Resistance of K-RasB(V12) proteins to farnesyltransferase inhibitors in Rat1 cells
Resistance of K-RasB(V12) proteins to farnesyltransferase inhibitors in Rat1 cells
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DOI：
10.1073/pnas.93.9.4454
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发表时间：
1996-04-30
影响因子：
11.1
通讯作者：
Brown, MS
中科院分区：
文献类型：
--
作者：
James, G;Goldstein, JL;Brown, MS
苯二氮䓬（BZA）-5B是一种CAAX法尼基转移酶抑制剂，先前已表明它能阻断H - Ras的法尼基化，并逆转表达致癌H - Ras（V12）的Rat1细胞的转化形态。未转化的Rat1细胞不受BZA - 5B影响，这表明它们产生的一种Ras形式其异戊二烯化不受该化合物阻断。可能的候选者是K - RasB，它与H - Ras主要在末端24个氨基酸上有所不同。在当前研究中，我们检测了BZA - 5B对一种名为H/K - RasB（V12）的嵌合致癌Ras蛋白异戊二烯化的影响，该蛋白由H - Ras（V12）的前164个氨基酸和K - RasB的最后24个氨基酸组成。BZA - 5B未能阻断这种嵌合体的异戊二烯化，因此无法逆转表达它的Rat1细胞的转化形态。另一种强效的H - Ras法尼基化抑制剂L - 739,749也未能阻断H/K - RasB（V12）的异戊二烯化。在表达一种在其NH₂末端含有10个氨基酸延伸的广泛使用的K - RasB（V12）版本的转染细胞中也得到了类似结果。BZA - 5B和L - 739,749都未能逆转表达H/K - RasB（V12）的细胞的转化形态。K - RasB对法尼基转移酶抑制的抗性为未转化细胞对BZA - 5B和L - 739,749的生长抑制作用的抗性提供了一种可能的解释。
Benzodiazepine (BZA)-5B, a CAAX farnesyltransferase inhibitor, was previously shown to block the farnesylation of H-Ras and to reverse the transformed morphology of Rat1 cells expressing oncogenic H-Ras(V12). Nontransformed Rat1 cells were not affected by BW-SB, suggesting that they produce a form of Ras whose prenylation is not blocked by this compound. The likely candidate is K-RasB, which differs from H-Ras primarily in the terminal 24 amino acids. In the current study we examined the effect of BZA-5B on the prenylation of a chimeric oncogenic pas protein designated H/K-RasB(V12), consisting of the first 164 amino acids of H-Ras(V12) followed by the last 24 amino acids of K-RasB. BZA-5B failed to block the prenylation of this chimera and was thus unable to reverse the transformed morphology of Rat1 cells in which it was expressed. Another potent inhibitor of H-Ras farnesylation, L-739,749, also failed to block prenylation of H/K-RasB(V12), Similar results were obtained in transfected cells expressing a widely used version of K-RasB(V12) containing a 10-amino acid extension at its NH2 terminus. Neither BZA-5B nor L-739,749 reversed the transformed morphology of cells expressing H/K-RasB(V12). The resistance of K-RasB to farnesyltransferase inhibition provides a likely explanation for the resistance of nontransformed cells to the growth inhibitory effects of BZA-5B and L-739,749.