Ritter M, Dartsch P, Waldegger S, Haller T, Zwierzina H, Lang H J, Lang F
Department of Internal Medicine, University of Innsbruck, Austria.
Biochim Biophys Acta. 1997 Aug 21;1358(1):23-30. doi: 10.1016/s0167-4889(97)00046-3.
As shown previously, expression of Ha-ras oncogene in NIH 3T3 fibroblasts (+ ras cells) increases cellular concentrations of Ins(1,4,5)P3 and Ins(1,3,4,5)P4 and enhances bradykinin induced Ca2+ entry [1-3]. These cells respond to low concentrations of serum or bradykinin with sustained oscillations of the cell membrane potential due to pulsatile release of calcium from internal stores and subsequent activation of calcium sensitive K+ channels [1]. Furthermore Ha-ras oncogene expression leads to depolymerization of the actin filament network and delayed increase of cell volume [4-6]. Pretreatment of the same cells not expressing the oncogene (-ras cells) with Li+ similarly increases Ins(1,4,5)P3 and Ins(1,3,4,5)P4 [2]. As shown in the present study, -ras cells pretreated with Li+ similar to Ha-ras oncogene expressing cells respond to bradykinin with sustained oscillations of cell membrane potential, depolymerization of the actin filament network and increase of cell volume. The oscillations of the cell membrane potential and the depolymerization of the actin cytoskeleton can be inhibited by the calcium channel blocker lanthanum and the bradykinin induced increase of cell volume is inhibited by HOE 694, pointing to involvement of Na+/H+ exchange. The data indicate a close functional linkage of the calcium oscillations, cytoskeletal rearrangement and activation of the Na+/H+ exchanger. Thus, Li+ pretreatment mimicks crucial cellular events triggered by expression of the Ha-ras oncogene. However, unlike in cells expressing the Ha-ras oncogene, Li+ pretreatment alone does not allow for growth factor-independent proliferation of the cells.
如前所示，NIH 3T3成纤维细胞（+ras细胞）中Ha-ras癌基因的表达会增加Ins(1,4,5)P3和Ins(1,3,4,5)P4的细胞浓度，并增强缓激肽诱导的Ca2+内流[1-3]。这些细胞对低浓度血清或缓激肽产生反应，由于从内部储存库中脉动释放钙以及随后激活钙敏感钾通道，导致细胞膜电位持续振荡[1]。此外，Ha-ras癌基因的表达会导致肌动蛋白丝网络解聚，并延迟细胞体积增加[4-6]。用Li+预处理不表达癌基因的相同细胞（-ras细胞）同样会增加Ins(1,4,5)P3和Ins(1,3,4,5)P4[2]。如本研究所示，与表达Ha-ras癌基因的细胞类似，用Li+预处理的-ras细胞对缓激肽产生反应，出现细胞膜电位持续振荡、肌动蛋白丝网络解聚和细胞体积增加。细胞膜电位的振荡和肌动蛋白细胞骨架的解聚可被钙通道阻滞剂镧抑制，缓激肽诱导的细胞体积增加可被HOE 694抑制，这表明Na+/H+交换参与其中。数据表明钙振荡、细胞骨架重排和Na+/H+交换器激活之间存在紧密的功能联系。因此，Li+预处理模拟了由Ha-ras癌基因表达引发的关键细胞事件。然而，与表达Ha-ras癌基因的细胞不同，单独的Li+预处理并不能使细胞实现不依赖生长因子的增殖。
