The cyclin D1 gene is a target of the beta-catenin/LEF-1 pathway

Proc Natl Acad Sci U S A. 1999 May 11;96(10):5522-7. doi: 10.1073/pnas.96.10.5522.

Abstract

beta-Catenin plays a dual role in the cell: one in linking the cytoplasmic side of cadherin-mediated cell-cell contacts to the actin cytoskeleton and an additional role in signaling that involves transactivation in complex with transcription factors of the lymphoid enhancing factor (LEF-1) family. Elevated beta-catenin levels in colorectal cancer caused by mutations in beta-catenin or by the adenomatous polyposis coli molecule, which regulates beta-catenin degradation, result in the binding of beta-catenin to LEF-1 and increased transcriptional activation of mostly unknown target genes. Here, we show that the cyclin D1 gene is a direct target for transactivation by the beta-catenin/LEF-1 pathway through a LEF-1 binding site in the cyclin D1 promoter. Inhibitors of beta-catenin activation, wild-type adenomatous polyposis coli, axin, and the cytoplasmic tail of cadherin suppressed cyclin D1 promoter activity in colon cancer cells. Cyclin D1 protein levels were induced by beta-catenin overexpression and reduced in cells overexpressing the cadherin cytoplasmic domain. Increased beta-catenin levels may thus promote neoplastic conversion by triggering cyclin D1 gene expression and, consequently, uncontrolled progression into the cell cycle.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Adenomatous Polyposis Coli Protein
  • Axin Protein
  • Binding Sites
  • Cadherins / metabolism
  • Colonic Neoplasms / genetics
  • Cyclin D1 / genetics*
  • Cyclin D1 / metabolism
  • Cytoskeletal Proteins / metabolism*
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / metabolism*
  • Gene Expression Regulation, Neoplastic / genetics
  • Humans
  • Lymphoid Enhancer-Binding Factor 1
  • Promoter Regions, Genetic
  • Proteins
  • Repressor Proteins*
  • Signal Transduction
  • Trans-Activators*
  • Transcription Factors / metabolism*
  • Transcriptional Activation
  • Transfection
  • Tumor Cells, Cultured
  • beta Catenin

Substances

  • Adenomatous Polyposis Coli Protein
  • Axin Protein
  • CTNNB1 protein, human
  • Cadherins
  • Cytoskeletal Proteins
  • DNA-Binding Proteins
  • LEF1 protein, human
  • Lymphoid Enhancer-Binding Factor 1
  • Proteins
  • Repressor Proteins
  • Trans-Activators
  • Transcription Factors
  • beta Catenin
  • Cyclin D1