Klefstrom J, Kovanen P E, Somersalo K, Hueber A O, Littlewood T, Evan G I, Greenberg A H, Saksela E, Timonen T, Alitalo K
Biochemistry of the Cell Nucleus Laboratory, Imperial Cancer Research Fund, London, UK.
Oncogene. 1999 Apr 1;18(13):2181-8. doi: 10.1038/sj.onc.1202546.
The contact of natural killer (NK) cells with foreign cells and with certain virus-infected or tumor cells triggers the cytolytic machinery of NK cells. This triggering leads to exocytosis of the cytotoxic NK cell granules. The oncoproteins c-Myc and E1A render cells vulnerable to NK cell mediated cytolysis yet the mechanisms of sensitization are not well understood. In a model where foreign cells (rat fibroblasts) were cocultured with human IL-2 activated NK cells, we observed that NK cells were capable of efficiently killing their targets only if the cells overexpressed the oncogene c-Myc or E1A. Both the parental and the oncogene expressing fibroblasts similarly triggered phosphoinositide hydrolysis in the bound NK cells, demonstrating that NK cells were cytolytically activated in contact with both resistant parental and oncogene expressing sensitive target fibroblasts. The cell death was independent of wild-type p53 and was not inhibited by an anti-apoptotic protein EIB19K. These results provided evidence that c-Myc and E1A activated the NK cell induced cytolysis at a post-triggering stage of NK cell-target cell interaction. In consistence, the c-Myc and E1A overexpressing fibroblasts were more sensitive to the cytolytic effects of isolated NK cell-derived granules than parental cells. The data indicate that oncogenes activate the cytotoxicity of NK cell granules. This mechanism can have a role in directing the cytolytic action of NK cells towards the virus-infected and cancer cells.
自然杀伤（NK）细胞与外来细胞以及某些病毒感染或肿瘤细胞的接触会触发NK细胞的溶细胞机制。这种触发会导致细胞毒性NK细胞颗粒的胞吐作用。癌蛋白c-Myc和E1A使细胞易受NK细胞介导的细胞溶解作用影响，但其致敏机制尚不清楚。在一个将外来细胞（大鼠成纤维细胞）与人IL-2激活的NK细胞共培养的模型中，我们观察到，只有当细胞过度表达癌基因c-Myc或E1A时，NK细胞才能有效地杀伤其靶标。亲本成纤维细胞和表达癌基因的成纤维细胞在结合的NK细胞中同样触发了磷酸肌醇水解，这表明NK细胞在与抗性亲本成纤维细胞和表达癌基因的敏感靶标成纤维细胞接触时均被溶细胞激活。细胞死亡与野生型p53无关，且不受抗凋亡蛋白EIB19K的抑制。这些结果证明，c-Myc和E1A在NK细胞-靶细胞相互作用的触发后阶段激活了NK细胞诱导的细胞溶解作用。与此一致的是，与亲本细胞相比，过表达c-Myc和E1A的成纤维细胞对分离的NK细胞衍生颗粒的溶细胞作用更敏感。数据表明癌基因激活了NK细胞颗粒的细胞毒性。这一机制可能在引导NK细胞对病毒感染细胞和癌细胞的溶细胞作用中发挥作用。
