title: The β-TrCP-FBXW2-SKP2 axis regulates lung cancer cell growth with FBXW2 acting as a tumour suppressor.
abstract: β-TrCP and SKP2 are two well-studied F-box proteins, which often act as oncogenes. Whether and how they communicate with each other is unknown. Here we report that FBXW2, a poorly characterized F-box, is a substrate of β-TrCP1 and an E3 ligase for SKP2. While β-TrCP1 promotes FBXW2 ubiquitylation and shortens its half-life, FBXW2 does the same to SKP2. FBXW2 has tumour suppressor activity against lung cancer cells and blocks oncogenic function of both β-TrCP1 and SKP2. The levels of β-TrCP1-FBXW2-SKP2 are inversely correlated during cell cycle with FBXW2 and β-TrCP/SKP2 being high or low, respectively, in arrested cells, whereas the opposite is true in proliferating cells. Consistently, FBXW2 predicts a better patient survival, whereas β-TrCP1 and SKP2 predict a worse survival. Finally, the gain- and loss-of-function mutations of FBXW2 are found in various human cancers. Collectively, our data show that the β-TrCP-FBXW2-SKP2 axis forms an oncogene-tumour suppressor-oncogene cascade to control cancer cell growth with FBXW2 acting as a tumour suppressor by promoting SKP2 degradation.
authors.affiliation: Division of Radiation and Cancer Biology, Department of Radiation Oncology, University of Michigan, Ann Arbor, Michigan 48109, USA.
authors.forename: Jie
authors.initials: J
authors.lastname: Xu
authors.affiliation: Division of Radiation and Cancer Biology, Department of Radiation Oncology, University of Michigan, Ann Arbor, Michigan 48109, USA.
authors.forename: Weihua
authors.initials: W
authors.lastname: Zhou
authors.affiliation: Institute of Translational Medicine, Zhejiang University School of Medicine, Hangzhou 310029, China.
authors.forename: Fei
authors.initials: F
authors.lastname: Yang
authors.affiliation: Department of Surgery, University of Michigan, Ann Arbor, Michigan 48109, USA.
authors.forename: Guoan
authors.initials: G
authors.lastname: Chen
authors.affiliation: Institute of Translational Medicine, Zhejiang University School of Medicine, Hangzhou 310029, China.|Affiliated Children Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China.
authors.forename: Haomin
authors.initials: H
authors.lastname: Li
authors.affiliation: Division of Radiation and Cancer Biology, Department of Radiation Oncology, University of Michigan, Ann Arbor, Michigan 48109, USA.|Institute of Translational Medicine, Zhejiang University School of Medicine, Hangzhou 310029, China.|Key laboratory of combined multi-organ transplantation, Ministry of Public Health, First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310058, China.
authors.forename: Yongchao
authors.initials: Y
authors.lastname: Zhao
authors.affiliation: Institute of Translational Medicine, Zhejiang University School of Medicine, Hangzhou 310029, China.|Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou 310020, China.
authors.forename: Pengyuan
authors.initials: P
authors.lastname: Liu
authors.affiliation: Division of Radiation and Cancer Biology, Department of Radiation Oncology, University of Michigan, Ann Arbor, Michigan 48109, USA.
authors.forename: Hua
authors.initials: H
authors.lastname: Li
authors.affiliation: Division of Radiation and Cancer Biology, Department of Radiation Oncology, University of Michigan, Ann Arbor, Michigan 48109, USA.
authors.forename: Mingjia
authors.initials: M
authors.lastname: Tan
authors.affiliation: Institute of Translational Medicine, Zhejiang University School of Medicine, Hangzhou 310029, China.
authors.forename: Xiufang
authors.initials: X
authors.lastname: Xiong
authors.affiliation: Division of Radiation and Cancer Biology, Department of Radiation Oncology, University of Michigan, Ann Arbor, Michigan 48109, USA.|Institute of Translational Medicine, Zhejiang University School of Medicine, Hangzhou 310029, China.|Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Zhejiang University, Hangzhou 310058, China.
authors.forename: Yi
authors.initials: Y
authors.lastname: Sun
mesh_terms: D000818:Animals; D002453:Cell Cycle; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D044783:F-Box Proteins / Q000235:genetics / Q000378:metabolism*; D005260:Female; D016147:Genes, Tumor Suppressor; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology*; D008297:Male; D051379:Mice; D008819:Mice, Nude; D059748:Proteolysis; D044786:S-Phase Kinase-Associated Proteins / Q000235:genetics / Q000378:metabolism*; D044844:beta-Transducin Repeat-Containing Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D044783:F-Box Proteins; C499832:FBXW2 protein, human; D044786:S-Phase Kinase-Associated Proteins; C000628447:SKP2 protein, human; D044844:beta-Transducin Repeat-Containing Proteins