PMID- 15103385
OWN - NLM
STAT- MEDLINE
DCOM- 20040521
LR  - 20191210
IS  - 1476-4687 (Electronic)
IS  - 0028-0836 (Linking)
VI  - 429
IP  - 6987
DP  - 2004 May 6
TI  - The ubiquitin ligase COP1 is a critical negative regulator of p53.
PG  - 86-92
AB  - COP1 (constitutively photomorphogenic 1) is a RING-finger-containing protein that 
      functions to repress plant photomorphogenesis, the light-mediated programme of 
      plant development. Mutants of COP1 are constitutively photomorphogenic, and this 
      has been attributed to their inability to negatively regulate the proteins LAF1 
      (ref. 1) and HY5 (ref. 2). The role of COP1 in mammalian cells is less well 
      characterized. Here we identify the tumour-suppressor protein p53 as a 
      COP1-interacting protein. COP1 increases p53 turnover by targeting it for 
      degradation by the proteasome in a ubiquitin-dependent fashion, independently of 
      MDM2 or Pirh2, which are known to interact with and negatively regulate p53. 
      Moreover, COP1 serves as an E3 ubiquitin ligase for p53 in vitro and in vivo, and 
      inhibits p53-dependent transcription and apoptosis. Depletion of COP1 by short 
      interfering RNA (siRNA) stabilizes p53 and arrests cells in the G1 phase of the 
      cell cycle. Furthermore, we identify COP1 as a p53-inducible gene, and show that 
      the depletion of COP1 and MDM2 by siRNA cooperatively sensitizes U2-OS cells to 
      ionizing-radiation-induced cell death. Overall, these results indicate that COP1 
      is a critical negative regulator of p53 and represents a new pathway for 
      maintaining p53 at low levels in unstressed cells.
FAU - Dornan, David
AU  - Dornan D
AD  - Department of Molecular Oncology, Genentech, Inc., 1 DNA Way, South San 
      Francisco, California 94080, USA.
FAU - Wertz, Ingrid
AU  - Wertz I
FAU - Shimizu, Harumi
AU  - Shimizu H
FAU - Arnott, David
AU  - Arnott D
FAU - Frantz, Gretchen D
AU  - Frantz GD
FAU - Dowd, Patrick
AU  - Dowd P
FAU - O'Rourke, Karen
AU  - O'Rourke K
FAU - Koeppen, Hartmut
AU  - Koeppen H
FAU - Dixit, Vishva M
AU  - Dixit VM
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20040421
PL  - England
TA  - Nature
JT  - Nature
JID - 0410462
RN  - 0 (Carrier Proteins)
RN  - 0 (Multienzyme Complexes)
RN  - 0 (Nuclear Proteins)
RN  - 0 (Proto-Oncogene Proteins)
RN  - 0 (RNA, Small Interfering)
RN  - 0 (Tumor Suppressor Protein p53)
RN  - 0 (Ubiquitin)
RN  - EC 2.3.2.27 (COP1 protein, human)
RN  - EC 2.3.2.27 (MDM2 protein, human)
RN  - EC 2.3.2.27 (Proto-Oncogene Proteins c-mdm2)
RN  - EC 2.3.2.27 (Ubiquitin-Protein Ligases)
RN  - EC 3.4.22.- (Cysteine Endopeptidases)
RN  - EC 3.4.25.1 (Proteasome Endopeptidase Complex)
SB  - IM
MH  - Amino Acid Sequence
MH  - Apoptosis
MH  - Base Sequence
MH  - Carrier Proteins/genetics/*metabolism
MH  - Cell Line
MH  - Cell Line, Tumor
MH  - Cysteine Endopeptidases/metabolism
MH  - G1 Phase
MH  - Gene Expression Regulation
MH  - Humans
MH  - Molecular Sequence Data
MH  - Multienzyme Complexes/metabolism
MH  - Nuclear Proteins/genetics/*metabolism
MH  - Promoter Regions, Genetic/genetics
MH  - Proteasome Endopeptidase Complex
MH  - Protein Binding
MH  - Proto-Oncogene Proteins/genetics/metabolism
MH  - Proto-Oncogene Proteins c-mdm2
MH  - RNA, Small Interfering/genetics/metabolism
MH  - Transcription, Genetic
MH  - Tumor Suppressor Protein p53/chemistry/*metabolism
MH  - Ubiquitin/metabolism
MH  - Ubiquitin-Protein Ligases/genetics/metabolism
EDAT- 2004/04/23 05:00
MHDA- 2004/05/22 05:00
CRDT- 2004/04/23 05:00
PHST- 2003/12/23 00:00 [received]
PHST- 2004/03/29 00:00 [accepted]
PHST- 2004/04/23 05:00 [pubmed]
PHST- 2004/05/22 05:00 [medline]
PHST- 2004/04/23 05:00 [entrez]
AID - nature02514 [pii]
AID - 10.1038/nature02514 [doi]
PST - ppublish
SO  - Nature. 2004 May 6;429(6987):86-92. doi: 10.1038/nature02514. Epub 2004 Apr 21.