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Chromatin-specific regulation of LEF-1-beta-catenin transcription activation and inhibition in vitro.

Transcriptional activation of Wnt/Wg-responsive genes requires the stabilization and nuclear accumulation of beta-catenin, a dedicated coactivator of LEF/TCF enhancer-binding proteins. Here we report that recombinant beta-catenin strongly enhances binding and transactivation by LEF-1 on chromatin templates in vitro. Interestingly, different LEF-1 isoforms vary in their ability to bind nucleosomal templates in the absence of beta-catenin, owing to N-terminal residues that repress binding to chromatin, but not nonchromatin, templates. Transcriptional activation in vitro requires both the armadillo (ARM) repeats and the C terminus of beta-catenin, whereas the phosphorylated N terminus is inhibitory to transcription. A fragment spanning the C terminus (CT) and ARM repeats 11 and 12 (CT-ARM), but not the CT alone, functions as a dominant negative inhibitor of LEF-1-beta-cat activity in vitro and can block ATP-dependent binding of the complex to chromatin. LEF-1-beta-cat transactivation in vitro was also repressed by inhibitor of beta-catenin and Tcf-4 (ICAT), a physiological inhibitor of Wnt/Wg signaling that interacts with ARM repeats 11 and 12, and by the nonsteroidal anti-inflammatory compound, sulindac. None of these transcription inhibitors (CT-ARM, ICAT, or sulindac) could disrupt the LEF-1-beta-cat complex after it was stably bound to chromatin. We conclude that the CT-ARM region of beta-catenin functions as a chromatin-specific activation domain, and that several inhibitors of the Wnt/Wg pathway directly modulate LEF-1-beta-cat activity on chromatin.

Pubmed ID: 11751639

Authors

  • Tutter AV
  • Fryer CJ
  • Jones KA

Journal

Genes & development

Publication Data

December 15, 2001

Associated Grants

None

Mesh Terms

  • Amino Acid Sequence
  • Animals
  • Anti-Inflammatory Agents, Non-Steroidal
  • Binding Sites
  • Cell Nucleus
  • Chromatin
  • Cytoskeletal Proteins
  • DNA-Binding Proteins
  • Drosophila
  • Humans
  • Lymphoid Enhancer-Binding Factor 1
  • Molecular Sequence Data
  • Mutation
  • Nuclear Proteins
  • Proto-Oncogene Proteins
  • Sequence Homology, Amino Acid
  • Signal Transduction
  • Sulindac
  • TCF Transcription Factors
  • Trans-Activators
  • Transcription Factor 7-Like 2 Protein
  • Transcription Factors
  • Transcription, Genetic
  • Transcriptional Activation
  • Wnt Proteins
  • Zebrafish Proteins
  • beta Catenin