title: NE-dlg, a mammalian homolog of Drosophila dlg tumor suppressor, induces growth suppression and impairment of cell adhesion: possible involvement of down-regulation of beta-catenin by NE-dlg expression.
abstract: Membrane-associated guanylate kinases (MAGUKs) are known to function as scaffolds for forming multiprotein complexes at the synaptic junctions of neuronal cells and at sites of epithelial cell-cell contact. In Drosophila, mutations of the lethal (1)-discs large (dlg) gene, which encodes a MAGUK protein, leads to post-synaptic structure defects in neuronal cells and neoplastic overgrowth of epithelial cells. We previously showed that NE-dlg (neuronal and endocrine dlg), a human homolog of the dlg, plays a crucial role in formation of synaptic structure in human neuronal cells. Here we demonstrate that NE-dlg, similar to Drosophila dlg, is involved in regulation of cell cycle progression and adhesive ability of non-neuronal cells. Overexpression of NE-dlg in proliferating cells including various cancer cell lines induced growth suppression and impairment of cell adhesive ability. Furthermore, NE-dlg overexpression caused the down-regulation of beta-catenin in cancer cells regardless of mutations in the APC (adenomatous polyposis coli) gene. The PDZ domains of NE-dlg were found to be essential for the growth suppression, loss of adhesive property and down-regulation of beta-catenin. We propose that NE-dlg regulates the cell growth and adhesive ability by controlling the level of beta-catenin through an APC-independent pathway. Inactivation of NE-dlg may therefore contribute to development and/or progression of human neoplasms.
authors.affiliation: Department of Tumor Genetics and Biology, Kumamoto University School of Medicine, Kumamoto, Japan.
authors.forename: N
authors.initials: N
authors.lastname: Hanada
authors.forename: K
authors.initials: K
authors.lastname: Makino
authors.forename: H
authors.initials: H
authors.lastname: Koga
authors.forename: T
authors.initials: T
authors.lastname: Morisaki
authors.forename: H
authors.initials: H
authors.lastname: Kuwahara
authors.forename: N
authors.initials: N
authors.lastname: Masuko
authors.forename: Y
authors.initials: Y
authors.lastname: Tabira
authors.forename: T
authors.initials: T
authors.lastname: Hiraoka
authors.forename: N
authors.initials: N
authors.lastname: Kitamura
authors.forename: A
authors.initials: A
authors.lastname: Kikuchi
authors.forename: H
authors.initials: H
authors.lastname: Saya
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D002448:Cell Adhesion; D002453:Cell Cycle; D002455:Cell Division; D003598:Cytoskeletal Proteins / Q000235:genetics*; D000074288:Discs Large Homolog 1 Protein; D005786:Gene Expression Regulation; D016147:Genes, Tumor Suppressor; D006801:Humans; D007150:Immunohistochemistry; D008565:Membrane Proteins; D009687:Nuclear Proteins; D011506:Proteins / Q000032:analysis / Q000235:genetics / Q000502:physiology*; D015534:Trans-Activators; D014157:Transcription Factors; D014407:Tumor Cells, Cultured; D051176:beta Catenin
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C495270:CTNNB1 protein, human; D003598:Cytoskeletal Proteins; C513314:DLG1 protein, human; C116869:DLG3 protein, human; D000074288:Discs Large Homolog 1 Protein; D008565:Membrane Proteins; D009687:Nuclear Proteins; D011506:Proteins; D015534:Trans-Activators; D014157:Transcription Factors; D051176:beta Catenin