Abstract
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.
Publication types
-
Research Support, Non-U.S. Gov't
MeSH terms
-
3T3 Cells
-
Animals
-
Base Sequence
-
Binding Sites
-
Blotting, Northern
-
Blotting, Western
-
Cell Adhesion
-
Cell Adhesion Molecules / genetics*
-
Cell Adhesion Molecules / metabolism
-
Cell Adhesion Molecules / physiology*
-
Cell Line
-
Cell Membrane / metabolism
-
Cell Movement
-
Colonic Neoplasms / metabolism*
-
Cytoskeletal Proteins / biosynthesis*
-
Cytoskeletal Proteins / metabolism
-
DNA-Binding Proteins / biosynthesis*
-
Desmoplakins
-
Genes, Dominant
-
Humans
-
Luciferases / metabolism
-
Lymphoid Enhancer-Binding Factor 1
-
Male
-
Melanoma / metabolism*
-
Mice
-
Mice, Nude
-
Microscopy, Fluorescence
-
Molecular Sequence Data
-
Oligonucleotide Array Sequence Analysis
-
Plasmids / metabolism
-
Promoter Regions, Genetic
-
Protein Binding
-
Protein Biosynthesis
-
RNA / metabolism
-
Retroviridae / genetics
-
Reverse Transcriptase Polymerase Chain Reaction
-
Signal Transduction
-
Time Factors
-
Trans-Activators / biosynthesis*
-
Trans-Activators / metabolism
-
Transcription Factors / biosynthesis*
-
Transcriptional Activation
-
Transduction, Genetic
-
Transfection
-
Tumor Cells, Cultured
-
Wound Healing
-
beta Catenin
-
gamma Catenin
Substances
-
CTNNB1 protein, human
-
CTNNB1 protein, mouse
-
Cell Adhesion Molecules
-
Cytoskeletal Proteins
-
DNA-Binding Proteins
-
Desmoplakins
-
JUP protein, human
-
Jup protein, mouse
-
LEF1 protein, human
-
Lef1 protein, mouse
-
Lymphoid Enhancer-Binding Factor 1
-
NRCAM protein, human
-
Nrcam protein, mouse
-
Trans-Activators
-
Transcription Factors
-
beta Catenin
-
gamma Catenin
-
RNA
-
Luciferases