title: Early Growth Response Protein-1 Expression by Insulin-Like Growth Factor-1 Requires ROS-Dependent Activation of ERK1/2 and PKB Pathways in Vascular Smooth Muscle Cells.
abstract: Early growth response protein-1 (Egr-1) is a transcription factor that plays an important role in the regulation of several genes implicated in the pathogenesis of cardiovascular disease (CVD) such as atherosclerosis. Insulin-like growth factor-1 (IGF-1), a potent mitogen, is believed to contribute to the development of CVD through the hyperactivation of mitogenic and growth promoting pathways, including the MAPK and PKB pathways, as well as regulation of multiple transcription factors. Reactive oxygen species (ROS) have been shown to mediate the effects of IGF-1 and are believed to contribute to the pathogenesis of vascular abnormalities. We have previously shown that IGF-1 induces the expression of Egr-1 in vascular smooth muscle cells (VSMC); however, the signaling pathways involved in this process remain unexplored. Therefore, we have investigated the involvement of MAPK, PKB, and ROS in IGF-1-induced Egr-1 expression in VSMC. Treatment of VSMC with IGF-1 enhanced Egr-1 protein levels in a time and dose-dependent fashion and PD98059 and SP600125, two selective inhibitors of ERK1/2 and JNK, respectively, significantly decreased IGF-1-induced increase in Egr-1 expression in these cells. In addition, blockade of PI3-K/PKB pathways by Wortmannin/SC-66 respectively, also attenuated IGF-1-induced Egr-1 protein as well as mRNA expression. Diphenyleneiodonium (DPI), an NAD(P)H oxidase inhibitor, blocked the Egr-1 expression in response to IGF-1. In summary, these data demonstrate that ROS-dependent activation of ERK1/2/JNK, PI3-K/PKB signaling events play a critical role in IGF-1 induced expression of Egr-1 in VSMC.
authors.affiliation: Laboratory of Cell Signaling, Research Centre, Centre hospitalier de l'Université de Montréal (CHUM) - CRCHUM, Department of Montreal, Université de Montréal, Montréal, Québec, Canada.
authors.forename: Viktoria
authors.initials: V
authors.lastname: Youreva
authors.affiliation: Laboratory of Cell Signaling, Research Centre, Centre hospitalier de l'Université de Montréal (CHUM) - CRCHUM, Department of Montreal, Université de Montréal, Montréal, Québec, Canada.
authors.forename: Ashok K
authors.initials: AK
authors.lastname: Srivastava
mesh_terms: D000730:Androstadienes / Q000494:pharmacology; D000818:Animals; D002478:Cells, Cultured; D051766:Early Growth Response Protein 1 / Q000378:metabolism*; D007334:Insulin-Like Growth Factor I / Q000494:pharmacology*; D020935:MAP Kinase Signaling System / Q000187:drug effects; D009131:Muscle, Smooth, Vascular / Q000166:cytology*; D032389:Myocytes, Smooth Muscle / Q000187:drug effects* / Q000378:metabolism*; D009861:Onium Compounds / Q000494:pharmacology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011494:Protein Kinases / Q000378:metabolism; D051381:Rats; D017382:Reactive Oxygen Species; D015398:Signal Transduction / Q000187:drug effects; D000077191:Wortmannin
chemical_list: D000730:Androstadienes; D051766:Early Growth Response Protein 1; D007334:Insulin-Like Growth Factor I; D009861:Onium Compounds; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011494:Protein Kinases; D017382:Reactive Oxygen Species; D000077191:Wortmannin; C007517:diphenyleneiodonium
keywords: ERK1/2; Egr-1; IGF-1; IGF-1R; JNK; PI3-K; PKB; VSMC