TGF-BETA INHIBITION OF CDK4 SYNTHESIS IS LINKED TO CELL-CYCLE ARREST

Transforming growth factor beta1 (TGFbeta1) causes G1 growth arrest and the accumulation of unphosphorylated retinoblastoma protein (Rb) in responsive cells. Cdk4 (cyclin-dependent kinase), a major catalytic subunit of the mammalian D-type G1 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 TGFbetga1 induces suppression of cdk4 synthesis in G1 in mink lung epithelial cells. Constitutive cdk4 synthesis in these cells led to TGFbeta1 resistance. It also resulted in growth in low serum medium when these cells were released from contact inhibition. Cdk2 activity was also suppressed by TGFbeta1 action, but its constitutive expression failed to override a TGFbeta1-induced G1 block. Hence, the TGFbeta1 block is primarily mediated by cdk4 modulation. Further evidence suggests that TGFbeta1-induced down-modulation of cdk4 leads to inhibition of cdk2 activation and that both events might contribute to TGFbeta1 growth suppression.