We have previously demonstrated that growth inhibition of untransformed intestinal epithelial cells by transforming growth factor  1 (TGF) and TGF 2 was associated with a rapid activation of both Ras and extracellular signal-regulated kinase 1 (Erk1) In order to determine whether the activation of Ras by TGF was required for the growth inhibitory effect of TGF, we examined TGF 2 effects on Cdk2-associated histone H1 kinase activity, cyclin A protein expression levels, and DNA synthesis in two intestinal epithelial cell clones transfected with RasN17. In cells expressing RasN17, we observed a 50% reversal of the inhibition of Cdk2 activity, a 78% reversal of the down-regulation of cyclin A protein expression, and a 21% reversal of the inhibition of DNA synthesis by TGF. Collectively, these results indicate that Ras activation is obligatory for TGF-mediated activation of Erk1, whereas it is partially required for the growth inhibitory effect of TGF.(The transforming growth factor- (TGF) 1 family currently consists of three mammalian secreted polypeptides (TGF 1 , TGF 2 , and TGF 3 ) that regulate cellular growth, morphogenesis, differentiation, and adhesion (3). TGF exerts these cellular effects through a heteromeric complex of the type I (RI) and type II (RII) TGF receptors, each containing serine/threonine kinase domains that interact in a phosphorylation-dependent manner (4, 5). However, little is currently known regarding TGF regulation of cytoplasmic components that are rapidly activated after receptor interaction with ligand. Twohybrid screens have indicated that immunophilin FKBP-12 and farnesyltransferase-␣ specifically bind RI and that a novel protein, termed TGF-receptor interacting protein-1, interacts with RII (6 -9). The functional significance of these receptor interacting proteins has yet to be elucidated. We have reported direct evidence for the rapid activation of cytoplasmic signaling components by TGF in a mammalian cell system. That is, we have shown that both Ras and Erk1 are rapidly activated by TGF 1 and TGF 2 in TGF-sensitive epithelial cells but not in TGF-resistant cells (1, 2). These effects occurred in asynchronous cultures of epithelial cells under conditions where DNA synthesis was inhibited by 95-98% (2). The recent identification of the interaction between RI and farnesyltransferase-␣ mentioned above (7, 8) suggests a potential upstream mechanism for the activation of Ras in the TGF signaling pathway. The only other cytoplasmic signaling events that have been shown to be modulated by TGF in untransformed epithelial cells are an activation of protein phosphatase 1 (10), an involvement of protein kinase C in early TGF responses (11,12), and an association of phospholipase C with the elevation of gene expression by TGF (12).In contrast to the effects of TGF on cytoplasmic signaling components, a direct association between TGF modulation of nuclear cell cycle components and the growth inhibitory effects of TGF has been demonstrated. The G 1 cell cycle event...
Our previous data demonstrated that Ras activation is necessary and sucient for transforming growth factor b (TGFb)-mediated Erk1 activation, and is partially required for the inhibition of cyclin-dependent kinase 2 (Cdk2) activity, cyclin A expression and DNA synthesis by TGFb (KM Mulder and SL Morris,
The role of reactive oxygen metabolites in the toxic effects of asbestos on pleural mesothelial cells is not well defined. We exposed rat pleural mesothelial cells (RPMC) to chrysotile and crocidolite fibers (0-40 micrograms/cm2) in the presence or absence of catalase and superoxide dismutase (SOD). Cell injury was measured using the colorimetric 3-4 (5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay and DNA damage was evaluated in terms of unscheduled DNA synthesis (UDS). Catalase (100 U/ml) and SOD (250 U/ml) protected RPMC against asbestos-induced cytotoxicity and DNA damage. However, the inactivated enzymes and bovine serum albumin also showed some protection, suggesting that the effect of antioxidant enzymes may be partly related to their protein nature. These results suggest that oxygen derivatives are partly involved in the toxic effects of asbestos on cultures of RPMC. The presence of extracellular proteins may also decrease asbestos-produced toxicity by reducing the degree of RPMC-fiber interaction.
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