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 正常和异常功能的分子，参与 增殖信号转导。我们开始证明， 某些类别的G蛋白的突变基因正在转化， 许多G蛋白偶联受体（GPCR） 作为强效激动剂依赖性致癌基因。随后，我们聚焦 关键分子传递促有丝分裂信号， 从细胞质到细胞核，包括MAP激酶家族。我们 这项工作发现了一条新的生化途径， GPCR对MAP激酶的作用，涉及G 蛋白质β γ我们还证明了GPCR可以 刺激与细胞凋亡密切相关的新酶jun激酶（JNK）的活性， 与磷酸化c-jun的MAP激酶相关 原癌基因产物，从而增加其转录 活动我们接下来发现，尽管Ras弱激活JNK， 小GTP结合蛋白Rac 1和Cdc 42启动了一个独立的 导致JNK活化激酶级联，以及Rac和Cdc 42 是信号通路的组成部分，连接许多细胞表面 受体和天然存在的人类癌基因的JNK。的 从这些和其他研究中浮现的图像是细胞表面 受体调节平行激酶级联的活性， 转，控制基因程序的表达，导致正常的 或者细胞生长异常我们相信这些发现有助于 确定一些潜在的候选人作为目标， 癌症的治疗干预。

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.