PMID- 25945542
OWN - NLM
STAT- MEDLINE
DCOM- 20160421
LR  - 20220317
IS  - 1551-4005 (Electronic)
IS  - 1538-4101 (Print)
IS  - 1551-4005 (Linking)
VI  - 14
IP  - 14
DP  - 2015
TI  - Regulating the stability and localization of CDK inhibitor p27(Kip1) via 
      CSN6-COP1 axis.
PG  - 2265-73
LID - 10.1080/15384101.2015.1046655 [doi]
AB  - 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.
FAU - Choi, Hyun Ho
AU  - Choi HH
AD  - a Department of Molecular and Cellular Oncology ; The University of Texas MD 
      Anderson Cancer Center ; Houston , TX USA.
FAU - Guma, Sergei
AU  - Guma S
FAU - Fang, Lekun
AU  - Fang L
FAU - Phan, Liem
AU  - Phan L
FAU - Ivan, Cristina
AU  - Ivan C
FAU - Baggerly, Keith
AU  - Baggerly K
FAU - Sood, Anil
AU  - Sood A
FAU - Lee, Mong-Hong
AU  - Lee MH
LA  - eng
GR  - CA16672/CA/NCI NIH HHS/United States
GR  - R01CA089266/CA/NCI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
PT  - Research Support, U.S. Gov't, Non-P.H.S.
DEP - 20150506
PL  - United States
TA  - Cell Cycle
JT  - Cell cycle (Georgetown, Tex.)
JID - 101137841
RN  - 0 (Adaptor Proteins, Signal Transducing)
RN  - 0 (COPS6 protein, human)
RN  - 0 (RNA, Small Interfering)
RN  - 0 (Ubiquitin)
RN  - 147604-94-2 (Cyclin-Dependent Kinase Inhibitor p27)
RN  - EC 2.3.2.27 (COP1 protein, human)
RN  - EC 2.3.2.27 (Ubiquitin-Protein Ligases)
RN  - EC 3.4.19.12 (COP9 Signalosome Complex)
SB  - IM
MH  - Active Transport, Cell Nucleus
MH  - Adaptor Proteins, Signal Transducing/antagonists & 
      inhibitors/genetics/*metabolism
MH  - Animals
MH  - COP9 Signalosome Complex
MH  - Cell Line, Tumor
MH  - Cell Nucleus/metabolism
MH  - Cyclin-Dependent Kinase Inhibitor p27/metabolism
MH  - Down-Regulation
MH  - Female
MH  - HCT116 Cells
MH  - HEK293 Cells
MH  - Humans
MH  - Mice
MH  - Mice, Nude
MH  - Microscopy, Fluorescence
MH  - Multiple Myeloma/metabolism/mortality/pathology
MH  - Ovarian Neoplasms/metabolism/mortality/pathology
MH  - Protein Stability
MH  - RNA, Small Interfering/metabolism
MH  - Real-Time Polymerase Chain Reaction
MH  - Ubiquitin/metabolism
MH  - Ubiquitin-Protein Ligases/antagonists & inhibitors/genetics/*metabolism
MH  - Ubiquitination
PMC - PMC4613181
OTO - NOTNLM
OT  - COP1
OT  - COP9 signalosome
OT  - CSN6
OT  - p27
OT  - ubiquitination
EDAT- 2015/05/07 06:00
MHDA- 2016/04/22 06:00
PMCR- 2016/05/06
CRDT- 2015/05/07 06:00
PHST- 2015/05/07 06:00 [entrez]
PHST- 2015/05/07 06:00 [pubmed]
PHST- 2016/04/22 06:00 [medline]
PHST- 2016/05/06 00:00 [pmc-release]
AID - 1046655 [pii]
AID - 10.1080/15384101.2015.1046655 [doi]
PST - ppublish
SO  - Cell Cycle. 2015;14(14):2265-73. doi: 10.1080/15384101.2015.1046655. Epub 2015 
      May 6.