Molecular Mechanisms of Growth Control and Carcinogenesis

该项目的目标是探索 癌症的分子基础，通过对癌症的研究来解决这个问题 参与细胞分裂的分子的正常和异常功能 增殖信号的转导。我们开始证明 某些类型的G蛋白的突变基因正在转化， 以及一些G蛋白偶联受体(GPCR)的行为 作为强有力的激动剂依赖癌基因。随后，我们专注于 从细胞中传递有丝分裂信号的关键分子 胞质到胞核，包括MAP激酶家族。我们的 这项工作导致了一种新的生物化学路线的发现 涉及G激活RAS的GPCRs映射激酶 蛋白质β-伽马。我们还演示了GPCRs可以 刺激一种新的紧密结合的酶--Jun激酶(JNK)的活性 与c-jun磷酸化的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微弱地激活了JNK，但 小GTP结合蛋白rac1和CDc42启动独立的 激活级联导致JNK激活，而Rac和CDC42 是信号通路不可或缺的一部分，连接许多细胞表面 JNK的受体和自然发生的人类癌基因。这个 从这些和其他研究中出现的情况是，细胞表面 受体调节平行的激酶级联反应的活性，在 转而，控制遗传程序的表达，使之正常 或者细胞的异常生长。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.