Role of protein kinase system in the signal transduction of stretch-mediated protooncogene expression and hypertrophy of cardiac myocytes.
To examine the molecular mechanisms by which mechanical stimuli induce protooncogene expression and hypertrophy of cardiac myocytes directly, we cultured rat neonatal cardiac myocytes in deformable dishes and imposed mechanical load on adherent cultured cardiac myocytes by stretching the dishes. Myocyte stretching increased total cell RNA content and mRNA levels of c-fos and skeletal alpha-actin followed by the amino acid incorporation into cardiac proteins. CAT assay analysis indicated that the sequences containing serum response element were required for the efficient transcription of c-fos gene by stretching. This accumulation of c-fos mRNA by myocyte stretching was inhibited markedly by down-regulation of protein kinase C. Moreover, myocyte stretching increased inositol phosphate levels. These findings suggests that mechanical stimuli might directly induce protooncogene expression possibly via protein kinase C activation. Furthermore, we observed the activation of MAP kinase by myocytes stretching. This result suggests that MAP kinase activation induced by mechanical stimuli might increase the efficiency of protein synthesis on ribosomes induced by mechanical stimuli.
Third Department of Internal Medicine, Faculty of Medicine, University of Tokyo, Japan.
Y
Y
Yazaki
I
I
Komuro
T
T
Yamazaki
K
K
Tobe
K
K
Maemura
T
T
Kadowaki
R
R
Nagai
D000199:Actins / Q000096:biosynthesis; D000470:Alkaloids / Q000494:pharmacology; D000818:Animals; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D002478:Cells, Cultured; D004268:DNA-Binding Proteins; D004789:Enzyme Activation; D005786:Gene Expression Regulation / Q000187:drug effects; D006321:Heart / Q000502:physiology*; D006984:Hypertrophy / Q000378:metabolism; D007295:Inositol Phosphates / Q000096:biosynthesis; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology; D009687:Nuclear Proteins; D011493:Protein Kinase C / Q000378:metabolism*; D011494:Protein Kinases / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D016760:Proto-Oncogene Proteins c-fos / Q000096:biosynthesis*; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D017208:Rats, Wistar; D019893:Ribosomal Protein S6 Kinases; D026362:Serum Response Factor; D015398:Signal Transduction; D019311:Staurosporine; D013314:Stress, Mechanical
D000199:Actins; D000470:Alkaloids; D004268:DNA-Binding Proteins; D007295:Inositol Phosphates; D009687:Nuclear Proteins; D016760:Proto-Oncogene Proteins c-fos; D012333:RNA, Messenger; D026362:Serum Response Factor; D011494:Protein Kinases; D017346:Protein Serine-Threonine Kinases; D019893:Ribosomal Protein S6 Kinases; D011493:Protein Kinase C; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D019311:Staurosporine