Targeted disruption of the BCL9/β-catenin complex inhibits oncogenic Wnt signaling
| Autor: | Ramesh A. Shivdasani, Di Zhu, Nikhil C. Munshi, Andrew L. Kung, Daniel R. Carrasco, Madeleine E. Lemieux, Jeremy Ryan, Daniel E. Carrasco, Gregory H. Bird, Kohichi Takada, David Horst, Wenqing Xu, Mala Mani, Loren D. Walensky, Jianjun Zhao, Kumar Sukhdeo, Mariateresa Fulciniti |
|---|---|
| Rok vydání: | 2012 |
| Předmět: |
Transcription
Genetic Angiogenesis Molecular Sequence Data Biology Protein Structure Secondary Article Mice BCL9 Transcription (biology) Cell Movement Cell Line Tumor Animals Humans Amino Acid Sequence Intestinal Mucosa Transcription factor Wnt Signaling Pathway beta Catenin Cell Proliferation Neovascularization Pathologic Protein Stability Wnt signaling pathway LRP6 LRP5 General Medicine Oncogenes Molecular biology Xenograft Model Antitumor Assays Cell biology Neoplasm Proteins Gene Targeting Catenin complex Colorectal Neoplasms Peptides TCF Transcription Factors Protein Binding Transcription Factors |
| Zdroj: | Science translational medicine. 4(148) |
| ISSN: | 1946-6242 |
| Popis: | Deregulated Wnt/β-catenin signaling underlies the pathogenesis of a broad range of human cancers, yet the development of targeted therapies to disrupt the resulting aberrant transcription has proved difficult because the pathway comprises large protein interaction surfaces and regulates many homeostatic functions. Therefore, we have directed our efforts toward blocking the interaction of β-catenin with B cell lymphoma 9 (BCL9), a co-activator for β-catenin–mediated transcription that is highly expressed in tumors but not in the cells of origin. BCL9 drives β-catenin signaling through direct binding mediated by its α-helical homology domain 2. We developed a stabilized α helix of BCL9 (SAH-BCL9), which we show targets β-catenin, dissociates native β-catenin/BCL9 complexes, selectively suppresses Wnt transcription, and exhibits mechanism-based antitumor effects. SAH-BCL9 also suppresses tumor growth, angiogenesis, invasion, and metastasis in mouse xenograft models of Colo320 colorectal carcinoma and INA-6 multiple myeloma. By inhibiting the BCL9–β-catenin interaction and selectively suppressing oncogenic Wnt transcription, SAH-BCL9 may serve as a prototype therapeutic agent for cancers driven by deregulated Wnt signaling. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|