Maruta H, Burgess A W
Ludwig Institute for Cancer Research, Melbourne, Australia.
Bioessays. 1994 Jul;16(7):489-96. doi: 10.1002/bies.950160708.
The mitogenic action of cytokines such as epidermal growth factor (EGF) or platelet derived growth factor (PDGF) involves the stimulation of a signal cascade controlled by a small G protein called Ras. Mutations of Ras can cause its constitutive activation and, as a consequence, bypass the regulation of cell growth by cytokines. Both growth factor-induced and oncogenic activation of Ras involve the conversion of Ras from the GDP-bound (D-Ras) to the GTP-bound (T-Ras) forms. T-Ras activates a network of protein kinases including c-Mos, c-Raf-1 and MAP kinase. Eventually the activation of MAP kinase leads to the activation of the elongation factor 4E and several transcription factors such as c-Jun, c-Myc and c-Fos. There are several modulators of Ras activity, such as the GTPase activating proteins (GAP1 and NF1), which stimulate the conversion of T-Ras to D-Ras. A series of small NF1 fragments, which bind T-Ras, as well as truncated forms of derivatives of c-Raf-1, c-Jun and c-Myc, are capable of blocking the T-Ras-activated mitogenesis in a competitive manner. These agents offer a unique opportunity to control the proliferation of T-Ras-associated tumors, which represent more than 30% of total human carcinomas.
细胞因子如表皮生长因子（EGF）或血小板衍生生长因子（PDGF）的促有丝分裂作用涉及对由一种名为Ras的小G蛋白控制的信号级联的刺激。Ras突变可导致其组成性激活，结果是绕过细胞因子对细胞生长的调节。生长因子诱导的Ras激活和致癌激活都涉及Ras从结合GDP的（D-Ras）形式转变为结合GTP的（T-Ras）形式。T-Ras激活包括c-Mos、c-Raf-1和MAP激酶在内的蛋白激酶网络。最终，MAP激酶的激活导致延伸因子4E和几种转录因子如c-Jun、c-Myc和c-Fos的激活。有几种Ras活性调节剂，如GTP酶激活蛋白（GAP1和NF1），它们刺激T-Ras向D-Ras的转化。一系列与T-Ras结合的小NF1片段，以及c-Raf-1、c-Jun和c-Myc衍生物的截短形式，能够以竞争方式阻断T-Ras激活的有丝分裂。这些药物为控制与T-Ras相关的肿瘤的增殖提供了独特的机会，这类肿瘤占人类癌症总数的30%以上。
