Negative regulation of G1 in mammalian cells: Inhibition of cyclin E-dependent kinase by TGF-β

Transforming growth factor-β (TGF-β) is a naturally occurring growth inhibitory polypeptide that arrests the cell cycle in middle to late G1 phase. Cell treated with TGF-β contained normal amounts of cyclin E and cyclin-dependent protein kinaae 2 (Cdk2) but failed to stably assemble cydin E-Cdk2 complexes or accumulate cyclin E-associated kinase activity. Moreover, G1 phase extracts from TGF-β-treated cells did not support activation of endogenous cyclin-dependent protein kinases by exogenous cyclins. These effects of TGF-β, which correlated with the inhibition of retinoblastoma protein phosphorylation, suggest that mammalian G1 cyclin-dependent kinases, like their counterparts in yeast, are targets for negative regulators of the cell cycle.