GENETIC AND PHARMACOLOGICAL SUPPRESSION OF ONCOGENIC MUTATIONS IN RAS GENES OF YEAST AND HUMANS
GENETIC AND PHARMACOLOGICAL SUPPRESSION OF ONCOGENIC MUTATIONS IN RAS GENES OF YEAST AND HUMANS
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DOI：
10.1126/science.2569235
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发表时间：
1989-07-28
期刊：
影响因子：
56.9
通讯作者：
RINE, J
中科院分区：
文献类型：
--
作者：
SCHAFER, WR;KIM, R;RINE, J
一种癌蛋白的活性和信息素的分泌会受到一种不寻常的蛋白质修饰的影响。具体来说，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中间物。这种修饰显然是生物活性所必需的。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盐，这是甾醇和其他异戊二烯（如焦磷酸法尼酯）的前体。此外，在非洲爪蟾卵母细胞实验中，抑制甲羟戊酸生物合成的药物阻断了人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因子的翻译后加工和分泌，这是一种法酰化的肽。因此，甲羟戊酸对Ras激活的要求可能表明甲羟戊酸衍生的（类异戊二烯）片段附着在Ras蛋白上是膜结合和生物学功能所必需的。这些观察结果建立了胆固醇生物合成途径与ras癌基因转化之间的联系，并为研究和可能控制ras介导的恶性转化提供了一种新的药理学方法。
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 biosynethetic 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.