REGULATORY ROLE OF RAC AND CDC42 ON TUMOR METASTASIS

描述：(改编自调查人员的摘要)描述 定向运动的分子机制对于理解 肿瘤转移和侵袭的过程。作为基础的过程 原发肿瘤细胞向异位部位的迁移涉及重组 肌动蛋白细胞骨架。调节肌动蛋白变化的几个因素 运动细胞的细胞骨架已被鉴定，然而，信号转导 指导肌动蛋白从头聚合的分子及其终极 需要明确空间和动态组织。该委员会的几名成员 Rho家族的小分子GTP酶(Rho、Rac和CDC42)已被确定为关键 连接细胞表面受体和肌动蛋白细胞骨架的信号转导。 我们的目标是检验RAC和CDC42是重要的调节因子的假设。 乳腺癌细胞转移。 我们的研究计划涉及到利用分子遗传学的总体策略 结合细胞和生化技术的方法。这个 人和大鼠乳腺癌细胞稳定表达载体的构建 RAC的显性活性、显性负性和效应域突变 和CDC42将被执行。我们将评估激活或 失活Rac和CDC42对乳腺癌转移的影响。这些转染体 将以细胞、生化和组织病理学分析为特征。 转染型乳腺癌细胞的转移潜能 突变的RAC和CDC42将在注射到大鼠(大鼠)后进行评估 乳腺癌)和裸鼠(人乳腺癌)。 这项研究有望将RAC和/或CDC42确立为重要的介体 癌症转移的可能性。我们的长期目标是勾勒出信号级联 RAC和/或CDC42介导的侵袭和转移。识别 这些定向迁移的关键监管机构预计将增加对 转移的细胞和分子基础，也可能导致新的 癌症治疗的方法。

DESCRIPTION: (Adapted from the investigator's abstract) Delineation of the molecular mechanisms of directed motility is important for understanding the processes of cancer metastasis and invasion. The processes underlying the migration of primary tumor cells to ectopic sites involve the reorganization of the actin cytoskeleton. Several factors that regulate changes in the actin cytoskeleton of motile cells have been identified, however, the signaling molecules that direct the de novo polymerization of actin and its ultimate spatial and dynamic organization need to be clarified. Several members of the Rho family of small GTPases (Rho, Rac and Cdc42) have been identified as key signal transducers that link cell surface receptors to the actin cytoskeleton. We aim to test the hypothesis that Rac and Cdc42 are important regulators of breast cancer cell metastasis. Our research plan involves general strategy of using molecular genetics approach in combination with cellular and biochemical techniques. The construction of stable transfectants of human and rat mammary carcinoma cells with dominant active, dominant negative, and effector domain mutations of Rac and Cdc42 will be performed. We will evaluate the effect of activating or inactivating Rac and Cdc42 on breast cancer metastasis. These transfectants will be characterized by cellular, biochemical, and histopathological analysis. The metastatic potential of the transfected breast cancer cells expressing mutant Rac and Cdc42 will be assessed following injection into rats (rat mammary carcinomas) and nude mice (human mammary carcinomas). This research is expected to establish Rac and/or Cdc42 as important mediators of cancer metastasis. Our long-term goal is to delineate the signaling cascades mediated by Rac and/or Cdc42 that underlie invasion and metastasis. Identifying such key regulators of directed migration is expected to increase knowledge of the cellular and molecular basis of metastasis and may also lead to novel approaches in cancer therapy.