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PMID: 8196612 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, Non-P.H.S. Research Support, U.S. Gov't, P.H.S.

A novel inhibitor of cyclin-Cdk activity detected in transforming growth factor beta-arrested epithelial cells.

Molecular and cellular biology ·Vol. 14 ·No. 6 ·1994-06-00 ·Pages 3683-94

Slingerland JM, Hengst L, Pan CH, Alexander D, Stampfer MR, Reed SI

Abstract

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.

MeSH Terms
Animals Biological Factors/isolation & purification,metabolism,pharmacology CDC2-CDC28 Kinases Cell Cycle/drug effects,physiology Cell Line Cyclin-Dependent Kinase 2 Cyclin-Dependent Kinases Cyclins/biosynthesis,metabolism Epithelial Cells Epithelium/drug effects,metabolism Gene Expression/drug effects Kinetics Lung Mink Protein Kinase Inhibitors Protein Kinases/biosynthesis,metabolism Protein Serine-Threonine Kinases Transforming Growth Factor beta/pharmacology
Chemicals
Biological Factors Cyclins Protein Kinase Inhibitors Transforming Growth Factor beta Protein Kinases Protein Serine-Threonine Kinases CDC2-CDC28 Kinases Cyclin-Dependent Kinase 2 Cyclin-Dependent Kinases
Authors & Affiliations
6 authors, click to expand affiliations / ORCID
Slingerland J M
Department of Molecular Biology, Scripps Research Institute, La Jolla, California 92037.
Hengst L
Pan C H
Alexander D
Stampfer M R
Reed S I
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Article Info
Journal
Molecular and cellular biology
Abbr.
Mol Cell Biol
ISSN
0270-7306
DOI
10.1128/mcb.14.6.3683-3694.1994
Published
1994-06-00
Pages
3683-94
Language
English
Region
United States
NLM ID
8109087
PMCID
PMC358736
Subset
IM
Grants
NCI NIH HHS · CA-24844 · United States
NIGMS NIH HHS · GM46006 · United States
External Links
PubMed source DOI: 10.1128/mcb.14.6.3683-3694.1994 PMC Full Text View journal details
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