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PMID: 12972599 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, Non-P.H.S. Research Support, U.S. Gov't, P.H.S.

Disruption of the COP9 signalosome Csn2 subunit in mice causes deficient cell proliferation, accumulation of p53 and cyclin E, and early embryonic death.

Molecular and cellular biology ·Vol. 23 ·No. 19 ·2003-10-00 ·Pages 6790-7

Lykke-Andersen K, Schaefer L, Menon S, Deng XW, Miller JB, Wei N

Abstract

Csn2 (Trip15/Cops2/Alien) encodes the second subunit of the COP9 signalosome (CSN), an eight-subunit heteromeric complex homologous to the lid subcomplex of the 26S proteasome. CSN is a regulator of SCF (Skp1-cullin-F-box protein)ubiquitin ligases, mostly through the enzymatic activity that deconjugates the ubiquitin-like protein Nedd8 from the SCF Cul1 component. In addition, CSN associates with protein kinase activities targeting p53, c-Jun, and IkappaB for phosphorylation. Csn2 also interacts with and regulates a subset of nuclear hormone receptors and is considered a novel corepressor. We report that targeted disruption of Csn2 in mice caused arrest of embryo development at the peri-implantation stage. Csn2(-/-) blastocysts failed to outgrow in culture and exhibited a cell proliferation defect in inner cell mass, accompanied by a slight decrease in Oct4. In addition, lack of Csn2 disrupted the CSN complex and resulted in a drastic increase in cyclin E, supporting a role for CSN in cooperating with the SCF-ubiquitin-proteasome system to regulate protein turnover. Furthermore, Csn2(-/-) embryos contained elevated levels of p53 and p21, which may contribute to premature cell cycle arrest of the mutant.

MeSH Terms
Animals Blastocyst/metabolism COP9 Signalosome Complex Cell Division/physiology Crosses, Genetic Cyclin E/metabolism Cyclin-Dependent Kinase Inhibitor p21 Cyclins/metabolism DNA-Binding Proteins/metabolism Gene Deletion Gene Expression Regulation, Developmental Genes, Essential HeLa Cells Heterozygote Humans Mice Mice, Inbred C57BL Mice, Knockout Multiprotein Complexes Octamer Transcription Factor-3 Peptide Hydrolases Protein Subunits Proteins/genetics,metabolism Recombination, Genetic Signal Transduction Transcription Factors Tumor Suppressor Protein p53/metabolism
Chemicals
CDKN1A protein, human Cdkn1a protein, mouse Cyclin E Cyclin-Dependent Kinase Inhibitor p21 Cyclins DNA-Binding Proteins Multiprotein Complexes Octamer Transcription Factor-3 POU5F1 protein, human Pou5f1 protein, mouse Protein Subunits Proteins Transcription Factors Tumor Suppressor Protein p53 Peptide Hydrolases COP9 Signalosome Complex
Authors & Affiliations
6 authors, click to expand affiliations / ORCID
Lykke-Andersen Karin
Department of Molecular, Cellular, and Developmental Biology, Yale University, New Haven, Connecticut 06520-8104, USA.
Schaefer Laura
Menon Suchithra
Deng Xing-Wang
Miller Jeffrey Boone
Wei Ning
References (51)
51 references, click to expand
  1. Unified nomenclature for the COP9 signalosome and its subunits: an essential regulator of development.
    Trends Genet. 2000 May;16(5):202-3 PMID: 10782111
  2. Loss of Cul1 results in early embryonic lethality and dysregulation of cyclin E.
    Nat Genet. 1999 Oct;23(2):245-8 PMID: 10508527
  3. The CUL1 C-terminal sequence and ROC1 are required for efficient nuclear accumulation, NEDD8 modification, and ubiquitin ligase activity of CUL1.
    Mol Cell Biol. 2000 Nov;20(21):8185-97 PMID: 11027288
  4. The F-box protein Skp2 is a ubiquitylation target of a Cul1-based core ubiquitin ligase complex: evidence for a role of Cul1 in the suppression of Skp2 expression in quiescent fibroblasts.
    EMBO J. 2000 Oct 16;19(20):5362-75 PMID: 11032804
  5. Conjugation of Nedd8 to CUL1 enhances the ability of the ROC1-CUL1 complex to promote ubiquitin polymerization.
    J Biol Chem. 2000 Oct 13;275(41):32317-24 PMID: 10921923
  6. Interaction between interferon consensus sequence-binding protein and COP9/signalosome subunit CSN2 (Trip15). A possible link between interferon regulatory factor signaling and the COP9/signalosome.
    J Biol Chem. 2000 Dec 15;275(50):39081-9 PMID: 10991940
  7. COP9 signalosome-specific phosphorylation targets p53 to degradation by the ubiquitin system.
    EMBO J. 2001 Apr 2;20(7):1630-9 PMID: 11285227
  8. Interactions of the COP9 signalosome with the E3 ubiquitin ligase SCFTIRI in mediating auxin response.
    Science. 2001 May 18;292(5520):1379-82 PMID: 11337587
  9. Promotion of NEDD-CUL1 conjugate cleavage by COP9 signalosome.
    Science. 2001 May 18;292(5520):1382-5 PMID: 11337588
  10. NEDD8 recruits E2-ubiquitin to SCF E3 ligase.
    EMBO J. 2001 Aug 1;20(15):4003-12 PMID: 11483504
  11. The NEDD8 system is essential for cell cycle progression and morphogenetic pathway in mice.
    J Cell Biol. 2001 Nov 12;155(4):571-9 PMID: 11696557
  12. Drosophila JAB1/CSN5 acts in photoreceptor cells to induce glial cells.
    Neuron. 2002 Jan 3;33(1):35-46 PMID: 11779478
  13. CSN1 N-terminal-dependent activity is required for Arabidopsis development but not for Rub1/Nedd8 deconjugation of cullins: a structure-function study of CSN1 subunit of COP9 signalosome.
    Mol Biol Cell. 2002 Feb;13(2):646-55 PMID: 11854419
  14. Oncogenic functions of tumour suppressor p21(Waf1/Cip1/Sdi1): association with cell senescence and tumour-promoting activities of stromal fibroblasts.
    Cancer Lett. 2002 May 8;179(1):1-14 PMID: 11880176
  15. The COP9 signalosome inhibits p27(kip1) degradation and impedes G1-S phase progression via deneddylation of SCF Cul1.
    Curr Biol. 2002 Apr 16;12(8):667-72 PMID: 11967155
  16. COP9 signalosome subunits 4 and 5 regulate multiple pleiotropic pathways in Drosophila melanogaster.
    Development. 2002 Oct;129(19):4399-409 PMID: 12223399
  17. Role of predicted metalloprotease motif of Jab1/Csn5 in cleavage of Nedd8 from Cul1.
    Science. 2002 Oct 18;298(5593):608-11 PMID: 12183637
  18. CSN5/Jab1 mutations affect axis formation in the Drosophila oocyte by activating a meiotic checkpoint.
    Development. 2002 Nov;129(21):5053-64 PMID: 12397113
  19. The fission yeast COP9/signalosome is involved in cullin modification by ubiquitin-related Ned8p.
    BMC Biochem. 2001;2:7 PMID: 11504566
  20. Inositol 1,3,4-trisphosphate 5/6-kinase associates with the COP9 signalosome by binding to CSN1.
    J Biol Chem. 2002 Nov 29;277(48):45759-64 PMID: 12324474
  21. COP9 signalosome components play a role in the mating pheromone response of S. cerevisiae.
    EMBO Rep. 2002 Dec;3(12):1215-21 PMID: 12446563
  22. NEDD8 modification of CUL1 dissociates p120(CAND1), an inhibitor of CUL1-SKP1 binding and SCF ligases.
    Mol Cell. 2002 Dec;10(6):1511-8 PMID: 12504025
  23. CAND1 binds to unneddylated CUL1 and regulates the formation of SCF ubiquitin E3 ligase complex.
    Mol Cell. 2002 Dec;10(6):1519-26 PMID: 12504026
  24. Implication of Trip15/CSN2 in early stage of neuronal differentiation of P19 embryonal carcinoma cells.
    Brain Res Dev Brain Res. 2003 Jan 10;140(1):45-56 PMID: 12524175
  25. Nedd8-modification of Cul1 is promoted by Roc1 as a Nedd8-E3 ligase and regulates its stability.
    Biochem Biophys Res Commun. 2003 Feb 7;301(2):392-8 PMID: 12565873
  26. Characterization of the last subunit of the Arabidopsis COP9 signalosome: implications for the overall structure and origin of the complex.
    Plant Cell. 2003 Mar;15(3):719-31 PMID: 12615944
  27. The COP9 signalosome interacts with SCF UFO and participates in Arabidopsis flower development.
    Plant Cell. 2003 May;15(5):1071-82 PMID: 12724534
  28. The COP9 signalosome interacts physically with SCF COI1 and modulates jasmonate responses.
    Plant Cell. 2003 May;15(5):1083-94 PMID: 12724535
  29. Arabidopsis COP9 is a component of a novel signaling complex mediating light control of development.
    Cell. 1994 Jul 15;78(1):117-24 PMID: 8033203
  30. Requirement of FGF-4 for postimplantation mouse development.
    Science. 1995 Jan 13;267(5195):246-9 PMID: 7809630
  31. Two classes of proteins dependent on either the presence or absence of thyroid hormone for interaction with the thyroid hormone receptor.
    Mol Endocrinol. 1995 Feb;9(2):243-54 PMID: 7776974
  32. The Drosophila gene alien is expressed in the muscle attachment sites during embryogenesis and encodes a protein highly conserved between plants, Drosophila and vertebrates.
    Mech Dev. 1996 Jun;57(1):59-68 PMID: 8817453
  33. The COP9 signalosome is essential for development of Drosophila melanogaster.
    Curr Biol. 1999 Oct 21;9(20):1187-90 PMID: 10531038
  34. Deletion of the Cul1 gene in mice causes arrest in early embryogenesis and accumulation of cyclin E.
    Curr Biol. 1999 Oct 21;9(20):1191-4 PMID: 10531039
  35. COP9 signalosome-directed c-Jun activation/stabilization is independent of JNK.
    J Biol Chem. 1999 Dec 10;274(50):35297-300 PMID: 10585392
  36. The COP9/signalosome complex is conserved in fission yeast and has a role in S phase.
    Curr Biol. 1999 Dec 2;9(23):1427-30 PMID: 10607571
  37. Interaction of the corepressor Alien with DAX-1 is abrogated by mutations of DAX-1 involved in adrenal hypoplasia congenita.
    J Biol Chem. 2000 Mar 17;275(11):7662-7 PMID: 10713076
  38. Nedd8 modification of cul-1 activates SCF(beta(TrCP))-dependent ubiquitination of IkappaBalpha.
    Mol Cell Biol. 2000 Apr;20(7):2326-33 PMID: 10713156
  39. Quantitative expression of Oct-3/4 defines differentiation, dedifferentiation or self-renewal of ES cells.
    Nat Genet. 2000 Apr;24(4):372-6 PMID: 10742100
  40. Modification of cullin-1 by ubiquitin-like protein Nedd8 enhances the activity of SCF(skp2) toward p27(kip1).
    Biochem Biophys Res Commun. 2000 Apr 21;270(3):1093-6 PMID: 10772955
  41. A Nedd8 conjugation pathway is essential for proteolytic targeting of p27Kip1 by ubiquitination.
    Proc Natl Acad Sci U S A. 2000 Apr 25;97(9):4579-84 PMID: 10781063
  42. A novel protein complex involved in signal transduction possessing similarities to 26S proteasome subunits.
    FASEB J. 1998 Apr;12(6):469-78 PMID: 9535219
  43. The COP9 complex is conserved between plants and mammals and is related to the 26S proteasome regulatory complex.
    Curr Biol. 1998 Jul 30-Aug 13;8(16):919-22 PMID: 9707402
  44. A subcomplex of the proteasome regulatory particle required for ubiquitin-conjugate degradation and related to the COP9-signalosome and eIF3.
    Cell. 1998 Sep 4;94(5):615-23 PMID: 9741626
  45. Formation of pluripotent stem cells in the mammalian embryo depends on the POU transcription factor Oct4.
    Cell. 1998 Oct 30;95(3):379-91 PMID: 9814708
  46. Arabidopsis homologs of a c-Jun coactivator are present both in monomeric form and in the COP9 complex, and their abundance is differentially affected by the pleiotropic cop/det/fus mutations.
    Plant Cell. 1998 Nov;10(11):1779-90 PMID: 9811788
  47. Ubiquitination and degradation of the substrate recognition subunits of SCF ubiquitin-protein ligases.
    Mol Cell. 1998 Nov;2(5):571-80 PMID: 9844630
  48. Coding sequence, genomic organization, chromosomal localization, and expression pattern of the signalosome component Cops2: the mouse homologue of Drosophila alien.
    Genomics. 1999 Mar 15;56(3):310-6 PMID: 10087198
  49. Alien, a highly conserved protein with characteristics of a corepressor for members of the nuclear hormone receptor superfamily.
    Mol Cell Biol. 1999 May;19(5):3383-94 PMID: 10207062
  50. Cullin-3 targets cyclin E for ubiquitination and controls S phase in mammalian cells.
    Genes Dev. 1999 Sep 15;13(18):2375-87 PMID: 10500095
  51. Evolution and function of ubiquitin-like protein-conjugation systems.
    Nat Cell Biol. 2000 Aug;2(8):E153-7 PMID: 10934491
Article Info
Journal
Molecular and cellular biology
Abbr.
Mol Cell Biol
ISSN
0270-7306
DOI
10.1128/MCB.23.19.6790-6797.2003
Published
2003-10-00
Pages
6790-7
Language
English
Region
United States
NLM ID
8109087
PMCID
PMC193936
Subset
IM
Grants
NHLBI NIH HHS · HL64641 · United States
NIEHS NIH HHS · ES11384 · United States
NIEHS NIH HHS · U19 ES011384 · United States
NIGMS NIH HHS · GM61812 · United States
NHLBI NIH HHS · R01 HL064641 · United States
NIAMS NIH HHS · AR49496 · United States
NIAMS NIH HHS · R01 AR049496 · United States
NIGMS NIH HHS · R01 GM061812 · United States
External Links
PubMed source DOI: 10.1128/MCB.23.19.6790-6797.2003 PMC Full Text View journal details
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