The Fbx4 Tumor Suppressor Regulates Cyclin D1 Accumulation and Prevents Neoplastic Transformation
| Autor: | Olena Barbash, Anil K. Rustgi, Mariusz A. Wasik, Andres J. Klein-Szanto, Laura Pontano Vaites, Darshan Roy, J A Diehl, Zhaorui Lian, Eric K. Lee |
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| Rok vydání: | 2011 |
| Předmět: |
Cyclin D
Cyclin A Cyclin B Cell Cycle Proteins Mice Transgenic Proto-Oncogene Proteins p21(ras) Gene Knockout Techniques Mice Cyclin D1 Neoplasms Animals Molecular Biology Cells Cultured Cell Proliferation Cell Nucleus SKP Cullin F-Box Protein Ligases biology F-Box Proteins Cell Cycle Articles Cell Biology Fibroblasts G2-M DNA damage checkpoint Cell cycle Ubiquitin ligase Cell biology Cell Transformation Neoplastic biology.protein Cancer research Cyclin A2 DNA Damage |
| Zdroj: | Molecular and Cellular Biology. 31:4513-4523 |
| ISSN: | 1098-5549 |
| Popis: | Skp1-Cul1-F-box (SCF) E3 ubiquitin ligase complexes modulate the accumulation of key cell cycle regulatory proteins. Following the G(1)/S transition, SCF(Fbx4) targets cyclin D1 for proteasomal degradation, a critical event necessary for DNA replication fidelity. Deregulated cyclin D1 drives tumorigenesis, and inactivating mutations in Fbx4 have been identified in human cancer, suggesting that Fbx4 may function as a tumor suppressor. Fbx4(+/-) and Fbx4(-/-) mice succumb to multiple tumor phenotypes, including lymphomas, histiocytic sarcomas and, less frequently, mammary and hepatocellular carcinomas. Tumors and premalignant tissue from Fbx4(+/-) and Fbx4(-/-) mice exhibit elevated cyclin D1, an observation consistent with cyclin D1 as a target of Fbx4. Molecular dissection of the Fbx4 regulatory network in murine embryonic fibroblasts (MEFs) revealed that loss of Fbx4 results in cyclin D1 stabilization and nuclear accumulation throughout cell division. Increased proliferation in early passage primary MEFs is antagonized by DNA damage checkpoint activation, consistent with nuclear cyclin D1-driven genomic instability. Furthermore, Fbx4(-/-) MEFs exhibited increased susceptibility to Ras-dependent transformation in vitro, analogous to tumorigenesis observed in mice. Collectively, these data reveal a requisite role for the SCF(Fbx4) E3 ubiquitin ligase in regulating cyclin D1 accumulation, consistent with tumor suppressive function in vivo. |
| Databáze: | OpenAIRE |
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