Bombesin induction of c‐fos and c‐myc proto‐oncogenes in Swiss 3T3 cells: Significance for the mitogenic response

Enrique Rozengurt; James W. Sinnett‐Smith

摘要

AbstractBombesin is a potent mitogen for Swiss 3T3 cells and acts synergistically with insulin and other growth factors. We show here that addition of bombesin to quiescent Swiss 3T3 cells causes a striking increase in the levels of c‐fos and c‐myc mRNAs. Enhanced expression of c‐fos (122 ± 14‐fold) occurred within minutes of peptide addition followed by increased expression of c‐myc (82 ± 16‐fold). The concentrations of peptide required for half‐maximal increase in the levels of c‐fos and c‐myc mRNAs were 1.0 and 0.9 nM, respectively. The peptide D‐Arg1, D‐Pro2, D‐Trp7,9, Leu11 substance P which inhibits the binding of bombesin to its receptor and bombesin‐stimulated DNA synthesis in Swiss 3T3 cells blocked the increase in c‐fos and c‐myc mRNA levels promoted by bombesin. Down‐regulation of protein kinase C by long‐term exposure to phorbol esters prevented c‐fos and c‐myc induction by bombesin. This and other results indicate that the induction of these proto‐oncogenes by bombesin could be mediated by the coordinated effects of protein kinase C activation and Ca2+mobilization. The marked synergistic effect between bombesin and insulin was used to assess whether the increase in the induction of c‐fos and c‐myc is an obligatory event in cell activation. In the presence of insulin, bombesin stimulated DNA synthesis at subnanomolar concentrations but had only a small effect on c‐fos and c‐myc mRNA levels. This apparent dissociation of mitogenesis from proto‐oncogene induction was even more dramatic in 3T3 cells with down‐regulated protein kinase C. In these cells bombesin stimulated DNA synthesis in the presence of insulin but failed to enhance c‐fos and c‐myc mRNA levels at comparable concentrations. Thus, the induction of c‐fos and c‐myc may be a necessary step in the mitogenic response initiated by ligands that act through activation of protein kinase C but the expression of these proto‐oncogenes may not be an obligatory event in the stimulation of mitogenesis

Bombesin induction of c‐fos and c‐myc proto‐oncogenes in Swiss 3T3 cells: Significance for the mitogenic response

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