Wagner A J, Small M B, Hay N
Ben May Institute, Department of Biochemistry and Molecular Biology, University of Chicago, Illinois 60637.
Mol Cell Biol. 1993 Apr;13(4):2432-40. doi: 10.1128/mcb.13.4.2432-2440.1993.
The product of the c-myc proto-oncogene is an important positive regulator of cell growth and proliferation. Recently, c-Myc has also been demonstrated to be a potent inducer of apoptosis when expressed in the absence of serum or growth factors. To further examine Myc-induced apoptosis, we coexpressed the proto-oncogene bcl2, which has been shown to block apoptosis in other systems, with c-myc in serum-deprived Rat 1a fibroblasts. Here we report that ectopic expression of bcl2 specifically blocks apoptosis induced by constitutive c-myc expression. Constitutive c-myc expression in serum-deprived Rat 1a cells caused a > 15-fold increase in the number of dead cells, accompanied by DNA fragmentation. However, coexpression of bcl2 with c-myc in these cells led to a 10-fold increase in the number of live cells and a significant decrease in DNA fragmentation. Thus, Bcl-2 effectively inhibits Myc-induced apoptosis in serum-deprived Rat 1a fibroblasts without blocking entry into the cell cycle. These results imply that apoptosis serves as a protective mechanism to prevent tumorigenicity elicited by deregulated Myc expression. This protective mechanism is abrogated, however, by Bcl-2 and therefore may explain the synergism between Myc and Bcl-2 observed in certain tumor cells.
原癌基因c-myc的产物是细胞生长和增殖的重要正调控因子。最近，c-Myc在无血清或生长因子存在时表达，也被证明是一种有效的凋亡诱导因子。为了进一步研究Myc诱导的凋亡，我们在血清饥饿的大鼠1a成纤维细胞中，将已被证明在其他系统中可阻断凋亡的原癌基因bcl2与c-myc共表达。在此我们报告，bcl2的异位表达特异性地阻断了由组成型c-myc表达诱导的凋亡。血清饥饿的大鼠1a细胞中组成型c-myc表达导致死细胞数量增加15倍以上，并伴有DNA片段化。然而，在这些细胞中bcl2与c-myc共表达导致活细胞数量增加10倍，DNA片段化显著减少。因此，Bcl-2有效抑制血清饥饿的大鼠1a成纤维细胞中Myc诱导的凋亡，而不阻断进入细胞周期。这些结果表明，凋亡作为一种保护机制，可防止Myc表达失调引发的肿瘤发生。然而，这种保护机制被Bcl-2消除，因此可能解释了在某些肿瘤细胞中观察到的Myc与Bcl-2之间的协同作用。
