GROWTH MODULATION AND ANALYSIS OF TUMORS BEARING RAF-1 MUTATIONS

Raf蛋白丝氨酸/苏氨酸激酶是一种重要的介导剂， 促有丝分裂信号转导及其改变的表达或活性， 与包括肺癌在内的几种人类癌症有关。 我们 开发了诱导这种肿瘤类型的小鼠模型，并对其进行了检查， 因为拉夫的参与 经胎盘注射法诱发肿瘤 1-乙基-1-亚硝基脲，然后用丁基化的 羟基甲苯 该方案在100%的患者中诱导肺腺癌。 后代和T细胞淋巴瘤70%。 检查肿瘤的改变 一组癌基因的表达或结构显示出一致的 c-raf-1突变，沿着明显缺乏Ras突变。 所有这些突变都导致氨基酸取代，并且功能性地改变。 对突变的Raf-1的测定证明突变是激活的。 这是第一个点突变的c-raf-1在体内的例子， 一类新的激活RAF突变。 它们在子域中的位置 VIII的激酶结构域在表面的底物口袋表明， 它们可能被开发用于开发特定于muscle的 抑制剂的

The Raf protein serine/threonine kinase is a crucial mediator of mitogenic signal transduction, and its altered expression or activity has been associated with several types of human cancer, including lung. We developed a mouse model for induction of this tumor type and examined it for Raf involvement. Tumors were inducted by transplacental injection of 1-ethyl-1-nitrosourea followed by promotion with butylated hydroxytoluene. This regimen induces lung adenocarcinomas in 100% of offspring and T-cell lymphomas in 70%. Examination of tumors for altered expression or structure of a panel of oncogenes revealed consistent mutations of c-raf-1, along with a conspicuous lack of Ras mutations. All of these mutations result in amino acid substitutions, and functional assays for mutated Raf-1 demonstrated that the mutations were activating. This is the first example of point-mutated c-raf-1 in vivo, demonstrating a new class of activating raf mutations. Their location in subdomain VIII of the kinase domain at the surface of the substrate pocket suggests that they might be exploited for the development of mutant-specific inhibitors.