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

Transforming growth factor beta1 (TGFbeta1) causes G1 growth arrest an d the accumulation of unphosphorylated retinoblastoma protein (Rb) in responsive cells. Cdk4 (cyclin-dependent kinase), a major catalytic su bunit of the mammalian D-type G1 cyclins, can phosphorylate Rb in vitr o, and at least one D-type cyclin, D2, directs the phosphorylation of Rb in vivo. Here we show that TGFbetga1 induces suppression of cdk4 sy nthesis in G1 in mink lung epithelial cells. Constitutive cdk4 synthes is in these cells led to TGFbeta1 resistance. It also resulted in grow th in low serum medium when these cells were released from contact inh ibition. Cdk2 activity was also suppressed by TGFbeta1 action, but its constitutive expression failed to override a TGFbeta1-induced G1 bloc k. Hence, the TGFbeta1 block is primarily mediated by cdk4 modulation. Further evidence suggests that TGFbeta1-induced down-modulation of cd k4 leads to inhibition of cdk2 activation and that both events might c ontribute to TGFbeta1 growth suppression.