MOLECULAR MECHANISMS OF GROWTH CONTROL AND CARCINOGENESIS

该项目的目标是探索癌症的分子基础，通过研究参与增殖信号转导的分子的正常和异常功能来解决这个问题。我们开始证明某些类别G蛋白的突变基因正在转化，并且许多G蛋白偶联受体（gpcr）表现为有效的激动剂依赖性癌基因。随后，我们将重点放在从细胞质向细胞核传递有丝分裂信号的关键分子上，包括MAP激酶家族。我们的工作导致发现了连接gpcr和MAP激酶的新的生化途径，包括G蛋白β - γ对Ras的激活。我们还证明了gpcr可以刺激jun激酶（JNK）的活性，JNK是一种与MAP激酶密切相关的新型酶，可以磷酸化c-jun原癌基因产物，从而增加其转录活性。接下来，我们发现Ras弱激活JNK，而小的gtp结合蛋白Rac1和Cdc42启动一个独立的激酶级联，导致JNK激活，并且Rac和Cdc42是信号通路的一个组成部分，将许多细胞表面受体和自然发生的人类癌基因与JNK连接起来。从这些研究和其他研究中得出的结论是，细胞表面受体调节平行激酶级联反应的活性，而平行激酶级联反应反过来又控制导致正常或异常细胞生长的遗传程序的表达。我们相信这些发现有助于确定一些潜在的候选者作为癌症治疗干预的靶点。- G蛋白，Ras， MAP激酶，JNK，细胞周期控制

The objective of the project is to explore the molecular basis of cancer, approaching this problem by the study of normal and aberrant functions of molecules that participate in the transduction of proliferative signals. We began demonstrating that mutated genes for certain classes of G proteins are transforming, and that a number of G protein-coupled receptors (GPCRs) behave as potent agonist-dependent oncogenes. Subsequently, we focused on critical molecules conveying mitogenic signals from the cytoplasm to the nucleus, including the family of MAP kinases. Our work led to the discovery of a new biochemical route connecting GPCRs to MAP kinases, involving the activation of Ras by G protein beta gamma. We also demonstrated that GPCRs can stimulate the activity of jun kinase (JNK), a novel enzyme closely related to MAP kinases which phosphorylates the c-jun proto-oncogene product thereby increasing its transcriptional activity. We next found that whereas Ras weakly activates JNK, the small GTP-binding proteins Rac1 and Cdc42 initiate an independent kinase cascade leading to JNK activation, and that Rac and Cdc42 are an integral part of the signaling route, linking many cell surface receptors and naturally occurring human oncogenes to JNK. The emerging picture from these and other studies is that cell surface receptors regulate the activity of parallel kinase cascades which, in turn, control the expression of genetic programs leading to normal or aberrant cell growth. We believe that these findings have helped to identify a number of potential candidates as targets for therapeutic intervention in cancer. - G proteins, Ras, MAP kinases, JNK, Cell cycle control