The Role of RAC1 in Cancer

RAC1 在癌症中的作用

• 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
• 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

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.

项目总结