Katzav S, Packham G, Sutherland M, Aroca P, Santos E, Cleveland J L
Terry Fox Molecular Oncology Group, Lady Davis Institute for Medical Research, Jewish General Hospital, Montreal, Quebec, Canada.
Oncogene. 1995 Sep 21;11(6):1079-88.
Recent evidence has suggested that the Vav oncoprotein may function as a hematopoietic-specific GTP exchange factor for the Ras superfamily of proteins. However, transformation of NIH3T3 fibroblast cells by Vav is morphologically distinct from that induced by activated Ras oncogenes, suggesting that the two oncoproteins induce separate signal transduction pathways which promote transformation. To address this issue, the effects of dominant negative mutants of H-ras and proto-Vav (proto-VavR695L, a mutation in the VavSH2 domain) were tested on Vav- and Ras-induced transformation. These mutants partially inhibited both Vav- and Ras-induced transformation, suggesting that they may induce a common downstream signaling pathway which potentiates transformation. As an independent measure of Vav function we also tested the ability of the purified protein encoded by VavSH2 to influence Germinal Vesicle Breakdown (GVBD) during Xenopus oocyte maturation. Microinjection of the VavSH2 protein alone, but not mutant VavR695L SH2 protein, was sufficient to induce GVBD and accelerated maturation induced by normal Ras, suggesting that in this system as well Vav and Ras signals overlap through a common effector. A key target of multiple signalling pathways is c-Myc. Dominant negative versions of c-Myc totally abolished morphologic transformation of NIH3T3 cells by both Vav and Ras oncogenes. These results suggest that distinct, but overlapping, signalling pathways are induced by Vav and Ras and that fibroblast cell transformation by either oncogene requires c-Myc functions.
最近有证据表明，Vav癌蛋白可能作为Ras蛋白超家族的造血特异性GTP交换因子发挥作用。然而，Vav对NIH3T3成纤维细胞的转化在形态上与活化的Ras癌基因诱导的转化不同，这表明这两种癌蛋白诱导促进转化的独立信号转导途径。为了解决这个问题，测试了H-ras显性负突变体和原Vav（原VavR695L，Vav SH2结构域中的一个突变）对Vav和Ras诱导的转化的影响。这些突变体部分抑制了Vav和Ras诱导的转化，表明它们可能诱导一条共同的下游信号通路，该通路增强转化作用。作为Vav功能的一项独立检测，我们还测试了Vav SH2编码的纯化蛋白在非洲爪蟾卵母细胞成熟过程中影响生发泡破裂（GVBD）的能力。单独显微注射Vav SH2蛋白，而不是突变的VavR695L SH2蛋白，足以诱导GVBD并加速正常Ras诱导的成熟，这表明在这个系统中Vav和Ras信号也通过一个共同的效应器重叠。多个信号通路的一个关键靶点是c-Myc。c-Myc的显性负性形式完全消除了Vav和Ras癌基因对NIH3T3细胞的形态转化。这些结果表明，Vav和Ras诱导不同但重叠的信号通路，并且任何一种癌基因诱导的成纤维细胞转化都需要c-Myc发挥作用。
