Insulin-like growth factor 1 (IGF-1)-induced Twist expression is involved in the anti-apoptotic effects of the IGF-1 receptor

In this study we investigated the molecular mechanisms whereby insulin-like growth factor 1 (IGF-1) induced Twist gene expression and the role of Twis t in the anti-apoptotic actions of the IGF-1 receptor. In NIH-3T3 fibroblas ts overexpressing the human IGF-1 receptor (NWTb3), treatment with IGF-1 (1 0(-8) M) for 1 and 4 h increased the level of Twist mRNA as well as protein by 3-fold. In contrast, insulin at physiological concentrations did not st imulate Twist expression in NIH-3T3 fibroblasts overexpressing the human in sulin receptor. The IGF-1 effect was specific for the IGF-1 receptor since, in cells overexpressing a dominant negative IGF-1 receptor, IGF-1 failed t o increase Twist expression. Preincubation with the ERK1/2 inhibitor U0126 or expression of a dominant negative MEK-1 abolished the effect of IGF-1 on Twist mRNA expression in NWTb3 cells, suggesting that Twist induction by I GF-1 occurs via the mitogen-activated protein kinase signaling pathway. In vivo, IGF-1 injection increased the mRNA level of Twist in mouse skeletal m uscle, the major site of Twist expression. Finally, using an antisense stra tegy, we demonstrated that a reduction of 40% in Twist expression decreased significantly the ability of IGF-1 to rescue NWTb3 cells from etoposide-in duced apoptosis, Taken together, these results define Twist as an important factor involved in the anti-apoptotic actions of the IGF-1 receptor.