Alvarado Yesid, Giles Francis J
University of Texas MD Anderson Cancer Center, Department of Leukemia, Box 428, 1515 Holcombe Boulevard, Houston, Texas 77030, USA.
Expert Opin Emerg Drugs. 2007 May;12(2):271-84. doi: 10.1517/14728214.12.2.271.
The RAS gene product is normally a membrane-localized G protein (N-Ras, K-Ras and H-Ras) of 21 kDa classically described as a molecular off/on switch. It is inactive when bound to guanosine diphosphate and active when bound to GTP. When mutated, the gene produces an abnormal protein resistant to GTP hydrolysis by GTPase, resulting in a constitutively active GTP-bound protein that stimulates a critical network of signal transduction pathways that lead to cellular proliferation, survival and differentiation. At least three downstream effector pathways have been described, including Raf/MEK/ERK, PI3K/AKT and RalGDS, but they are not completely understood. Ras pathways are also important downstream effectors of several receptor tyrosine kinases localized in the cell membrane, most notably the BCR-ABL fusion protein seen in patients with Philadelphia chromosome positive chronic myelogenous leukemia. An important consideration in designing strategies to block Ras stimulatory effect is that Ras proteins are synthesized in the cytosol, but require post-translational modifications and attachment to anchor proteins or membrane binding sites in the cell membrane to be biologically active. Farnesyl transferase inhibitors (FTIs) are probably the best-studied class of Ras inhibitors in hematologic malignancies. They block the enzyme farnesyl-transferase (FTase), which is essential for post-translational modification. However, it has been observed that the Ras proteins also can be geranylgeranylated in the presence of FTIs, thus allowing membrane localization and activation, which limits their effectiveness. It is now hypothesized that their mechanism of action may be through FTase inhibition involving other signal transduction pathways. S-trans, trans-farnesylthiosalicylic acid, which was first designed as a prenylated protein methyltransferase inhibitor, has shown in vitro activity against all activated Ras proteins by dislodging them from their membrane-anchoring sites. Here, Ras biology, its signaling pathways and its implications as a therapeutic target in hematologic malignancies are reviewed.
RAS基因产物通常是一种21 kDa的膜定位G蛋白（N-Ras、K-Ras和H-Ras），传统上被描述为分子开关。它与二磷酸鸟苷结合时无活性，与GTP结合时则具有活性。当发生突变时，该基因会产生一种异常蛋白质，这种蛋白质对GTP酶介导的GTP水解具有抗性，从而导致一种持续激活的、与GTP结合的蛋白质，该蛋白质会刺激一个关键的信号转导通路网络，进而导致细胞增殖、存活和分化。目前已描述了至少三种下游效应通路，包括Raf/MEK/ERK、PI3K/AKT和RalGDS，但对它们的了解还不完全。Ras通路也是几种位于细胞膜上的受体酪氨酸激酶的重要下游效应器，最显著的是在费城染色体阳性慢性髓性白血病患者中出现的BCR-ABL融合蛋白。在设计阻断Ras刺激效应的策略时，一个重要的考虑因素是Ras蛋白在胞质溶胶中合成，但需要翻译后修饰并附着于锚定蛋白或细胞膜中的膜结合位点才能具有生物学活性。法尼基转移酶抑制剂（FTIs）可能是血液系统恶性肿瘤中研究最深入的一类Ras抑制剂。它们可阻断对翻译后修饰至关重要的法尼基转移酶（FTase）。然而，据观察，在存在FTIs的情况下，Ras蛋白也可被香叶基香叶基化，从而实现膜定位和激活，这限制了它们的有效性。现在推测它们的作用机制可能是通过抑制FTase并涉及其他信号转导通路。S-反式，反式-法尼基硫代水杨酸最初被设计为一种异戊二烯化蛋白甲基转移酶抑制剂，通过将所有活化的Ras蛋白从其膜锚定位点上移除，已显示出体外活性。本文对Ras生物学、其信号通路及其作为血液系统恶性肿瘤治疗靶点的意义进行了综述。
