aberrant expression of BAMBI in colorectal tumor cells. Furthermore, overexpression of BAMBI inhibited the response of tumor cells to transforming growth factor-beta signaling. These results suggest that beta-catenin interferes with transforming growth factor-beta-mediated growth arrest by inducing the expression of BAMBI, and this may contribute to colorectal and hepatocellular tumorigenesis.
authors.affiliation: Laboratory of Molecular and Genetic Information, Institute of Molecular and Cellular Biosciences, University of Tokyo, 1-1-1 Yayoi, Bunkyo-ku, Tokyo 113-0032, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Sekiya
authors.forename: Shungo
authors.initials: S
authors.lastname: Adachi
authors.forename: Kazuyoshi
authors.initials: K
authors.lastname: Kohu
authors.forename: Tatsuya
authors.initials: T
authors.lastname: Yamada
authors.forename: Osamu
authors.initials: O
authors.lastname: Higuchi
authors.forename: Yoichi
authors.initials: Y
authors.lastname: Furukawa
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Nakamura
authors.forename: Tsutomu
authors.initials: T
authors.lastname: Nakamura
authors.forename: Kousuke
authors.initials: K
authors.lastname: Tashiro
authors.forename: Satoru
authors.initials: S
authors.lastname: Kuhara
authors.forename: Susumu
authors.initials: S
authors.lastname: Ohwada
authors.forename: Tetsu
authors.initials: T
authors.lastname: Akiyama
mesh_terms: D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D015152:Blotting, Northern; D019556:COS Cells; D006528:Carcinoma, Hepatocellular / Q000378:metabolism; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000378:metabolism*; D015179:Colorectal Neoplasms / Q000378:metabolism*; D003598:Cytoskeletal Proteins / Q000378:metabolism*; D004252:DNA Mutational Analysis; D004268:DNA-Binding Proteins / Q000378:metabolism; D019281:Dimerization; D017930:Genes, Reporter; D006801:Humans; D007150:Immunohistochemistry; D008099:Liver / Q000378:metabolism; D008156:Luciferases / Q000378:metabolism; D051821:Lymphoid Enhancer-Binding Factor 1; D008565:Membrane Proteins / Q000737:chemistry* / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D010957:Plasmids / Q000378:metabolism; D011401:Promoter Regions, Genetic; D017434:Protein Structure, Tertiary; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D013997:Time Factors; D015534:Trans-Activators / Q000378:metabolism*; D014157:Transcription Factors / Q000378:metabolism; D014158:Transcription, Genetic; D015533:Transcriptional Activation; D016212:Transforming Growth Factor beta / Q000037:antagonists & inhibitors / Q000378:metabolism*; D051176:beta Catenin
chemical_list: C485671:BAMBI protein, human; C495270:CTNNB1 protein, human; D003598:Cytoskeletal Proteins; D004268:DNA-Binding Proteins; D051821:Lymphoid Enhancer-Binding Factor 1; D008565:Membrane Proteins; D015534:Trans-Activators; D014157:Transcription Factors; D016212:Transforming Growth Factor beta; D051176:beta Catenin; D008156:Luciferases