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 Kinase-Activating Kinase
-
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
-
Sirolimus
-
Cyclin-Dependent Kinase-Activating Kinase