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Molecular and Cellular Biology, October 2003, p. 6790-6797, Vol. 23, No. 19
0270-7306/03/$08.00+0     DOI: 10.1128/MCB.23.19.6790-6797.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

Disruption of the COP9 Signalosome Csn2 Subunit in Mice Causes Deficient Cell Proliferation, Accumulation of p53 and Cyclin E, and Early Embryonic Death

Karin Lykke-Andersen,1,{dagger} Laura Schaefer,2 Suchithra Menon,1 Xing-Wang Deng,1 Jeffrey Boone Miller,2 and Ning Wei1*

Department of Molecular, Cellular, and Developmental Biology, Yale University, New Haven, Connecticut 06520-8104,1 Neuromuscular Biology & Disease Group, Boston Biomedical Research Institute, Watertown, Massachusetts 024782

Received 25 April 2003/ Returned for modification 19 May 2003/ Accepted 27 June 2003

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 I{kappa}B 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.

* Corresponding author. Mailing address: Department of Molecular, Cellular, and Developmental Biology, OML 127, Yale University, P.O. Box 208104, New Haven, CT 06520-8104. Phone: (203) 432-3897. Fax: (203) 432-5726. E-mail: ning.wei{at}yale.edu.

{dagger} Present address: The Wellcome Trust and Cancer Research UK Institute, University of Cambridge, Cambridge CB2 1QR, United Kingdom.

Molecular and Cellular Biology, October 2003, p. 6790-6797, Vol. 23, No. 19
0022-538X/03/$08.00+0     DOI: 10.1128/MCB.23.19.6790-6797.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.



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