A novel frizzled gene identified in human esophageal carcinoma mediates APC/beta-catenin signals.
A novel member of the human frizzled (Fz) gene family was cloned and found to be specifically expressed in 3 of 13 well differentiated (23%), 13 of 20 moderately differentiated (62%), and 12 of 14 poorly differentiated (86%) squamous cell esophageal carcinomas compared with the adjacent uninvolved normal mucosa. The FzE3 cDNA encodes a protein of 574 amino acids and shares high sequence homology with the human FzD2 gene particularly in the putative ligand binding region of the cysteine-rich extracellular domain. Functional analysis revealed that transfection and expression of the FzE3 cDNA in esophageal carcinoma cells stimulates complex formation between adenomatous polyposis coli (APC) and beta-catenin followed by nuclear translocation of beta-catenin. Furthermore, cotransfection of a mutant construct encoding a FzE3 protein with a C-terminal truncation completely inhibited the interaction of APC with beta-catenin in cells. Finally, coexpression of FzE3 with Lef-1 transcription factor enhanced beta-catenin translocation to the nucleus. These observations suggest that FzE3 gene expression may down-regulate APC function and enhance beta-catenin mediated signals in poorly differentiated human esophageal carcinomas.
Department of Surgery, Medical Institute of Bioregulation, and Department of Surgery II, Faculty of Medicine, Kyushu University, Japan. shinji@tsurumi.beppu.kyushu-u.ac.jp
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Tanaka
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Akiyoshi
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Mori
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Wands
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Sugimachi
D025601:Adenomatous Polyposis Coli Protein; D000595:Amino Acid Sequence; D001483:Base Sequence; D003001:Cloning, Molecular; D003598:Cytoskeletal Proteins / Q000378:metabolism*; D017931:DNA Primers / Q000235:genetics; D018076:DNA, Complementary / Q000235:genetics; D004273:DNA, Neoplasm / Q000235:genetics; D004938:Esophageal Neoplasms / Q000235:genetics* / Q000378:metabolism*; D051157:Frizzled Receptors; D015870:Gene Expression; D006801:Humans; D008954:Models, Biological; D008969:Molecular Sequence Data; D016133:Polymerase Chain Reaction; D011506:Proteins / Q000235:genetics*; D017386:Sequence Homology, Amino Acid; D015398:Signal Transduction; D015534:Trans-Activators; D014407:Tumor Cells, Cultured; D051176:beta Catenin
D025601:Adenomatous Polyposis Coli Protein; C495270:CTNNB1 protein, human; D003598:Cytoskeletal Proteins; D017931:DNA Primers; D018076:DNA, Complementary; D004273:DNA, Neoplasm; D051157:Frizzled Receptors; D011506:Proteins; D015534:Trans-Activators; D051176:beta Catenin