TGF-beta inhibits growth factor-induced DNA synthesis in hamster fibroblasts without affecting the early mitogenic events.
Transforming growth factor beta (TGF-beta) was found to inhibit (IC50 = 0.1 ng/ml) alpha-thrombin or FGF-induced mitogenicity in G0-arrested Chinese hamster lung fibroblasts. Growth factor-stimulated cells became rapidly insensitive to TGF-beta addition during their progression through G0/G1 suggesting that an early step of the mitogenic response was the target of TGF-beta action. Surprisingly, none of the well characterized early mitogenic events commonly triggered by growth factors was found to be affected by TGF-beta addition. These responses included: phosphoinositide breakdown, activation of protein kinase C as determined by EGF receptor down-modulation, subsequent rises in pHi, 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-beta, with maximal inhibition when TGF-beta was added early in G1. These results indicate that the inhibitory action of TGF-beta does not affect the growth factors signalling pathways but touches an early event different from those so far analyzed.
Chambard
J C
JC
Centre de Biochimie, CNRS, Université de Nice, Faculté des Sciences, Parc Valrose, France.
Pouysségur
J
J
D000818:Animals; D002453:Cell Cycle / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D002460:Cell Line; D006224:Cricetinae; D003412:Cricetulus; D004261:DNA Replication / Q000187:drug effects*; D005347:Fibroblasts / Q000166:cytology; D006133:Growth Substances / Q000494:pharmacology*; D006863:Hydrogen-Ion Concentration; D008168:Lung; D010455:Peptides / Q000494:pharmacology*; D011493:Protein Kinase C / Q000378:metabolism; D012413:Rubidium / Q000378:metabolism; D013917:Thrombin / Q000494:pharmacology; D013937:Thymidine Kinase / Q000037:antagonists & inhibitors; D015291:Transforming Growth Factors
D006133:Growth Substances; D010455:Peptides; D015291:Transforming Growth Factors; D013937:Thymidine Kinase; D011493:Protein Kinase C; D013917:Thrombin; D012413:Rubidium