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

Joyce M. Slingerland, Ludger Hengst, Chin Huei Pan, David Alexander, Martha R. Stampfer, Steven I. Reed

Research output: Contribution to journalArticlepeer-review

298 Scopus citations

Abstract

Transforming growth factor β (TGF-β) 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-β-mediated growth arrest on G1/S cyclins E and A. Inhibition of cyclin A-associated kinase by TGF-β is primarily due to a decrease in cyclin A mRNA and protein. By contrast, while TGF-β 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-β-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.

Original languageEnglish (US)
Pages (from-to)3683-3694
Number of pages12
JournalMolecular and cellular biology
Volume14
Issue number6
DOIs
StatePublished - Jun 1994
Externally publishedYes

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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