title: Regulating the stability and localization of CDK inhibitor p27(Kip1) via CSN6-COP1 axis.
abstract: The COP9 signalosome subunit 6 (CSN6), which is involved in ubiquitin-mediated protein degradation, is overexpressed in many types of cancer. CSN6 is critical in causing p53 degradation and malignancy, but its target in cell cycle progression is not fully characterized. Constitutive photomorphogenic 1 (COP1) is an E3 ubiquitin ligase associating with COP9 signalosome to regulate important target proteins for cell growth. p27 is a critical G1 CDK inhibitor involved in cell cycle regulation, but its upstream regulators are not fully characterized. Here, we show that the CSN6-COP1 link is regulating p27(Kip1) stability, and that COP1 is a negative regulator of p27(Kip1). Ectopic expression of CSN6 can decrease the expression of p27(Kip1), while CSN6 knockdown leads to p27(Kip1) stabilization. Mechanistic studies show that CSN6 interacts with p27(Kip1) and facilitates ubiquitin-mediated degradation of p27(Kip1). CSN6-mediated p27 degradation depends on the nuclear export of p27(Kip1), which is regulated through COP1 nuclear exporting signal. COP1 overexpression leads to the cytoplasmic distribution of p27, thereby accelerating p27 degradation. Importantly, the negative impact of COP1 on p27 stability contributes to elevating expression of genes that are suppressed through p27 mediation. Kaplan-Meier analysis of tumor samples demonstrates that high COP1 expression was associated with poor overall survival. These data suggest that tumors with CSN6/COP1 deregulation may have growth advantage by regulating p27 degradation and subsequent impact on p27 targeted genes.
authors.affiliation: a Department of Molecular and Cellular Oncology ; The University of Texas MD Anderson Cancer Center ; Houston , TX USA.
authors.forename: Hyun Ho
authors.initials: HH
authors.lastname: Choi
authors.forename: Sergei
authors.initials: S
authors.lastname: Guma
authors.forename: Lekun
authors.initials: L
authors.lastname: Fang
authors.forename: Liem
authors.initials: L
authors.lastname: Phan
authors.forename: Cristina
authors.initials: C
authors.lastname: Ivan
authors.forename: Keith
authors.initials: K
authors.lastname: Baggerly
authors.forename: Anil
authors.initials: A
authors.lastname: Sood
authors.forename: Mong-Hong
authors.initials: MH
authors.lastname: Lee
mesh_terms: D021581:Active Transport, Cell Nucleus; D048868:Adaptor Proteins, Signal Transducing / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D000075686:COP9 Signalosome Complex; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000378:metabolism; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000378:metabolism; D015536:Down-Regulation; D005260:Female; D045325:HCT116 Cells; D057809:HEK293 Cells; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D008856:Microscopy, Fluorescence; D009101:Multiple Myeloma / Q000378:metabolism / Q000401:mortality / Q000473:pathology; D010051:Ovarian Neoplasms / Q000378:metabolism / Q000401:mortality / Q000473:pathology; D055550:Protein Stability; D034741:RNA, Small Interfering / Q000378:metabolism; D060888:Real-Time Polymerase Chain Reaction; D025801:Ubiquitin / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D054875:Ubiquitination
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C470634:COPS6 protein, human; D034741:RNA, Small Interfering; D025801:Ubiquitin; D050760:Cyclin-Dependent Kinase Inhibitor p27; C471981:COP1 protein, human; D044767:Ubiquitin-Protein Ligases; D000075686:COP9 Signalosome Complex
keywords: COP1; COP9 signalosome; CSN6; p27; ubiquitination