Schafer W R, Kim R, Sterne R, Thorner J, Kim S H, Rine J
Department of Biochemistry, University of California, Berkeley 94720.
Science. 1989 Jul 28;245(4916):379-85. doi: 10.1126/science.2569235.
The activity of an oncoprotein and the secretion of a pheromone can be affected by an unusual protein modification. Specifically, posttranslational modification of yeast a-factor and Ras protein requires an intermediate of the cholesterol biosynthetic pathway. This modification is apparently essential for biological activity. Studies of yeast mutants blocked in sterol biosynthesis demonstrated that the membrane association and biological activation of the yeast Ras2 protein require mevalonate, a precursor of sterols and other isoprenes such as farnesyl pyrophosphate. Furthermore, drugs that inhibit mevalonate biosynthesis blocked the in vivo action of oncogenic derivatives of human Ras protein in the Xenopus oocyte assay. The same drugs and mutations also prevented the posttranslational processing and secretion of yeast a-factor, a peptide that is farnesylated. Thus, the mevalonate requirement for Ras activation may indicate that attachment of a mevalonate-derived (isoprenoid) moiety to Ras proteins is necessary for membrane association and biological function. These observations establish a connection between the cholesterol biosynthetic pathway and transformation by the ras oncogene and offer a novel pharmacological approach to investigating, and possibly controlling, ras-mediated malignant transformations.
一种癌蛋白的活性和一种信息素的分泌可能会受到一种异常蛋白质修饰的影响。具体而言，酵母a因子和Ras蛋白的翻译后修饰需要胆固醇生物合成途径的一种中间体。这种修饰显然对生物活性至关重要。对甾醇生物合成受阻的酵母突变体的研究表明，酵母Ras2蛋白的膜结合和生物激活需要甲羟戊酸，它是甾醇和其他异戊二烯（如法尼基焦磷酸）的前体。此外，抑制甲羟戊酸生物合成的药物在非洲爪蟾卵母细胞试验中阻断了人Ras蛋白致癌衍生物的体内作用。同样的药物和突变也阻止了酵母a因子（一种被法尼基化的肽）的翻译后加工和分泌。因此，Ras激活对甲羟戊酸的需求可能表明，将甲羟戊酸衍生的（类异戊二烯）部分连接到Ras蛋白上对于膜结合和生物学功能是必要的。这些观察结果建立了胆固醇生物合成途径与ras癌基因介导的转化之间的联系，并为研究以及可能控制ras介导的恶性转化提供了一种新的药理学方法。
