E3 ubiquitin ligase Mule targets β-catenin under conditions of hyperactive Wnt signaling
| Autor: | Shakiba P. Baniasadi, Zhenyue Hao, Yi Sheng, Jillian Haight, Lisa Jones, Kelsie L. Thu, Carmen Dominguez-Brauer, Rahima Khatun, Andrew J. Elia, Tak W. Mak, Parameswaran Ramachandran |
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| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
Beta-catenin Genes APC Adenomatous polyposis coli Ubiquitin-Protein Ligases Adenomatous Polyposis Coli Protein Down-Regulation medicine.disease_cause 03 medical and health sciences Mice Axin Protein medicine Animals Humans Cyclin D1 Genes Tumor Suppressor RNA Small Interfering Wnt Signaling Pathway beta Catenin Genetics Cell Nucleus Mice Knockout Multidisciplinary biology Tumor Suppressor Proteins Wnt signaling pathway Ubiquitination LRP6 LRP5 Recombinant Proteins 3. Good health Ubiquitin ligase Cell biology Neoplasm Proteins Organoids 030104 developmental biology HEK293 Cells PNAS Plus Catenin Colonic Neoplasms Proteolysis biology.protein RNA Interference Carcinogenesis Protein Processing Post-Translational Protein Binding |
| Zdroj: | Proceedings of the National Academy of Sciences of the United States of America. 114(7) |
| ISSN: | 1091-6490 |
| Popis: | Wnt signaling, named after the secreted proteins that bind to cell surface receptors to activate the pathway, plays critical roles both in embryonic development and the maintenance of homeostasis in many adult tissues. Two particularly important cellular programs orchestrated by Wnt signaling are proliferation and stem cell self-renewal. Constitutive activation of the Wnt pathway resulting from mutation or improper modulation of pathway components contributes to cancer development in various tissues. Colon cancers frequently bear inactivating mutations of the adenomatous polyposis coli (APC) gene, whose product is an important component of the destruction complex that regulates β-catenin levels. Stabilization and nuclear localization of β-catenin result in the expression of a panel of Wnt target genes. We previously showed that Mule/Huwe1/Arf-BP1 (Mule) controls murine intestinal stem and progenitor cell proliferation by modulating the Wnt pathway via c-Myc. Here we extend our investigation of Mule's influence on oncogenesis by showing that Mule interacts directly with β-catenin and targets it for degradation under conditions of hyperactive Wnt signaling. Our findings suggest that Mule uses various mechanisms to fine-tune the Wnt pathway and provides multiple safeguards against tumorigenesis. |
| Databáze: | OpenAIRE |
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