TGF beta inhibition of Cdk4 synthesis is linked to cell cycle arrest.
Transforming growth factor beta 1 (TGF beta 1) 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 TGF beta 1 induces suppression of cdk4 synthesis in G1 in mink lung epithelial cells. Constitutive cdk4 synthesis in these cells led to TGF beta 1 resistance. It also resulted in growth in low serum medium when these cells were released from contact inhibition. Cdk2 activity was also suppressed by TGF beta 1 action, but its constitutive expression failed to override a TGF beta 1-induced G1 block. Hence, the TGF beta 1 block is primarily mediated by cdk4 modulation. Further evidence suggests that TGF beta 1- induced down-modulation of cdk4 leads to inhibition of cdk2 activation and that both events might contribute to TGF beta 1 growth suppression.[1]References
- TGF beta inhibition of Cdk4 synthesis is linked to cell cycle arrest. Ewen, M.E., Sluss, H.K., Whitehouse, L.L., Livingston, D.M. Cell (1993) [Pubmed]
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