COP9 signalosome subunit 6 stabilizes COP1, which functions as an E3 ubiquitin ligase for 14-3-3?.

ABSTRACT: 14-3-3?, 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. 14-3-3? 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 14-3-3? through proteasomal degradation. We show for the first time that COP9 signalosome subunit 6 (CSN6) associates with COP1 and is involved in 14-3-3? 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 14-3-3? ubiquitination is compromised when COP1 is knocked down. Thus, CSN6 mediates 14-3-3? ubiquitination through enhancing COP1 stability. Subsequently, we show that CSN6 causes 14-3-3? downregulation, thereby activating Akt and promoting cell survival. Also, CSN6 overexpression leads to increased cell growth, transformation and promotes tumorigenicity. Significantly, 14-3-3? expression can correct the abnormalities mediated by CSN6 expression. These data suggest that the CSN6-COP1 axis is involved in 14-3-3? degradation, and that deregulation of this axis will promote cell growth and tumorigenicity.

SUBMITTER: Choi HH 

PROVIDER: S-EPMC3358116 | biostudies-literature | 2011 Dec

REPOSITORIES: biostudies-literature