title: Disruption of the COP9 signalosome Csn2 subunit in mice causes deficient cell proliferation, accumulation of p53 and cyclin E, and early embryonic death.
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.
authors.affiliation: Department of Molecular, Cellular, and Developmental Biology, Yale University, New Haven, Connecticut 06520-8104, USA.
authors.forename: Karin
authors.initials: K
authors.lastname: Lykke-Andersen
authors.forename: Laura
authors.initials: L
authors.lastname: Schaefer
authors.forename: Suchithra
authors.initials: S
authors.lastname: Menon
authors.forename: Xing-Wang
authors.initials: XW
authors.lastname: Deng
authors.forename: Jeffrey Boone
authors.initials: JB
authors.lastname: Miller
authors.forename: Ning
authors.initials: N
authors.lastname: Wei
mesh_terms: D000818:Animals; D001755:Blastocyst / Q000378:metabolism; D000075686:COP9 Signalosome Complex; D002455:Cell Division / Q000502:physiology; D003433:Crosses, Genetic; D019927:Cyclin E / Q000378:metabolism*; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism; D017353:Gene Deletion; D018507:Gene Expression Regulation, Developmental; D020043:Genes, Essential; D006367:HeLa Cells; D006579:Heterozygote; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D046912:Multiprotein Complexes; D050814:Octamer Transcription Factor-3; D010447:Peptide Hydrolases; D021122:Protein Subunits; D011506:Proteins / Q000235:genetics / Q000378:metabolism*; D011995:Recombination, Genetic; D015398:Signal Transduction; D014157:Transcription Factors; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*
chemical_list: C493956:CDKN1A protein, human; C493957:Cdkn1a protein, mouse; D019927:Cyclin E; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D004268:DNA-Binding Proteins; D046912:Multiprotein Complexes; D050814:Octamer Transcription Factor-3; C494173:POU5F1 protein, human; C494174:Pou5f1 protein, mouse; D021122:Protein Subunits; D011506:Proteins; D014157:Transcription Factors; D016159:Tumor Suppressor Protein p53; D010447:Peptide Hydrolases; D000075686:COP9 Signalosome Complex