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. Here, we identify Mammalian Constitutive Photomorphogenic 1 (COP1) as a novel E3 ubiquitin ligase for targeting 14-3-3σ through proteasome 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.

Degrons in cancer

“…Degradation processes in the p53 pathway add additional layers of complexity because several p53-targeting E3 ligases, including MDM2 and COP1, also have autoubiquitination activity (140,141). Furthermore, genes encoding the E3 ligases COP1, MDM2, PIRH2, and JFK, all of which target p53, are induced by the transcriptional activity of p53 (138,139,(142)(143)(144).…”

Ubiquitination of p53 is Involved in Troglitazone Induced Apoptosis in Cervical Cancer Cells

“…To evaluate whether this effect was mediated via MG132 was used to block the proteasomal degradation in Hela cells ( Okamoto et al, 2009;Choi et al, 2011;Tian et al, 2012). Our results showed that TGZ-mediated was reduced in TGZ treatment cells versus control group and apoptosis has been investigated in various cancer cells, including cervical cancer cell (Nagamine et al, 2003).…”

COP9 Signalosome Subunit Csn8 Is Involved in Maintaining Proper Duration of the G1 Phase

“…In contrast, Csn3 appears to negatively regulate cell proliferation as its knockdown accelerates cell growth in cultured cells (20). In addition, Csn3 and Csn6 affect human COP1 levels in different ways (20,21). In Neurospora crassa, which lacks Csn8, knock-out of Csn3 results in a faster growth rate, whereas knock-out of other CSN genes reduces growth (23).…”