REGULATORY ROLE OF RAC AND CDC42 ON TUMOR METASTASIS

描述：（改编自研究者摘要） 定向运动的分子机制对于理解 癌症转移和侵袭的过程。这些进程的基础是 原发性肿瘤细胞向异位部位的迁移涉及 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确定，然而，信号传导 这些分子指导肌动蛋白的重新聚合， 需要明确空间和动态组织。的几名成员 Rho家族的小GTP酶（Rho、Rac和Cdc 42）已被鉴定为关键的 将细胞表面受体连接到肌动蛋白细胞骨架的信号传导器。 我们的目的是测试假设，Rac和Cdc 42是重要的调节因子， 乳腺癌细胞转移。 我们的研究计划包括使用分子遗传学的总体策略 方法结合细胞和生物化学技术。的 人和大鼠乳腺癌细胞稳定转染子的构建 Rac的显性活性、显性阴性和效应子结构域突变 将执行Cdc 42。我们将评估激活或 失活Rac和Cdc 42对乳腺癌转移的影响。这些转染子 将通过细胞、生物化学和组织病理学分析来表征。 转染人乳腺癌细胞株的转移潜能 将突变体Rac和Cdc 42注射到大鼠（大鼠 乳腺癌）和裸鼠（人乳腺癌）。 这项研究有望确立Rac和/或Cdc 42作为重要的介导因子 癌症转移的可能性我们的长期目标是描绘信号级联 由Rac和/或Cdc 42介导，是侵袭和转移的基础。识别 这些定向迁移的关键调节者预计将增加对以下方面的了解： 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.