The Role of RAC1 in Cancer

RAC1 在癌症中的作用

基本信息

批准号：
8204980
负责人：
JOSEPH KISSIL
金额：
$ 21.13万
依托单位：
WISTAR INSTITUTE
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-03-01 至 2012-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8204980
关键词：
Address Alleles Animal Model Animals Cancer Etiology Cell Proliferation Cell Survival Cell model Cells Cessation of life Cytoskeleton Data Death Rate Dependence Detection Diagnosis Diagnostic Neoplasm Staging Disease Endocytosis Epithelial Cells Epithelium Family Gene Expression Goals Human K-ras Gene Knock-out Knowledge Light Lung Lung Adenocarcinoma Lung Neoplasms Malignant Neoplasms Malignant neoplasm of lung Mediating Modeling Molecular Monomeric GTP-Binding Proteins Mus Mutant Strains Mice Mutate Mutation Nature Neoplasm Metastasis Normal Cell Oncogenes Oncogenic Outcome Pathway interactions Physiological Play Prevalence Process Protein Family RNA Splicing Regulation Reporting Role Signal Pathway Staging System Testing Tissues Toxic effect Work base cell motility epithelial to mesenchymal transition in vivo member mouse model public health relevance rac GTP-Binding Proteins rho therapeutic development tumor tumor initiation tumor progression tumorigenesis tumorigenic

项目摘要

Project Summary Lung cancer is the leading cause of cancer deaths worldwide. It is estimated that in 2006, more than 163,500 people, in the US alone, will die from this disease. The reasons for the high death rate are detection and diagnosis at advanced stages and a lack of efficient treatments for advanced lung cancer. To identify treatments for advanced stage cancers, we must first understand the molecular mechanisms underlying the disease if we are to identify appropriate targets for the development of therapeutics. One the most common mutations found in lung adenocarcinoma are activating mutations of the K-ras gene, found in 20-30% of all lung adenocarcinomas. We have used this knowledge to develop a mouse model of lung adenocarcinoma that closely recapitulates the human form of the disease. Given the emerging data implicating the small G-proteins of the Rac family in Ras-induced tumorigenesis we examined the potential function of Rac1 as an oncogene and the requirement for Rac1 downstream of K-ras in lung adenocarcinoma. The Rac small G-proteins are regulators of diverse signaling pathways including those mediating cytoskeleton reorganization, gene expression, endocytosis and cell proliferation and survival. The deregulation of these pathways is a reoccurring theme in tumorigenesis. Our findings indicate that a naturally occurring splice form of Rac1 is upregulated in a significant percentage of human lung adenocarcinomas and that Rac1 is required for K- ras induced lung tumors. Furthermore, while Rac1 deletion alone was compatible with cell viability and proliferation, when combined with K-ras activation in primary epithelial cells, loss of Rac1 caused a profound reduction in proliferation. Thus, there is a synthetic requirement for Rac1 function in cells expressing oncogenic K-ras. These studies will shed light on the process of tumor initiation and progression and enhance our understanding of the molecular pathways involved in lung cancer. The finding that loss of Rac1 is "lethal" in the context of activated K-ras raises the possibility that targeting Rac1 in Ras-mutated tumors would be therapeutically beneficial with, perhaps, limited toxicity towards normal cells.

项目摘要肺癌是全球癌症死亡的主要原因。据估计 2006年，仅在美国，就有163,500多人将死于这种疾病。这高死亡率的原因是高级阶段的检测和诊断和缺乏对晚期肺癌的有效治疗方法。确定治疗方法高级阶段癌症，我们必须首先了解分子机制如果我们要确定适当的靶标的发展目标疗法。肺腺癌中最常见的突变之一是在所有肺腺癌的20-30％中发现的K-RAS基因的激活突变。我们已经使用这些知识来开发一种肺腺癌的小鼠模型紧密概括了该疾病的人类形式。考虑到新兴数据暗示了RAC家族的小g蛋白 RAS诱导的肿瘤发生，我们研究了Rac1的潜在功能以及肺腺癌K-RAS下游Rac1的需求。 RAC 小型G蛋白是各种信号通路的调节剂，包括介导的途径细胞骨架重组，基因表达，内吞作用和细胞增殖以及生存。这些途径的放松管制是肿瘤发生的重复主题。我们的发现表明，Rac1的自然存在的剪接形式在人类肺腺癌的很大比例是K-所必需的Rac1 RAS诱导肺部肿瘤。此外，虽然仅Rac1删除与细胞活力和增殖，与原发性上皮中的K-RAS激活结合细胞，Rac1的损失导致增殖大幅下降。因此，有一个合成在表达致癌K-RAS的细胞中Rac1功能的需求。这些研究将阐明肿瘤起步和进展的过程并增强我们对肺癌中涉及的分子途径的理解。这在激活的K-Ras的背景下，发现Rac1的丢失是“致命的”，这增加了可能性 RAS突变肿瘤中的Rac1在治疗上对也许，对正常细胞的毒性有限。