Cdc2-cyclin E Complexes Regulate the G1/S Phase Transition

Nat Cell Biol. 2005 Aug;7(8):831-6. doi: 10.1038/ncb1284. Epub 2005 Jul 10.

Abstract

The cyclin-dependent kinase inhibitor p27(Kip1) is known as a negative regulator of cell-cycle progression and as a tumour suppressor. Cdk2 is the main target of p27 (refs 2, 3) and therefore we hypothesized that loss of Cdk2 activity should modify the p27(-/-) mouse phenotype. Here, we show that although p27(-/-) Cdk2(-/-) mice developed ovary tumours and tumours in the anterior lobe of the pituitary, we failed to detect any functional complementation in p27(-/-) Cdk2(-/-) double-knockout mice, indicating a parallel pathway regulated by p27. We observed elevated levels of S phase and mitosis in tissues of p27(-/-) Cdk2(-/-) mice concomitantly with elevated Cdc2 activity in p27(-/-) Cdk2(-/-) extracts. p27 binds to Cdc2, cyclin B1, cyclin A2, or suc1 complexes in wild-type and Cdk2(-/-) extracts. In addition, cyclin E binds to and activates Cdc2. Our in vivo results provide strong evidence that Cdc2 may compensate the loss of Cdk2 function.

Publication types

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

MeSH terms

  • 2-Aminopurine / analogs & derivatives
  • 2-Aminopurine / pharmacology
  • Animals
  • Body Weight / genetics
  • CDC2 Protein Kinase / genetics
  • CDC2 Protein Kinase / metabolism*
  • CDC2-CDC28 Kinases / genetics
  • CDC2-CDC28 Kinases / metabolism
  • Cell Cycle Proteins / genetics
  • Cell Cycle Proteins / metabolism
  • Cell Proliferation
  • Crosses, Genetic
  • Cyclin E / metabolism*
  • Cyclin-Dependent Kinase 2
  • Cyclin-Dependent Kinase Inhibitor p27
  • Cyclin-Dependent Kinases / antagonists & inhibitors
  • Cyclin-Dependent Kinases / metabolism
  • Cyclins / metabolism
  • Enzyme Inhibitors / pharmacology
  • Female
  • Fibroblasts / cytology
  • Fibroblasts / drug effects
  • Fibroblasts / metabolism
  • G1 Phase / genetics
  • G1 Phase / physiology*
  • Gonads / pathology
  • Infertility / genetics
  • Interphase / drug effects
  • Interphase / genetics
  • Interphase / physiology
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mitosis / genetics
  • Ovarian Neoplasms / genetics
  • Ovarian Neoplasms / pathology
  • Pituitary Neoplasms / genetics
  • Pituitary Neoplasms / pathology
  • Protein Binding
  • RNA, Double-Stranded / genetics
  • S Phase / drug effects
  • S Phase / genetics
  • S Phase / physiology*
  • Sex Factors
  • Spleen / metabolism
  • Thymus Gland / metabolism
  • Thymus Gland / pathology
  • Transfection
  • Tumor Suppressor Proteins / genetics
  • Tumor Suppressor Proteins / metabolism

Substances

  • Cdkn1b protein, mouse
  • Cell Cycle Proteins
  • Cyclin E
  • Cyclins
  • Enzyme Inhibitors
  • N(2)-(2-aminocyclohexyl)-N(6)-(3-chlorophenyl)-9-ethyl-9H-purine-2,6-diamine
  • RNA, Double-Stranded
  • Tumor Suppressor Proteins
  • Cyclin-Dependent Kinase Inhibitor p27
  • 2-Aminopurine
  • CDC2 Protein Kinase
  • CDC2-CDC28 Kinases
  • Cdk2 protein, mouse
  • Cyclin-Dependent Kinase 2
  • Cyclin-Dependent Kinases