Farnesyltransferase inhibitors alter the prenylation and growth-stimulating function of RhoB
Farnesyltransferase inhibitors alter the prenylation and growth-stimulating function of RhoB
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DOI：
10.1074/jbc.272.25.15591
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发表时间：
1997-06-20
影响因子：
4.8
通讯作者：
Thissen, JA
中科院分区：
文献类型：
--
作者：
Lebowitz, PF;Casey, PJ;Thissen, JA
蛋白法尼基转移酶抑制剂（FTIs）抑制Pas转化和HAS依赖性肿瘤细胞生长，但这些活动的生物学机制尚不清楚，在以前的工作中，我们提出了支持的假设，即FTIs的抗转化作用取决于RhoB，调节细胞骨架肌动蛋白，细胞粘附和细胞生长的Rho蛋白家族的成员的功能的改变。需要解决的一个重要问题是FTI是否可以直接改变细胞中RhoB的异戊二烯化以及功能。这个问题很复杂，因为RhoB的法尼基化和香叶基香叶基化形式在此，我们表明RhoB法尼基化在体外可以被蛋白法尼基转移酶催化，并且肽模拟物FTIL-739，在药物处理的细胞中，RhoB-GG的水平与RhoB-F的降低平行地增加。除了改变RhoB异戊烯化，L-739，749抑制RhoB依赖性细胞生长。结果表明FTIs对RhoB功能的抑制作用可以通过RhoB-F的相对损失、RhoB-GG的增加或两者来介导，我们的研究结果加强了RhoB抑制和FTIs的抗转化作用之间的因果关系，并表明RhoB的不同异戊二烯化形式可能具有独特的功能。
Protein farnesyltransferase inhibitors (FTIs) inhibit Pas transformation and has-dependent tumor cell growth, but the biological mechanisms underlying these activities is unclear, In previous work, we presented support for the hypothesis that the anti-transforming effects of FTIs depend upon alterations in the function of RhoB, a member of the Rho family of proteins that regulate cytoskeletal actin, cell adhesion, and cell growth. A significant question that needed to be addressed was whether FTIs could directly alter the prenylation as well as the function of RhoB in cells, This issue is complex because farnesylated and geranylgeranylated forms of RhoB (RhoB-F and RhoE-GG) both exist in cells, Here, we show that RhoB farnesylation in vitro can be catalyzed by protein farnesyltransferase and that the peptidomimetic FTI L-739,749 inhibits the farnesylation of RhoB both in vitro and in intact cells, In drug-treated cells, the level of RhoB-GG increased in parallel with the decrease in RhoB-F, In addition to altering RhoB prenylation, L-739,749 suppressed RhoB-dependent cell growth, Taken together, the results suggest that the inhibitory effects of FTIs on RhoB function can be mediated by a relative loss of RhoB-F, a gain of RhoB-GG, or both, Our findings strengthen the causal link between RhoB inhibition and the anti-transforming effects of FTIs and indicate that differently prenylated forms of RhoB may have unique functions.