Goalstone M L, Leitner J W, Wall K, Dolgonos L, Rother K I, Accili D, Draznin B
Research Service and the Department of Medicine, Denver Veterans Affairs Medical Center and University of Colorado Health Sciences Center, Denver, Colorado 80220, USA.
J Biol Chem. 1998 Sep 11;273(37):23892-6. doi: 10.1074/jbc.273.37.23892.
We have previously demonstrated that insulin activates farnesyltransferase (FTase) and augments the amounts of farnesylated p21 (Goalstone, M. L., and Draznin, B. (1996) J. Biol. Chem. 271, 27585-27589). We postulated that this aspect of insulin action might explain the "priming effect" of insulin on the cellular response to other growth factors. In the present study, we show the specificity of the effect of insulin on FTase. Insulin, but not insulin-like growth factor-1 (IGF-1), epidermal growth factor (EGF), or platelet-derived growth factor (PDGF), stimulated the phosphorylation of the alpha-subunit of FTase and the amounts of farnesylated p21. Even though all four growth factors utilized the Ras pathway to stimulate DNA synthesis, only insulin used this pathway to influence FTase. Insulin failed to stimulate FTase in cells expressing the chimeric insulin/IGF-1 receptor and in cells derived from the insulin receptor knock-out animals. Insulin potentiated the effects of IGF-1, EGF, and PDGF on DNA synthesis in cells expressing the wild type insulin receptor, but this potentiation was inhibited in the presence of the FTase inhibitor, alpha-hydroxyfarnesylphosphonic acid. We conclude that the effect of insulin on FTase is specific, requires the presence of an intact insulin receptor, and serves as a conduit for the "priming" influence of insulin on the nuclear effects of other growth factors.
我们之前已经证明，胰岛素可激活法尼基转移酶（FTase）并增加法尼基化p21的量（Goalstone，M. L.，和Draznin，B.（1996年）《生物化学杂志》271，27585 - 27589）。我们推测，胰岛素作用的这一方面可能解释了胰岛素对细胞对其他生长因子反应的“启动效应”。在本研究中，我们展示了胰岛素对FTase作用的特异性。胰岛素而非胰岛素样生长因子-1（IGF-1）、表皮生长因子（EGF）或血小板衍生生长因子（PDGF）刺激了FTaseα亚基的磷酸化以及法尼基化p21的量。尽管所有这四种生长因子都利用Ras途径来刺激DNA合成，但只有胰岛素利用该途径来影响FTase。胰岛素在表达嵌合胰岛素/IGF-1受体的细胞以及源自胰岛素受体基因敲除动物的细胞中未能刺激FTase。胰岛素增强了IGF-1、EGF和PDGF对表达野生型胰岛素受体细胞中DNA合成的作用，但在存在FTase抑制剂α-羟基法尼基膦酸的情况下，这种增强作用受到抑制。我们得出结论，胰岛素对FTase的作用具有特异性，需要完整的胰岛素受体存在，并且作为胰岛素对其他生长因子核效应“启动”影响的一个途径。
