title: The Fbx4 tumor suppressor regulates cyclin D1 accumulation and prevents neoplastic transformation.
abstract: 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.
authors.affiliation: The Leonard and Madlyn Abramson Family Cancer Research Institute, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
authors.forename: Laura Pontano
authors.initials: LP
authors.lastname: Vaites
authors.forename: Eric K
authors.initials: EK
authors.lastname: Lee
authors.forename: Zhaorui
authors.initials: Z
authors.lastname: Lian
authors.forename: Olena
authors.initials: O
authors.lastname: Barbash
authors.forename: Darshan
authors.initials: D
authors.lastname: Roy
authors.forename: Mariusz
authors.initials: M
authors.lastname: Wasik
authors.forename: Andres J P
authors.initials: AJ
authors.lastname: Klein-Szanto
authors.forename: Anil K
authors.initials: AK
authors.lastname: Rustgi
authors.forename: J Alan
authors.initials: JA
authors.lastname: Diehl
mesh_terms: D000818:Animals; D002453:Cell Cycle; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism; D002467:Cell Nucleus / Q000378:metabolism; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic; D002478:Cells, Cultured; D019938:Cyclin D1 / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D004249:DNA Damage; D044783:F-Box Proteins / Q000235:genetics* / Q000378:metabolism*; D005347:Fibroblasts / Q000378:metabolism; D055786:Gene Knockout Techniques; D051379:Mice; D008822:Mice, Transgenic; D009369:Neoplasms / Q000235:genetics; D016283:Proto-Oncogene Proteins p21(ras) / Q000378:metabolism; D044843:SKP Cullin F-Box Protein Ligases / Q000378:metabolism*
chemical_list: C530105:Ccnd1 protein, mouse; D018797:Cell Cycle Proteins; D044783:F-Box Proteins; C515213:Fbx4 protein, mouse; D019938:Cyclin D1; D044843:SKP Cullin F-Box Protein Ligases; D016283:Proto-Oncogene Proteins p21(ras)