Cyclin-dependent kinase-associated proteins Cks1 and Cks2 are essential during early embryogenesis and for cell cycle progression in somatic cells

Mol Cell Biol. 2008 Sep;28(18):5698-709. doi: 10.1128/MCB.01833-07. Epub 2008 Jul 14.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • CDC2 Protein Kinase / genetics
  • CDC2 Protein Kinase / metabolism
  • CDC2-CDC28 Kinases / genetics
  • CDC2-CDC28 Kinases / metabolism*
  • CDC28 Protein Kinase, S cerevisiae / genetics
  • CDC28 Protein Kinase, S cerevisiae / metabolism*
  • Carrier Proteins / genetics
  • Carrier Proteins / metabolism*
  • Cell Cycle / physiology*
  • Cell Cycle Proteins / genetics
  • Cell Cycle Proteins / metabolism*
  • Cell Proliferation
  • Cells, Cultured
  • Cyclin A / genetics
  • Cyclin A / metabolism
  • Cyclin B / genetics
  • Cyclin B / metabolism
  • Cyclin B1
  • Cyclin-Dependent Kinases / genetics
  • Cyclin-Dependent Kinases / metabolism*
  • Embryo, Mammalian / cytology
  • Embryo, Mammalian / physiology
  • Embryonic Development / physiology*
  • Female
  • Fibroblasts / cytology
  • Fibroblasts / physiology
  • Gene Expression Regulation, Developmental
  • Genotype
  • HeLa Cells
  • Humans
  • Male
  • Mice
  • Mice, Knockout
  • Open Reading Frames
  • Phenotype
  • Ploidies
  • Promoter Regions, Genetic
  • Protein Kinases / genetics
  • Protein Kinases / metabolism*
  • RNA Interference


  • CCNB1 protein, human
  • CKS1B protein, human
  • Carrier Proteins
  • Ccnb1 protein, mouse
  • Cell Cycle Proteins
  • Cyclin A
  • Cyclin B
  • Cyclin B1
  • Protein Kinases
  • CDC2 Protein Kinase
  • CDC2-CDC28 Kinases
  • CDC28 Protein Kinase, S cerevisiae
  • CKS2 protein, human
  • Cks1 protein, mouse
  • Cks2 protein, mouse
  • Cyclin-Dependent Kinases