title: Overexpression of Icat induces G(2) arrest and cell death in tumor cell mutants for adenomatous polyposis coli, beta-catenin, or Axin.
abstract: Aberrant activation of Wnt signaling caused by mutations in adenomatous polyposis coli (APC) or beta-catenin is a critical event in the development of human colorectal tumors. Wnt signaling stabilizes beta-catenin, which in turn associates with TCF/LEF family transcription factors, ultimately altering the expression of Wnt target genes. We have recently identified ICAT, a beta-catenin-interacting protein that interferes with the interaction between beta-catenin and TCF-4, thereby negatively regulating Wnt signaling. In the present study, we generated a recombinant adenovirus encoding ICAT and examined its effect on the growth of tumor cells. We found that Icat inhibits proliferation of colorectal tumor cells mutated in APC or beta-catenin and hepatocellular carcinoma cells mutated in AXIN: By contrast, Icat did not inhibit growth of either normal or tumor cells containing the wild-type APC, beta-catenin, and Axin genes. Icat also inhibited the anchorage-independent growth of colorectal tumor cells and tumorigenic growth of colorectal tumor xenografts. Furthermore, we found that Icat inhibits both dephosphorylation of Cdc2 and nuclear translocation of cyclin B1 and induces G(2) arrest followed by cell death in colorectal tumor cells. These results suggest that Wnt signaling is critical for the growth of colorectal tumors and some hepatocellular carcinomas and that expression of ICAT or drugs which mimic its effects may be useful in the treatment of these tumors.
authors.affiliation: Laboratory of Molecular and Genetic Information, Institute of Molecular and Cellular Biosciences, The University of Tokyo, 1-1-1 Yayoi, Bunkyo-ku, Tokyo 113, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Sekiya
authors.forename: Tsutomu
authors.initials: T
authors.lastname: Nakamura
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Kazuki
authors.forename: Mitsuo
authors.initials: M
authors.lastname: Oshimura
authors.forename: Kazuyoshi
authors.initials: K
authors.lastname: Kohu
authors.forename: Ken-Ichi
authors.initials: K
authors.lastname: Tago
authors.forename: Susumu
authors.initials: S
authors.lastname: Ohwada
authors.forename: Tetsu
authors.initials: T
authors.lastname: Akiyama
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D060466:Axin Protein; D019556:COS Cells; D006528:Carcinoma, Hepatocellular / Q000235:genetics / Q000473:pathology; D002448:Cell Adhesion / Q000235:genetics; D018797:Cell Cycle Proteins / Q000096:biosynthesis; D016923:Cell Death / Q000235:genetics; D002455:Cell Division / Q000235:genetics; D015179:Colorectal Neoplasms / Q000235:genetics* / Q000473:pathology*; D003598:Cytoskeletal Proteins / Q000096:biosynthesis / Q000235:genetics* / Q000502:physiology*; D016195:G2 Phase / Q000235:genetics; D017491:Genes, APC / Q000502:physiology*; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D008113:Liver Neoplasms / Q000235:genetics / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009124:Muscle Proteins / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D009154:Mutation; D011506:Proteins / Q000235:genetics*; D012097:Repressor Proteins; D015534:Trans-Activators; D023041:Xenograft Model Antitumor Assays; D051176:beta Catenin
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D060466:Axin Protein; C495270:CTNNB1 protein, human; C495267:CTNNB1 protein, mouse; C411982:CTNNBIP1 protein, human; D018797:Cell Cycle Proteins; C498785:Ctnnbip1 protein, mouse; D003598:Cytoskeletal Proteins; D047908:Intracellular Signaling Peptides and Proteins; D009124:Muscle Proteins; D011506:Proteins; D012097:Repressor Proteins; D015534:Trans-Activators; D051176:beta Catenin