A novel inhibitor of cyclin-Cdk activity detected in transforming growth factor beta-arrested epithelial cells.
Transforming growth factor beta (TGF-beta) is a potent inhibitor of epithelial cell growth. Cyclins E and A in association with Cdk2 have been shown to play a role in the G1-to-S phase transition in mammalian cells. We have studied the effects of TGF-beta-mediated growth arrest on G1/S cyclins E and A. Inhibition of cyclin A-associated kinase by TGF-beta is primarily due to a decrease in cyclin A mRNA and protein. By contrast, while TGF-beta inhibits accumulation of cyclin E mRNA, the reduction in cyclin E protein is minimal. Instead, we find that the activation of cyclin E-associated kinase that normally accompanies the G1-to-S phase transition is inhibited. A novel inhibitor of cyclin-Cdk complexes was detected in TGF-beta-treated cell lysates. Inhibition is mediated by a heat-stable protein that targets both Cdk2 and Cdc2 kinases. In G0-arrested cells, a similar inhibitor of Cdk2 kinase was detected. These data suggest the existence of an inhibitor of cyclin-dependent kinases induced under different conditions to mediate antiproliferative responses.
Slingerland
J M
JM
Department of Molecular Biology, Scripps Research Institute, La Jolla, California 92037.
Hengst
L
L
Pan
C H
CH
Alexander
D
D
Stampfer
M R
MR
Reed
S I
SI
D000818:Animals; D001685:Biological Factors / Q000302:isolation & purification / Q000378:metabolism* / Q000494:pharmacology; D042846:CDC2-CDC28 Kinases; D002453:Cell Cycle / Q000187:drug effects / Q000502:physiology*; D002460:Cell Line; D051357:Cyclin-Dependent Kinase 2; D018844:Cyclin-Dependent Kinases; D016213:Cyclins / Q000096:biosynthesis / Q000378:metabolism*; D004847:Epithelial Cells; D004848:Epithelium / Q000187:drug effects / Q000378:metabolism; D015870:Gene Expression / Q000187:drug effects; D007700:Kinetics; D008168:Lung; D008907:Mink; D047428:Protein Kinase Inhibitors; D011494:Protein Kinases / Q000096:biosynthesis / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases; D016212:Transforming Growth Factor beta / Q000494:pharmacology*
D001685:Biological Factors; D016213:Cyclins; D047428:Protein Kinase Inhibitors; D016212:Transforming Growth Factor beta; D011494:Protein Kinases; D017346:Protein Serine-Threonine Kinases; D042846:CDC2-CDC28 Kinases; D051357:Cyclin-Dependent Kinase 2; D018844:Cyclin-Dependent Kinases