TGF‐β inhibits growth factor‐induced DNA synthesis in hamster fibroblasts without affecting the early mitogenic events

Abstract

Transforming growth factor beta (TGF‐β) was found to inhibit (IC₅₀ =0.1 ng/ml) α‐thrombin or FGF‐induced mitogenicity in G0‐arrested Chinese hamster lung fibroblasts. Growth factor‐stimulated cells became rapidly insensitive to TGF‐β addition during their progression through G0/G1 suggesting that an early step of the mitogenic response was the target of TGF‐β action. Surprisingly, none of the well characterized early mitogenic events commonly triggered by growth factors was found to be affected by TGF‐β addition. These responses included: phosphoinositide breakdown, activation of protein kinase C as determined by EGF receptor down‐modulation, subsequent rises in pH_i, c‐fos, and c‐myc mRNA levels, ribosomal protein S₆ phosphorylation, the increase in RNA and protein synthesis, induction of ornithine decarboxylase. Only the induction of thymidine kinase, a marker of entry in the S phase, was found to be repressed by TGF‐β, with maximal inhibition when TGF‐β was added early in G₁. These results indicate that the inhibitory action of TGF‐β does not affect the growth factors signalling pathways but touches an early event different from those so far analyzed.