Lacal J C, Moscat J, Aaronson S A
Laboratory of Cellular and Molecular Biology, National Cancer Institute, Bethesda, Maryland 20892.
Nature. 1987;330(6145):269-72. doi: 10.1038/330269a0.
Genes involved in the transduction of signals required for normal cell proliferation commonly appear to be subverted in the neoplastic process. One such group is the highly conserved family of ras genes, which have been detected as transforming genes in a wide variety of naturally occurring tumours. By analogy with other known G proteins, the p21 proteins encoded by ras genes may act as regulatory proteins in the transduction of signals that lead to DNA synthesis. A major pathway involved in the DNA synthesis induced by growth factors is mediated by phosphatidylinositol turnover: cleavage of phosphoinositides by phospholipase C produces 1,2-diacylglycerol, and inositol phosphates. The former acts as an essential cofactor for protein kinase C (ref. 4), and inositol-(1,4,5)-triphosphate mobilizes Ca2+ from non-mitochondrial intracellular stores. We demonstrate a reproducible increase in 1,2-diacylglycerol, in the absence of a detectable increase in inositol phosphates, in transformed cells containing Ha-ras oncogenes and with different membrane targeting signals for the ras p21 protein. These findings suggest that a source other than phosphoinositides exists for the generation of 1,2-diacylglycerol and that the Ha-ras oncogene specifically activates this novel pathway for 1,2-diacylglycerol production.
正常细胞增殖所需信号转导过程中涉及的基因，在肿瘤形成过程中通常似乎会被颠覆。ras基因家族就是这样一组基因，它们高度保守，在多种自然发生的肿瘤中被检测为转化基因。与其他已知的G蛋白类似，ras基因编码的p21蛋白可能在导致DNA合成的信号转导中作为调节蛋白发挥作用。生长因子诱导DNA合成所涉及的一条主要途径是由磷脂酰肌醇代谢介导的：磷脂酶C对磷酸肌醇的切割产生1,2 - 二酰甘油和肌醇磷酸。前者作为蛋白激酶C的必需辅助因子（参考文献4），肌醇 -（1,4,5）- 三磷酸从非线粒体细胞内储存中动员Ca2+。我们证明，在含有Ha - ras癌基因且ras p21蛋白具有不同膜靶向信号的转化细胞中，1,2 - 二酰甘油可重复性增加，而肌醇磷酸没有可检测到的增加。这些发现表明，1,2 - 二酰甘油的产生存在磷酸肌醇以外的来源，并且Ha - ras癌基因特异性激活了这条产生1,2 - 二酰甘油的新途径。
