Amundadottir L T, Nass S J, Berchem G J, Johnson M D, Dickson R B
Vincent T Lombardi Cancer Research Center, Georgetown University, Washington DC 20007, USA.
Oncogene. 1996 Aug 15;13(4):757-65.
We have previously shown that TGF alpha and c-Myc interact in a strong, synergistic fashion to induce mammary gland tumors in double transgenic mice. Here we show this interaction can be explained, at least in part, by a cooperative growth stimulus by the two proteins, and by TGF alpha-mediated inhibition of c-Myc-induced apoptosis. We initially compared rapidly progressing mammary tumors from double transgenic mice to long latency tumors from single transgenic mice and observed a striking difference in the occurrence of apoptosis among the three groups. Tumors exhibiting apoptosis were derived exclusively from mice that expressed the c-myc transgene in the absence of the TGF alpha transgene, indicating that TGF alpha might protect c-Myc-overexpressing cells from programmed cell death. Cell lines were derived from single and double transgenic mammary tumors to examine further the mechanism underlying the cooperative interaction between the two gene products. In accordance with our in vivo data, apoptosis was only detected when the c-myc transgene was expressed without the TGF alpha transgene. Furthermore, exogenous addition of TGF alpha inhibited apoptosis in cells overexpressing c-Myc alone. In addition, tumor-derived cells that overexpressed both TGF alpha and c-Myc exhibited faster growth rates in vitro and in vivo and were less sensitive to the inhibitory effects of TGF beta in vitro compared to cell lines expressing only one of the transgenes. Based on our findings we propose that TGF alpha acts both as a proliferative and a survival factor for c-Myc-expressing tumor cells. Our results indicate that TGF alpha and c-Myc cooperate in tumorigenesis via a dual mechanism: TGF alpha can inhibit c-Myc-induced apoptosis and both proteins provide a growth stimulus.
我们之前已经表明，转化生长因子α（TGFα）和c-Myc以强烈的协同方式相互作用，在双转基因小鼠中诱导乳腺肿瘤。在此我们表明，这种相互作用至少部分可以通过这两种蛋白质的协同生长刺激以及TGFα介导的对c-Myc诱导的细胞凋亡的抑制来解释。我们最初将双转基因小鼠中快速进展的乳腺肿瘤与单转基因小鼠中潜伏期长的肿瘤进行比较，观察到三组之间细胞凋亡发生率存在显著差异。表现出细胞凋亡的肿瘤仅来自在没有TGFα转基因的情况下表达c-myc转基因的小鼠，这表明TGFα可能保护过表达c-Myc的细胞免于程序性细胞死亡。从单转基因和双转基因乳腺肿瘤中获取细胞系，以进一步研究这两种基因产物之间协同相互作用的潜在机制。与我们的体内数据一致，只有在没有TGFα转基因而表达c-myc转基因时才检测到细胞凋亡。此外，外源性添加TGFα可抑制单独过表达c-Myc的细胞中的细胞凋亡。此外，与仅表达其中一种转基因的细胞系相比，同时过表达TGFα和c-Myc的肿瘤来源细胞在体外和体内均表现出更快的生长速度，并且在体外对TGFβ的抑制作用不太敏感。基于我们的发现，我们提出TGFα作为表达c-Myc的肿瘤细胞的增殖因子和存活因子发挥作用。我们的结果表明，TGFα和c-Myc通过双重机制在肿瘤发生中协同作用：TGFα可以抑制c-Myc诱导的细胞凋亡，并且这两种蛋白质都提供生长刺激。
