We examined transforming growth factor-β1 (TGF-β1) effects on cell cycle progression of human colon carcinoma FET cells. TGF-β1 inhibited DNA synthesis and cyclin-dependent kinase (CDK) activity after release from growth arrest in association with induction of the p21 CDK inhibitor, whereas cyclins, CDKs, and p27 protein levels remained relatively unchanged. The decrease in CDK2 kinase activity was the result of increased p21 association with cyclin A-CDK2 and cyclin E-CDK2. TGF-β1 treatment in late G1 showed reduced induction of p21 protein levels in association with increased DNA synthesis. Consequently, p21 induction in early G1 is critical for TGF-β1 inhibition of CDK2 kinase activity. Although TGF-β1 treatments in late G1 failed to induce p21 protein, p21 mRNA induction was observed in late G1 and in S phase. Further analysis showed that TGF-β1 treatment in early G1 increases p21 protein stability throughout the G1 and S phases of the cell cycle. Our results demonstrate that TGF-β1 stimulation of p21 is regulated at the posttranscriptional and transcriptional levels. This is a novel mechanism of TGF-β1 inhibition requiring early G1 induction and stabilization of p21 protein, which binds to and inhibits cyclin E-CDK2 and cyclin A-CDK2 kinase activity rather than direct modulation of cyclin or CDK protein levels as seen in other systems.
|Original language||English (US)|
|Number of pages||7|
|State||Published - Jun 15 2003|
ASJC Scopus subject areas
- Cancer Research