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.
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.
Hanada
N
N
Department of Tumor Genetics and Biology, Kumamoto University School of Medicine, Kumamoto, Japan.
Makino
K
K
Koga
H
H
Morisaki
T
T
Kuwahara
H
H
Masuko
N
N
Tabira
Y
Y
Hiraoka
T
T
Kitamura
N
N
Kikuchi
A
A
Saya
H
H
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
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