Cyclic AMP-induced G1 phase arrest mediated by an inhibitor (p27Kip1) of cyclin-dependent kinase 4 activation.
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.
Kato
J Y
JY
Department of Tumor Cell Biology, St. Jude Children's Research Hospital, Memphis Tennessee 38105.
Matsuoka
M
M
Polyak
K
K
Massagué
J
J
Sherr
C J
CJ
D000818:Animals; D000936:Antigen-Antibody Complex; D018797:Cell Cycle Proteins; D002478:Cells, Cultured; D000242:Cyclic AMP / Q000494:pharmacology*; D051358:Cyclin-Dependent Kinase 4; D050760:Cyclin-Dependent Kinase Inhibitor p27; D018844:Cyclin-Dependent Kinases; D004789:Enzyme Activation; D005656:Fungal Proteins / Q000378:metabolism*; D016193:G1 Phase / Q000187:drug effects / Q000502:physiology*; D008264:Macrophages / Q000187:drug effects / Q000502:physiology*; D051379:Mice; D008869:Microtubule-Associated Proteins / Q000378:metabolism*; D010449:Peptide Mapping; D010766:Phosphorylation; D011090:Polyenes / Q000494:pharmacology; D011233:Precipitin Tests; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D011518:Proto-Oncogene Proteins; D020123:Sirolimus; D013997:Time Factors; D025521:Tumor Suppressor Proteins; D000095043:Cyclin-Dependent Kinase-Activating Kinase
D000936:Antigen-Antibody Complex; C493961:Cdkn1b protein, mouse; D018797:Cell Cycle Proteins; D005656:Fungal Proteins; D008869:Microtubule-Associated Proteins; D011090:Polyenes; D011518:Proto-Oncogene Proteins; D025521:Tumor Suppressor Proteins; D050760:Cyclin-Dependent Kinase Inhibitor p27; D000242:Cyclic AMP; D017346:Protein Serine-Threonine Kinases; C495902:Cdk4 protein, mouse; D051358:Cyclin-Dependent Kinase 4; D018844:Cyclin-Dependent Kinases; D020123:Sirolimus; D000095043:Cyclin-Dependent Kinase-Activating Kinase