Journal
MOLECULAR AND CELLULAR BIOLOGY
Volume 23, Issue 19, Pages 6790-6797Publisher
AMER SOC MICROBIOLOGY
DOI: 10.1128/MCB.23.19.6790-6797.2003
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Funding
- NHLBI NIH HHS [R01 HL064641, HL64641] Funding Source: Medline
- NIAMS NIH HHS [R01 AR049496, AR49496] Funding Source: Medline
- NIEHS NIH HHS [U19 ES011384, ES11384] Funding Source: Medline
- NIGMS NIH HHS [GM61812, R01 GM061812] Funding Source: Medline
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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 Cull 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.
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