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Molecular and Cellular Biology, September 2008, p. 5698-5709, Vol. 28, No. 18
0270-7306/08/$08.00+0     doi:10.1128/MCB.01833-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

Cyclin-Dependent Kinase-Associated Proteins Cks1 and Cks2 Are Essential during Early Embryogenesis and for Cell Cycle Progression in Somatic Cells {triangledown}

Hanna-Stina Martinsson-Ahlzén,{dagger} Vasco Liberal,{dagger} Björn Grünenfelder,{ddagger} Susana R. Chaves, Charles H. Spruck,§ and Steven I. Reed*

Department of Molecular Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037

Received 8 October 2007/ Returned for modification 28 November 2007/ Accepted 4 July 2008

Cks proteins associate with cyclin-dependent kinases and have therefore been assumed to play a direct role in cell cycle regulation. Mammals have two paralogs, Cks1 and Cks2, and individually deleting the gene encoding either in the mouse has previously been shown not to impact viability. In this study we show that simultaneously disrupting CKS1 and CKS2 leads to embryonic lethality, with embryos dying at or before the morula stage after only two to four cell division cycles. RNA interference (RNAi)-mediated silencing of CKS genes in mouse embryonic fibroblasts (MEFs) or HeLa cells causes cessation of proliferation. In MEFs CKS silencing leads to cell cycle arrest in G2, followed by rereplication and polyploidy. This phenotype can be attributed to impaired transcription of the CCNB1, CCNA2, and CDK1 genes, encoding cyclin B1, cyclin A, and Cdk1, respectively. Restoration of cyclin B1 expression rescues the cell cycle arrest phenotype conferred by RNAi-mediated Cks protein depletion. Consistent with a direct role in transcription, Cks2 is recruited to chromatin in general and to the promoter regions and open reading frames of genes requiring Cks function with a cell cycle periodicity that correlates with their transcription.

* Corresponding author. Mailing address: Department of Molecular Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037. Phone: (619) 784-9836. Fax: (858) 784-2781. E-mail: sreed{at}scripps.edu

{triangledown} Published ahead of print on 14 July 2008.

{dagger} Both authors contributed equally.

{ddagger} Present address: Novartis Pharma AG, Postfach 4002, Basel, Switzerland.

§ Present address: The Sydney Kimmel Cancer Center, 10835 Road to The Cure, San Diego, CA 92121.

Molecular and Cellular Biology, September 2008, p. 5698-5709, Vol. 28, No. 18
0270-7306/08/$08.00+0     doi:10.1128/MCB.01833-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.





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