Cyclin-dependent kinase-associated proteins Cks1 and Cks2 are essential during early embryogenesis and for cell cycle progression in somatic cells.
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 G(2), 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.
Martinsson-Ahlzén
Hanna-Stina
HS
Department of Molecular Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA.
Liberal
Vasco
V
Grünenfelder
Björn
B
Chaves
Susana R
SR
Spruck
Charles H
CH
Reed
Steven I
SI
D000818:Animals; D016203:CDC2 Protein Kinase / Q000235:genetics / Q000378:metabolism; D042846:CDC2-CDC28 Kinases / Q000235:genetics / Q000378:metabolism*; D017489:CDC28 Protein Kinase, S cerevisiae / Q000235:genetics / Q000378:metabolism*; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D002453:Cell Cycle / Q000502:physiology*; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism*; D049109:Cell Proliferation; D002478:Cells, Cultured; D019925:Cyclin A / Q000235:genetics / Q000378:metabolism; D019926:Cyclin B / Q000235:genetics / Q000378:metabolism; D056744:Cyclin B1; D018844:Cyclin-Dependent Kinases / Q000235:genetics / Q000378:metabolism*; D004622:Embryo, Mammalian / Q000166:cytology / Q000502:physiology; D047108:Embryonic Development / Q000502:physiology*; D005260:Female; D005347:Fibroblasts / Q000166:cytology / Q000502:physiology; D018507:Gene Expression Regulation, Developmental; D005838:Genotype; D006367:HeLa Cells; D006801:Humans; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D016366:Open Reading Frames; D010641:Phenotype; D011003:Ploidies; D011401:Promoter Regions, Genetic; D011494:Protein Kinases / Q000235:genetics / Q000378:metabolism*; D034622:RNA Interference
C534699:CCNB1 protein, human; C093090:CKS1B protein, human; D002352:Carrier Proteins; C534700:Ccnb1 protein, mouse; D018797:Cell Cycle Proteins; D019925:Cyclin A; D019926:Cyclin B; D056744:Cyclin B1; D011494:Protein Kinases; D016203:CDC2 Protein Kinase; D042846:CDC2-CDC28 Kinases; D017489:CDC28 Protein Kinase, S cerevisiae; C083689:CKS2 protein, human; C474110:Cks1 protein, mouse; C474109:Cks2 protein, mouse; D018844:Cyclin-Dependent Kinases