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 p53 expression and p21 promoter require activation of MAP kinase in cardiac muscle cells. Compared to cardiomyocytes transfected with control vector, activation of MAP kinase by IGF I was decreased by approximately 60-70% in the cells transfected with dominant negative MAP kinase Y185. Transfection with Y185 also resulted in decreased induction of p53 mRNA by IGF I (70% reduction). In the cells transfected with a wildtype p21WAF1/CIP1 promoter construct, activation of luciferase reporter gene by IGF I was decreased in the cells co-transfected with Y185. To further confirm these findings, cells were preincubated with PD98059, a specific MAP kinase kinase inhibitor. As expected, PD98059 inhibited induction of p53 mRNA and p21WAF1/CIP1 promoter by IGF I. These data indicate that transcriptional activation of p53 and p21WAF1/CIP1 by IGF I involves MAP kinase pathway in cardiomyocytes, and thus link MAP kinase to negative modulation of the cell cycle in cardiac muscle cells.
Wang
P H
PH
Department of Medicine, University of California, Irvine 92697, USA. phwang@uci.edu
Schaaf
G J
GJ
Chen
W H
WH
Feng
J
J
Prins
B A
BA
Levin
E R
ER
Bahl
J J
JJ
D000818:Animals; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D002478:Cells, Cultured; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins / Q000096:biosynthesis / Q000235:genetics; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005419:Flavonoids / Q000494:pharmacology; D006321:Heart / Q000187:drug effects; D007334:Insulin-Like Growth Factor I / Q000494:pharmacology*; D009206:Myocardium / Q000201:enzymology*; D011401:Promoter Regions, Genetic; D051381:Rats; D015398:Signal Transduction; D016159:Tumor Suppressor Protein p53 / Q000096:biosynthesis* / Q000235:genetics
C493958:Cdkn1a protein, rat; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D004791:Enzyme Inhibitors; D005419:Flavonoids; D016159:Tumor Suppressor Protein p53; D007334:Insulin-Like Growth Factor I; D017871:Calcium-Calmodulin-Dependent Protein Kinases; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one