University of Texas Health Science Center at Houston
Cop 9 Signalosome Subunit 6 Stabilizes Cop1, A Novel E3 Ubiquitin Ligase For 14-3-3Σ
Abstract
dc:description.abstract<p> 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 mediator 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 by suppressing FOXO, an Akt target, transcriptional activity. 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.</p>
Degree
thesis:*- Name thesis:degree_name
- Masters of Science (MS)
- Level thesis:degree_level
- Thesis (MS)
- Year dc:date.available
- 2011
Author and committee
dc:creator, dc:contributor.*- Author dc:creator
-
- Choi, Hyun Ho
- Contributors dc:contributor
-
- Mong-Hong Lee, Ph.D
- Elsa Flores, Ph.D
- Lei Li, Ph.D
Subjects
dc:subject × 9Identifiers
dc:identifier.*- Repository record dc:identifier
- https://digitalcommons.library.tmc.edu/utgsbs_dissertations/112
- OAI identifier oai:identifier
- oai:digitalcommons.library.tmc.edu:utgsbs_dissertations-1136