Garcia A M, Rowell C, Ackermann K, Kowalczyk J J, Lewis M D
Eisai Research Institute, Andover, Massachusetts 01810.
J Biol Chem. 1993 Sep 5;268(25):18415-8.
The ras protooncogene is involved in regulation of cell growth. Mutations that activate the protein result in uncontrolled cell growth. Ras undergoes a series of posttranslational processing events, the first of which, farnesylation, is crucial for the function of the protein. Inhibitors of the farnesyltransferase enzyme are therefore potential candidates for the development of anticancer drugs. Tetrapeptides have been reported to be good inhibitors of this enzyme in vitro. We have synthesized analogs of the tetrapeptide Cys-Val-Phe-Met by replacement of the amino-terminal amide bonds. One inhibitor, B581, is permeable to the cell membrane. In the cell, it inhibits processing of two farnesylated proteins, H-ras and lamin A, but it does not inhibit processing of a geranylgeranylated protein, Rap 1A. Microinjection of B581 into frog oocytes inhibits maturation induced by activated, farnesylated H-ras but not maturation induced by activated, geranylgeranylated H-ras or by progesterone. These results demonstrate that this peptide mimic inhibits farnesylation selectively in the cell. The inhibition of farnesylation results in inhibition of H-ras function.
原癌基因ras参与细胞生长的调控。激活该蛋白的突变会导致细胞生长失控。Ras经历一系列翻译后加工事件,其中第一步法尼基化对于该蛋白的功能至关重要。因此,法尼基转移酶抑制剂是开发抗癌药物的潜在候选物。据报道,四肽在体外是该酶的良好抑制剂。我们通过替换氨基末端酰胺键合成了四肽Cys-Val-Phe-Met的类似物。一种抑制剂B581可透过细胞膜。在细胞中,它抑制两种法尼基化蛋白H-ras和核纤层蛋白A的加工,但不抑制香叶基香叶基化蛋白Rap 1A的加工。将B581显微注射到蛙卵母细胞中可抑制由激活的、法尼基化的H-ras诱导的成熟,但不抑制由激活的、香叶基香叶基化的H-ras或孕酮诱导的成熟。这些结果表明,这种肽模拟物在细胞中选择性地抑制法尼基化。法尼基化的抑制导致H-ras功能的抑制。