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- Title
COP9 signalosome subunit 6 stabilizes COP1, which functions as an E3 ubiquitin ligase for 14-3-3σ.
- Authors
Choi, H H; Gully, C; Su, C-H; Velazquez-Torres, G; Chou, P-C; Tseng, C; Zhao, R; Phan, L; Shaiken, T; Chen, J; Yeung, S C; Lee, M-H
- 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.
- Subjects
LIGASES; PROTEINS; GENE expression; UBIQUITIN; DNA damage; GENETIC transformation
- Publication
Oncogene, 2011, Vol 30, Issue 48, p4791
- ISSN
0950-9232
- Publication type
Article
- DOI
10.1038/onc.2011.192