title: COP9 signalosome subunit 6 stabilizes COP1, which functions as an E3 ubiquitin ligase for 14-3-3σ.
abstract: 14-3-3σ, a gene upregulated by p53 in response to DNA damage, exists as part of a positive-feedback loop, which activates p53 and is a human cancer epithelial marker downregulated in various cancer types. 14-3-3σ levels are critical for maintaining p53 activity in response to DNA damage and regulating signal mediators such as Akt. In this study, we identify mammalian constitutive photomorphogenic 1 (COP1) as a novel E3 ubiquitin ligase for targeting 14-3-3σ through proteasomal degradation. We show for the first time that COP9 signalosome subunit 6 (CSN6) associates with COP1 and is involved in 14-3-3σ ubiquitin-mediated degradation. Mechanistic studies show that CSN6 expression leads to stabilization of COP1 through reducing COP1 self-ubiquitination and decelerating COP1's turnover rate. We also show that CSN6-mediated 14-3-3σ ubiquitination is compromised when COP1 is knocked down. Thus, CSN6 mediates 14-3-3σ ubiquitination through enhancing COP1 stability. Subsequently, we show that CSN6 causes 14-3-3σ downregulation, thereby activating Akt and promoting cell survival. Also, CSN6 overexpression leads to increased cell growth, transformation and promotes tumorigenicity. Significantly, 14-3-3σ expression can correct the abnormalities mediated by CSN6 expression. These data suggest that the CSN6-COP1 axis is involved in 14-3-3σ degradation, and that deregulation of this axis will promote cell growth and tumorigenicity.
authors.affiliation: Department of Molecular and Cellular Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, USA.
authors.forename: H H
authors.initials: HH
authors.lastname: Choi
authors.forename: C
authors.initials: C
authors.lastname: Gully
authors.forename: C-H
authors.initials: CH
authors.lastname: Su
authors.forename: G
authors.initials: G
authors.lastname: Velazquez-Torres
authors.forename: P-C
authors.initials: PC
authors.lastname: Chou
authors.forename: C
authors.initials: C
authors.lastname: Tseng
authors.forename: R
authors.initials: R
authors.lastname: Zhao
authors.forename: L
authors.initials: L
authors.lastname: Phan
authors.forename: T
authors.initials: T
authors.lastname: Shaiken
authors.forename: J
authors.initials: J
authors.lastname: Chen
authors.forename: S C
authors.initials: SC
authors.lastname: Yeung
authors.forename: M-H
authors.initials: MH
authors.lastname: Lee
mesh_terms: D048948:14-3-3 Proteins / Q000378:metabolism*; D014408:Biomarkers, Tumor / Q000378:metabolism*; D000075686:COP9 Signalosome Complex; D002460:Cell Line; D005092:Exonucleases / Q000378:metabolism*; D005095:Exoribonucleases; D005434:Flow Cytometry; D006801:Humans; D046912:Multiprotein Complexes / Q000502:physiology*; D010447:Peptide Hydrolases / Q000502:physiology*; D016133:Polymerase Chain Reaction; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism*; D054875:Ubiquitination
chemical_list: D048948:14-3-3 Proteins; D014408:Biomarkers, Tumor; D046912:Multiprotein Complexes; C471981:COP1 protein, human; D044767:Ubiquitin-Protein Ligases; D005092:Exonucleases; D005095:Exoribonucleases; C413442:SFN protein, human; D010447:Peptide Hydrolases; D000075686:COP9 Signalosome Complex