Nr-CAM is a target gene of the beta-catenin/LEF-1 pathway in melanoma and colon cancer and its expression enhances motility and confers tumorigenesis.
beta-catenin and plakoglobin (gamma-catenin) are homologous molecules involved in cell adhesion, linking cadherin receptors to the cytoskeleton. beta-catenin is also a key component of the Wnt pathway by being a coactivator of LEF/TCF transcription factors. To identify novel target genes induced by beta-catenin and/or plakoglobin, DNA microarray analysis was carried out with RNA from cells overexpressing either protein. This analysis revealed that Nr-CAM is the gene most extensively induced by both catenins. Overexpression of either beta-catenin or plakoglobin induced Nr-CAM in a variety of cell types and the LEF/TCF binding sites in the Nr-CAM promoter were required for its activation by catenins. Retroviral transduction of Nr-CAM into NIH3T3 cells stimulated cell growth, enhanced motility, induced transformation, and produced rapidly growing tumors in nude mice. Nr-CAM and LEF-1 expression was elevated in human colon cancer tissue and cell lines and in human malignant melanoma cell lines but not in melanocytes or normal colon tissue. Dominant negative LEF-1 decreased Nr-CAM expression and antibodies to Nr-CAM inhibited the motility of B16 melanoma cells. The results indicate that induction of Nr-CAM transcription by beta-catenin or plakoglobin plays a role in melanoma and colon cancer tumorigenesis, probably by promoting cell growth and motility.
Department of Molecular Cell Biology, The Weizmann Institute of Science, Rehovot 76100, Israel.
Maralice E
ME
Conacci-Sorrell
Tamar
T
Ben-Yedidia
Michael
M
Shtutman
Elena
E
Feinstein
Paz
P
Einat
Avri
A
Ben-Ze'ev
D016475:3T3 Cells; D000818:Animals; D001483:Base Sequence; D001665:Binding Sites; D015152:Blotting, Northern; D015153:Blotting, Western; D002448:Cell Adhesion; D015815:Cell Adhesion Molecules / Q000235:genetics* / Q000378:metabolism / Q000502:physiology*; D002460:Cell Line; D002462:Cell Membrane / Q000378:metabolism; D002465:Cell Movement; D003110:Colonic Neoplasms / Q000378:metabolism*; D003598:Cytoskeletal Proteins / Q000096:biosynthesis* / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000096:biosynthesis*; D051180:Desmoplakins; D005799:Genes, Dominant; D006801:Humans; D008156:Luciferases / Q000378:metabolism; D051821:Lymphoid Enhancer-Binding Factor 1; D008297:Male; D008545:Melanoma / Q000378:metabolism*; D051379:Mice; D008819:Mice, Nude; D008856:Microscopy, Fluorescence; D008969:Molecular Sequence Data; D020411:Oligonucleotide Array Sequence Analysis; D010957:Plasmids / Q000378:metabolism; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D014176:Protein Biosynthesis; D012313:RNA / Q000378:metabolism; D012190:Retroviridae / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D013997:Time Factors; D015534:Trans-Activators / Q000096:biosynthesis* / Q000378:metabolism; D014157:Transcription Factors / Q000096:biosynthesis*; D015533:Transcriptional Activation; D014161:Transduction, Genetic; D014162:Transfection; D014407:Tumor Cells, Cultured; D014945:Wound Healing; D051176:beta Catenin; D051185:gamma Catenin
C495270:CTNNB1 protein, human; C495267:CTNNB1 protein, mouse; D015815:Cell Adhesion Molecules; D003598:Cytoskeletal Proteins; D004268:DNA-Binding Proteins; D051180:Desmoplakins; C495292:JUP protein, human; C495293:Jup protein, mouse; C497573:LEF1 protein, human; C497574:Lef1 protein, mouse; D051821:Lymphoid Enhancer-Binding Factor 1; C491152:NRCAM protein, human; C491151:Nrcam protein, mouse; D015534:Trans-Activators; D014157:Transcription Factors; D051176:beta Catenin; D051185:gamma Catenin; D012313:RNA; D008156:Luciferases