Endo T, Nadal-Ginard B
Mol Cell Biol. 1986 May;6(5):1412-21. doi: 10.1128/mcb.6.5.1412-1421.1986.
It is widely accepted that the cellular oncogene c-myc plays an important role in the control of cell proliferation and that its expression diminishes in differentiated cells. We examined whether there is a correlation between c-myc expression and cell proliferation or differentiation by using a subclone of a rat skeletal muscle cell line L6E9. Myoblasts irreversibly withdraw from the cell cycle, fuse to form multinucleated myotubes, and express muscle-specific genes (terminal differentiation). Muscle-specific genes can also be expressed in the absence of fusion (biochemical differentiation). Such mononucleated but biochemically differentiated cells can be stimulated to reenter the cell cycle. c-myc was induced by insulin, insulin-like growth factor, or serum factors in G0-arrested cells, whereas induction by protein synthesis inhibitors or superinduction by protein synthesis inhibitors in combination with serum factors occurred in all physiological states tested. We found that c-myc expression was reduced in biochemically and terminally differentiated cells as well as in quiescent undifferentiated cells but that it remained inducible by growth factors in all three physiological states. Results of nuclear runoff transcription assays suggested that the induction of c-myc mRNA by growth factors and its deinduction in these physiological states were regulated mainly at the transcriptional level. In contrast, induction and superinduction of c-myc mRNA by protein synthesis inhibitors alone and in combination with growth factors, respectively, were regulated posttranscriptionally mainly by stabilization of c-myc mRNA. Moreover, c-myc and muscle-specific genes could be simultaneously transcribed in both biochemically and terminally differentiated cells. These results indicate that irreversible repression of c-myc is not required for terminal myogenic differentiation and that its expression is insufficient by itself to suppress the differentiated phenotype.
细胞癌基因c-myc在控制细胞增殖中起重要作用，且其表达在分化细胞中降低，这一观点已被广泛接受。我们使用大鼠骨骼肌细胞系L6E9的一个亚克隆，研究了c-myc表达与细胞增殖或分化之间是否存在相关性。成肌细胞不可逆地退出细胞周期，融合形成多核肌管，并表达肌肉特异性基因（终末分化）。肌肉特异性基因也可在无融合的情况下表达（生化分化）。这种单核但生化分化的细胞可被刺激重新进入细胞周期。在G0期停滞的细胞中，胰岛素、胰岛素样生长因子或血清因子可诱导c-myc表达，而在所有测试的生理状态下，蛋白质合成抑制剂均可诱导其表达，或与血清因子联合超诱导其表达。我们发现，在生化和终末分化细胞以及静止未分化细胞中，c-myc表达均降低，但在所有三种生理状态下，生长因子均可诱导其表达。核转录分析结果表明，生长因子诱导c-myc mRNA表达及其在这些生理状态下的去诱导主要在转录水平受到调控。相比之下，单独使用蛋白质合成抑制剂以及与生长因子联合使用时，分别对c-myc mRNA的诱导和超诱导主要在转录后水平通过稳定c-myc mRNA来调控。此外，在生化和终末分化细胞中，c-myc和肌肉特异性基因均可同时转录。这些结果表明，终末肌源性分化并不需要对c-myc进行不可逆的抑制，其自身表达不足以抑制分化表型。
