Yazaki Y, Komuro I
Third Department of Internal Medicine, Faculty of Medicine, University of Tokyo, Japan.
Basic Res Cardiol. 1992;87 Suppl 2:11-8. doi: 10.1007/978-3-642-72477-0_2.
To examine the molecular mechanisms by which mechanical stimuli induce protooncogene expression, we cultured rat neonatal cardiocytes in deformable dishes and imposed an in vitro mechanical load by stretching the adherent cells. Myocyte stretching increased total cell RNA content and mRNA levels of c-fos and skeletal alpha-actin followed by activation of protein synthesis. CAT assay indicated that sequences containing a serum response element were required for efficient transcription of c-fos gene by stretching. This accumulation of c-fos mRNA was suppressed by protein kinase C inhibitors at the transcriptional level and was inhibited markedly by down-regulation of protein kinase C. Moreover, myocyte stretching increased inositol phosphate levels. These findings suggest that mechanical stimuli might directly induce protooncogene expression, possibly, via protein kinase C activation. Furthermore, we observed the activation of mitogen activated protein (MAP) kinase by myocyte stretching. This result suggest that MAP kinase activation might increase the efficiency of protein synthesis in ribosomes induced by mechanical stimuli.
为了研究机械刺激诱导原癌基因表达的分子机制，我们将新生大鼠心肌细胞培养在可变形培养皿中，并通过拉伸贴壁细胞施加体外机械负荷。心肌细胞拉伸增加了总细胞RNA含量以及c-fos和骨骼肌α-肌动蛋白的mRNA水平，随后蛋白质合成被激活。CAT分析表明，拉伸c-fos基因高效转录需要含有血清反应元件的序列。c-fos mRNA的这种积累在转录水平被蛋白激酶C抑制剂抑制，并且通过下调蛋白激酶C而被显著抑制。此外，心肌细胞拉伸增加了肌醇磷酸水平。这些发现表明，机械刺激可能直接诱导原癌基因表达，可能是通过蛋白激酶C激活。此外，我们观察到心肌细胞拉伸激活了丝裂原活化蛋白（MAP）激酶。这一结果表明，MAP激酶激活可能会提高机械刺激诱导的核糖体中蛋白质合成的效率。
