Whyte D B, Kirschmeier P, Hockenberry T N, Nunez-Oliva I, James L, Catino J J, Bishop W R, Pai J K
Department of Tumor Biology, Schering-Plough Research Institute, Kenilworth, New Jersey 07033, USA.
J Biol Chem. 1997 May 30;272(22):14459-64. doi: 10.1074/jbc.272.22.14459.
The association of mutant forms of Ras protein with a variety of human cancers has stimulated intense interest in therapies based on inhibiting oncogenic Ras signaling. Attachment of Ras proteins to the plasma membrane is required for effective Ras signaling and is initiated by the enzyme farnesyl protein transferase. We found that in the presence of potent farnesyl protein transferase inhibitors, Ras proteins in the human colon carcinoma cell line DLD-1 were alternatively prenylated by geranylgeranyl transferase-1. When H-Ras, N-Ras, K-Ras4A, and K-Ras4B were expressed individually in COS cells, H-Ras prenylation and membrane association were found to be uniquely sensitive to farnesyl transferase inhibitors; N- and K-Ras proteins incorporated the geranylgeranyl isoprene group and remained associated with the membrane fraction. The alternative prenylation of N- and K-Ras has significant implications for our understanding of the mechanism of action of farnesyl protein transferase inhibitors as anti-cancer chemotherapeutics.
Ras蛋白的突变形式与多种人类癌症的关联激发了人们对基于抑制致癌Ras信号传导的疗法的浓厚兴趣。Ras蛋白与质膜的附着是有效Ras信号传导所必需的，并且由法尼基蛋白转移酶启动。我们发现，在强效法尼基蛋白转移酶抑制剂存在的情况下，人结肠癌细胞系DLD-1中的Ras蛋白可被香叶基香叶基转移酶-1进行替代异戊二烯化。当H-Ras、N-Ras、K-Ras4A和K-Ras4B分别在COS细胞中表达时，发现H-Ras的异戊二烯化和膜结合对法尼基转移酶抑制剂具有独特的敏感性；N-Ras和K-Ras蛋白掺入了香叶基香叶基异戊二烯基团，并与膜部分保持结合。N-Ras和K-Ras的替代异戊二烯化对于我们理解法尼基蛋白转移酶抑制剂作为抗癌化疗药物的作用机制具有重要意义。
