title: The FBXO4 tumor suppressor functions as a barrier to BRAFV600E-dependent metastatic melanoma.
abstract: Cyclin D1-cyclin-dependent kinase 4/6 (CDK4/6) dysregulation is a major contributor to melanomagenesis. Clinical evidence has revealed that p16(INK4A), an allosteric inhibitor of CDK4/6, is inactivated in over half of human melanomas, and numerous animal models have demonstrated that p16(INK4A) deletion promotes melanoma. FBXO4, a specificity factor for the E3 ligase that directs timely cyclin D1 proteolysis, has not been studied in melanoma. We demonstrate that Fbxo4 deficiency induces Braf-driven melanoma and that this phenotype depends on cyclin D1 accumulation in mice, underscoring the importance of this ubiquitin ligase in tumor suppression. Furthermore, we have identified a substrate-binding mutation, FBXO4 I377M, that selectively disrupts cyclin D1 degradation while preserving proteolysis of the other known FBXO4 substrate, TRF1. The I377M mutation and Fbxo4 deficiency result in nuclear accumulation of cyclin D1, a key transforming neoplastic event. Collectively, these data provide evidence that FBXO4 dysfunction, as a mechanism for cyclin D1 overexpression, is a contributor to human malignancy.
authors.affiliation: The Leonard and Madlyn Abramson Family Cancer Research Institute.
authors.forename: Eric K
authors.initials: EK
authors.lastname: Lee
authors.forename: Zhaorui
authors.initials: Z
authors.lastname: Lian
authors.forename: Kurt
authors.initials: K
authors.lastname: D'Andrea
authors.forename: Richard
authors.initials: R
authors.lastname: Letrero
authors.forename: WeiQi
authors.initials: W
authors.lastname: Sheng
authors.forename: Shujing
authors.initials: S
authors.lastname: Liu
authors.forename: J Nathaniel
authors.initials: JN
authors.lastname: Diehl
authors.forename: Dariusz
authors.initials: D
authors.lastname: Pytel
authors.forename: Olena
authors.initials: O
authors.lastname: Barbash
authors.forename: Lynn
authors.initials: L
authors.lastname: Schuchter
authors.forename: Ravi
authors.initials: R
authors.lastname: Amaravaradi
authors.forename: Xiaowei
authors.initials: X
authors.lastname: Xu
authors.forename: Meenhard
authors.initials: M
authors.lastname: Herlyn
authors.forename: Katherine L
authors.initials: KL
authors.lastname: Nathanson
authors.forename: J Alan
authors.initials: JA
authors.lastname: Diehl
mesh_terms: D019943:Amino Acid Substitution; D000818:Animals; D045744:Cell Line, Tumor; D019938:Cyclin D1 / Q000032:analysis / Q000378:metabolism; D044783:F-Box Proteins / Q000235:genetics / Q000378:metabolism*; D017353:Gene Deletion; D006801:Humans; D008545:Melanoma / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D017354:Point Mutation; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics* / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism*; D054875:Ubiquitination
chemical_list: D044783:F-Box Proteins; C508146:FBXO4 protein, human; C515213:Fbx4 protein, mouse; D025521:Tumor Suppressor Proteins; D019938:Cyclin D1; D048493:Proto-Oncogene Proteins B-raf
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