IGF-I INDUCTION OF P53 REQUIRES ACTIVATION OF MAP KINASE IN CARDIAC-MUSCLE-CELLS

The aim of this study was to investigate whether IGF I induction of p5 3 expression and p21 promoter require activation of MAP kinase in card iac muscle cells. Compared to cardiomyocytes transfected with control vector, activation of MAP kinase by IGF I was decreased by approximate ly 60-70% in the cells transfected with dominant negative MAP kinase Y 185, Transfection with Y185 also resulted in decreased induction of p5 3 mRNA by IGF I (70% reduction), In the cells transfected with a wildt ype p21(WAF1/CIP1) promoter construct, activation of luciferase report er gene by IGF I was decreased in the cells co-transfected with Y185. To further confirm these findings, cells were preincubated with PD9805 9, a specific MAP kinase kinase inhibitor. As expected, PD98059 inhibi ted induction of p53 mRNA and p21(WAF1/CIP1) promoter by IGF I. These data indicate that transcriptional activation of p53 and p21(WAF1/CIP1 ) by IGF I involves MAP kinase pathway in cardiomyocytes, and thus lin k MAP kinase to negative modulation of the cell cycle in cardiac muscl e cells. (C) 1998 Academic Press.