The CDK subunit CKS2 counteracts CKS1 to control cyclin A/CDK2 activity in maintaining replicative fidelity and neurodevelopment

Dev Cell. 2012 Aug 14;23(2):356-70. doi: 10.1016/j.devcel.2012.06.018.


CKS proteins are evolutionarily conserved cyclin-dependent kinase (CDK) subunits whose functions are incompletely understood. Mammals have two CKS proteins. CKS1 acts as a cofactor to the ubiquitin ligase complex SCF(SKP2) to promote degradation of CDK inhibitors, such as p27. Little is known about the role of the closely related CKS2. Using a Cks2(-/-) knockout mouse model, we show that CKS2 counteracts CKS1 and stabilizes p27. Unopposed CKS1 activity in Cks2(-/-) cells leads to loss of p27. The resulting unrestricted cyclin A/CDK2 activity is accompanied by shortening of the cell cycle, increased replication fork velocity, and DNA damage. In vivo, Cks2(-/-) cortical progenitor cells are limited in their capacity to differentiate into mature neurons, a phenotype akin to animals lacking p27. We propose that the balance between CKS2 and CKS1 modulates p27 degradation, and with it cyclin A/CDK2 activity, to safeguard replicative fidelity and control neuronal differentiation.

Publication types

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

MeSH terms

  • Animals
  • CDC2-CDC28 Kinases / metabolism*
  • CDC28 Protein Kinase, S cerevisiae / genetics
  • CDC28 Protein Kinase, S cerevisiae / metabolism*
  • Cell Cycle Checkpoints
  • Cell Cycle Proteins
  • Cell Differentiation
  • Cells, Cultured
  • Cyclin A / metabolism*
  • Cyclin-Dependent Kinase 2 / metabolism*
  • DNA Damage
  • Enzyme Activation
  • Mice
  • Mice, Knockout
  • Neurons / cytology
  • Neurons / metabolism*


  • Cell Cycle Proteins
  • Cyclin A
  • CDC2-CDC28 Kinases
  • CDC28 Protein Kinase, S cerevisiae
  • Cdk2 protein, mouse
  • Cks1 protein, mouse
  • Cks2 protein, mouse
  • Cyclin-Dependent Kinase 2