Transforming growth factor (31 (TGFgl) causes Gl growth arrest and the accumulation of unphosphorylated retinoblastoma protein (Fib) in responsive cells. Cdk4 (cyclin-dependent kinase), a major catalytic subunit of the mammalian D-type Gl cyclins, can phosphorylate Rb in vitro, and at least one D-type cyclin, D2, directs the phosphorylation of Rb in vivo. Here we show that TGFfll induces suppression of cdk4 synthesis in Gl in mink lung epithelial cells. Constitutive cdk4 synthesis in these cells led to TGFpl resistance. It also resulted in growth in low serum medium when these cells were released from contact inhibition. Cdk2 activity was also suppressed by TGFfM action, but its constitutive expression failed to override a TGFglinduced Gl block. Hence, theTGFg1 block is primarily mediated by cdk4 modulation. Further evidence suggests that TGFpl-induced down-modulation of cdk4 leads to inhibition of cdk2 activation and that both events might contribute to TGFgl growth suppression.