Joyce Patricia L, Cox Adrienne D
Departments of Pharmacology and Radiation Oncology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599-7512, USA.
Cancer Res. 2003 Nov 15;63(22):7959-67.
Rac1, a Rho family GTPase, is a mediator of diverse cellular functions including membrane ruffling, cell cycle progression, and transformation. Rac3, a close relative of Rac1, is less well characterized. Posttranslational addition of geranylgeranyl isoprenoid lipids to Rac proteins is required for biological activity. Inhibitors of geranylgeranyl transferase I (GGTIs) are currently under investigation as a possible anticancer therapy, although the targets of GGTIs have not been determined. We created COOH-terminal mutants of Rac1 and Rac3 that are farnesylated and used them to characterize Rac1 and Rac3 as physiological targets of GGTIs. We show that, like Rac1, activated Rac3 causes transformation and leads to membrane ruffling. Farnesylated versions of Rac1 and Rac3 retain the ability to signal to the transcription factor c-Jun and cause membrane ruffling and transformation, indicating that switching isoprenoid modification does not alter function. Finally, treatment with GGTIs led to the inhibition of membrane-ruffling and transforming activities of both activated and wild-type Rac1 and Rac3. However, the farnesylated versions of both activated and wild-type Rac1 and Rac3 were resistant to the inhibitory effects of GGTIs. These results illustrate that Rac1 and Rac3 are potential physiological targets for these novel drugs.
Rac1是一种Rho家族GTP酶，是多种细胞功能的介质，包括膜皱襞形成、细胞周期进程和细胞转化。Rac3是Rac1的近亲，其特征了解较少。Rac蛋白的生物学活性需要在翻译后添加香叶基香叶基类异戊二烯脂质。香叶基香叶基转移酶I（GGTIs）抑制剂目前正在作为一种可能的抗癌疗法进行研究，尽管GGTIs的靶点尚未确定。我们创建了法尼基化的Rac1和Rac3的羧基末端突变体，并用它们将Rac1和Rac3表征为GGTIs的生理靶点。我们发现，与Rac1一样，活化的Rac3会导致细胞转化并引起膜皱襞形成。Rac1和Rac3的法尼基化版本保留了向转录因子c-Jun发出信号并引起膜皱襞形成和细胞转化的能力，这表明改变类异戊二烯修饰不会改变功能。最后，用GGTIs处理导致活化型和野生型Rac1和Rac3的膜皱襞形成和转化活性受到抑制。然而，活化型和野生型Rac1和Rac3的法尼基化版本对GGTIs的抑制作用具有抗性。这些结果表明，Rac1和Rac3是这些新型药物的潜在生理靶点。
