Abstract
Beta-catenin acts as a transcriptional coactivator by forming a complex with T-cell factor/lymphoid enhancer factor (TCF/LEF) DNA-binding proteins. Aberrant transactivation of a certain set of target genes by beta-catenin and TCF4 complexes has been implicated in familial and sporadic colorectal tumorigenesis. A colorectal cancer cell line, DLD-1, becomes irregularly multilayered, when maintained confluent for 2-3 weeks, and forms numerous dome-like polypoid foci piled-up over the surface of cell sheets. By the use of a strict tetracycline-regulation system, we found that the continuous suppression of beta-catenin/TCF4-mediated gene transactivation by dominant-negative TCF4B (deltaN30) reduced these piled-up foci and restored a simple monolayer of polarized columnar cells resembling normal intestinal epithelium. The restoration of epithelial cell polarity was evident in two ways: (a) the formation of microvilli over the apical surface; and (b) the distribution of a tight junction protein, ZO-1, to the lateral plasma membrane. Retroviral expression of stabilized beta-catenin (deltaN89) induced the formation of similar piled-up foci in untransformed IEC6 intestinal epithelial cells. Sulindac, a nonsteroidal antiinflammatory drug effective against colorectal tumorigenesis in familial adenomatous polyposis syndrome, suppressed the formation of foci. The loss of epithelial cell polarity may be a critical cellular event driving beta-catenin/TCF4-mediated intestinal tumorigenesis.
Publication types
-
Research Support, Non-U.S. Gov't
MeSH terms
-
Adenocarcinoma / genetics
-
Adenocarcinoma / metabolism
-
Adenocarcinoma / pathology*
-
Amino Acid Sequence
-
Animals
-
Anti-Inflammatory Agents, Non-Steroidal / pharmacology
-
Cell Division / drug effects
-
Cell Division / physiology
-
Cell Membrane / metabolism
-
Cell Polarity / physiology*
-
Colorectal Neoplasms / genetics
-
Colorectal Neoplasms / metabolism
-
Colorectal Neoplasms / pathology*
-
Cytoskeletal Proteins / biosynthesis
-
Cytoskeletal Proteins / genetics
-
Cytoskeletal Proteins / physiology*
-
Doxycycline / pharmacology
-
Epithelial Cells / cytology
-
Epithelial Cells / metabolism
-
Genes, MDR
-
Humans
-
Intestinal Mucosa / cytology
-
Intestinal Mucosa / metabolism
-
Membrane Proteins / metabolism
-
Molecular Sequence Data
-
Phosphoproteins / metabolism
-
Rats
-
Retroviridae / genetics
-
Sulindac / pharmacology
-
TCF Transcription Factors
-
Trans-Activators*
-
Transcription Factor 7-Like 2 Protein
-
Transcription Factors / biosynthesis
-
Transcription Factors / genetics
-
Transcription Factors / physiology*
-
Transcriptional Activation / physiology*
-
Tumor Cells, Cultured
-
Zonula Occludens-1 Protein
-
beta Catenin
Substances
-
Anti-Inflammatory Agents, Non-Steroidal
-
CTNNB1 protein, human
-
Ctnnb1 protein, rat
-
Cytoskeletal Proteins
-
Membrane Proteins
-
Phosphoproteins
-
TCF Transcription Factors
-
TCF7L2 protein, human
-
TJP1 protein, human
-
Tcf7l2 protein, rat
-
Tjp1 protein, rat
-
Trans-Activators
-
Transcription Factor 7-Like 2 Protein
-
Transcription Factors
-
Zonula Occludens-1 Protein
-
beta Catenin
-
Sulindac
-
Doxycycline