title: FBXW7-mediated degradation of CCDC6 is impaired by ATM during DNA damage response in lung cancer cells.
abstract: CCDC6 is rearranged in approximately 20% of papillary thyroid carcinomas and some lung cancers participating in the formation of PTC1/ret proto-oncogene oncogene. CCDC6 is involved in the cellular response to DNA damage and is stabilized by ATM-mediated phosphorylation at Thr434. However, the E3 ligase that targets CCDC6 for destruction is unknown. Here, we show that FBXW7 interacts with and targets CCDC6 for ubiquitin-mediated proteasomal degradation. Moreover, FBXW7-mediated CCDC6 degradation is impaired in response to DNA damage. Mechanistically, phosphorylation of CCDC6 at Thr434 by ATM during DNA damage response prevents FBXW6-CCDC6 interaction and FBXW7-mediated CCDC6 degradation. Our results suggest that the involvement of FBXW7 in targeting CCDC6 for destruction will be useful for the establishment of new therapeutic approaches for cancer treatment.
authors.affiliation: Department of Thoracic Surgery, Shengjing Hospital of China Medical University, Shenyang 110004, Liaoning Province, China. zhaojungang1967@hotmail.com
authors.forename: JunGang
authors.initials: J
authors.lastname: Zhao
authors.forename: Jun
authors.initials: J
authors.lastname: Tang
authors.forename: WanFu
authors.initials: W
authors.lastname: Men
authors.forename: KaiMing
authors.initials: K
authors.lastname: Ren
mesh_terms: D064007:Ataxia Telangiectasia Mutated Proteins; D018797:Cell Cycle Proteins / Q000378:metabolism*; D045744:Cell Line, Tumor; D003598:Cytoskeletal Proteins / Q000378:metabolism*; D004249:DNA Damage; D004268:DNA-Binding Proteins / Q000378:metabolism*; D044783:F-Box Proteins / Q000378:metabolism*; D000073979:F-Box-WD Repeat-Containing Protein 7; D006801:Humans; D008175:Lung Neoplasms / Q000378:metabolism*; D010766:Phosphorylation; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D059748:Proteolysis; D000090063:Proto-Oncogene Mas; D013912:Threonine / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000378:metabolism*; D025801:Ubiquitin / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism*
chemical_list: C088832:CCDC6 protein, human; D018797:Cell Cycle Proteins; D003598:Cytoskeletal Proteins; D004268:DNA-Binding Proteins; D044783:F-Box Proteins; D000073979:F-Box-WD Repeat-Containing Protein 7; C513273:FBXW7 protein, human; C000715470:MAS1 protein, human; D000090063:Proto-Oncogene Mas; D025521:Tumor Suppressor Proteins; D025801:Ubiquitin; D013912:Threonine; D044767:Ubiquitin-Protein Ligases; C576324:ATM protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; D017346:Protein Serine-Threonine Kinases; D046988:Proteasome Endopeptidase Complex