Cyclic AMP-induced G1 phase arrest mediated by an inhibitor (p27Kip1) of cyclin-dependent kinase 4 activation

Cell. 1994 Nov 4;79(3):487-96. doi: 10.1016/0092-8674(94)90257-7.

Abstract

Cyclic AMP (cAMP) blocks the mitogenic effects of colony-stimulating factor 1 (CSF-1) in macrophages, inducing cell cycle arrest in mid-G1 phase. Complexes between cyclin D1 and cyclin-dependent kinase 4 (cdk4) assemble in growth arrested cells, but cdk4 is not phosphorylated in vivo by the cdk-activating kinase (CAK) and remains inactive. Although undetectable in lysates of cAMP-treated cells, active CAK is recovered after antibody precipitation, indicating that it is not the direct target of inhibition. Levels of the cdk inhibitor p27Klp1 increase in cAMP-treated cells, and its immunodepletion from inhibitory lysates restores CAK-mediated cdk4 activation. Kip1 does not bind to CAK, but its association with cyclin D-cdk4 prevents CAK from phosphorylating and activating the holoenzyme.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Antigen-Antibody Complex
  • Cell Cycle Proteins*
  • Cells, Cultured
  • Cyclic AMP / pharmacology*
  • Cyclin-Dependent Kinase 4
  • Cyclin-Dependent Kinase Inhibitor p27
  • Cyclin-Dependent Kinases*
  • Enzyme Activation
  • Fungal Proteins / metabolism*
  • G1 Phase / drug effects
  • G1 Phase / physiology*
  • Macrophages / drug effects
  • Macrophages / physiology*
  • Mice
  • Microtubule-Associated Proteins / metabolism*
  • Peptide Mapping
  • Phosphorylation
  • Polyenes / pharmacology
  • Precipitin Tests
  • Protein-Serine-Threonine Kinases / antagonists & inhibitors
  • Protein-Serine-Threonine Kinases / metabolism*
  • Proto-Oncogene Proteins*
  • Sirolimus
  • Time Factors
  • Tumor Suppressor Proteins*

Substances

  • Antigen-Antibody Complex
  • Cdkn1b protein, mouse
  • Cell Cycle Proteins
  • Fungal Proteins
  • Microtubule-Associated Proteins
  • Polyenes
  • Proto-Oncogene Proteins
  • Tumor Suppressor Proteins
  • Cyclin-Dependent Kinase Inhibitor p27
  • Cyclic AMP
  • Protein-Serine-Threonine Kinases
  • Cdk4 protein, mouse
  • Cyclin-Dependent Kinase 4
  • Cyclin-Dependent Kinases
  • cyclin-dependent kinase-activating kinase
  • Sirolimus