ROLE OF SYNAPTOJANIN 2 IN MALIGNANT TRANSFORMATION

描述：(改编自研究人员的摘要)小GTP酶rac1 对沙门氏菌的异常生长特性和入侵行为至关重要 转化的细胞。我们实验室的长期目标是阐明 由rac1调控的刺激细胞增殖的信号通路 和入侵。Rac1调节许多细胞功能，这些功能很可能 在恶变过程中发挥作用。这些措施包括抑制 受体介导的内吞作用和片状脂体形成的刺激。 内吞作用有助于下调生长因子受体和 抑制内皮细胞的转运已被证明能增强细胞 扩散。片状脂体被认为对细胞的运动很重要。他 最近鉴定出磷脂酰肌醇5‘-磷酸酶突触素2为 一种新型的rac1效应器。Synaptojanins被卷入了这一调控 受体介导的内吞作用和肌动蛋白的组织 细胞骨架，已知受磷脂酰肌醇调节的过程 新陈代谢。 这项提议的总体目标是检验这样一个假设 突触素2在rac1下游调控细胞内的作用 贩运和肌动蛋白动态，而这些功能反过来又有助于 细胞转化和侵袭。在目标1中，他将研究分子 Rac1对突触素2的调节机制。在《目标2》中，他将 检测突触素2是否介导了rac1对内吞作用的影响 肌动蛋白细胞骨架动力学。为了检验这些假设，他将使用两个截然不同的 反义策略抑制突触素2的表达。他将 补充这一途径，他将刺激细胞中突触素2的活性 使用RAC-1非依赖的突触素2版本的表达。在……里面 目标3他将使用类似的策略来检验假设 突触素2在细胞调节中的作用 扩散和侵袭。 这些研究将有助于对癌症分子的理解。 确定突触素2在调节任一细胞中的作用 转化或侵袭将为癌症治疗提供新的途径。

DESCRIPTION: (Adapted from the investigator's abstract) The small GTPase Rac1 is essential for the aberrant growth properties and invasive behavior of transformed cells. The long term goals of our laboratory are to elucidate the signaling pathways that are governed by Rac1 to stimulate cell proliferation and invasion. Rac1 regulates a number of cellular functions that are likely to play a role in malignant transformation. These include the inhibition of receptor-mediated endocytosis and the stimulation of lamellipodia formation. Endocytosis contributes to the down-regulation of growth factor receptors and inhibition of endocytic trafficking has been shown to enhance cell proliferation. Lamellipodia are thought to be important for cell motility. He recently identified the phosphatidylinositol 5'-phosphastase synaptojanin 2 as a novel effector of Rac1. Synaptojanins have been implicated in the regulation of receptor-mediated endocytosis and the organization of the actin cytoskeleton, processes that are known to by modulated by phosphatidylinositol metabolism. The overall objective of this proposal is to examine the hypothesis that synaptojanin 2 functions downstream of Rac1 in the regulation of endocytic trafficking and actin dynamics and that these functions in turn contribute to cell transformation and invasion. In Aim 1 he will study the molecular mechanisms of the regulation of synaptojanin 2 by Rac1. In Aim 2 he will examine whether synaptojanin 2 mediates the effects of Rac1 on endocytosis and actin cytoskeleton dynamics. To test these hypothesis, he will use two distinct antisense strategies to inhibit expression of synaptorjanin 2. He will complement this approach, he will stimulate synapotjanin 2 activity in cells using expression of a version of synaptojanin 2 that is Rac-1 independent. In Aim 3 he will use similar strategies to examine the hypothesis that synaptojanin 2 functions downstream of Rac1 in the regulation of cell proliferation and invasion. These studies will contribute to the understanding of the molecular of cancer. Identifying a role for synaptojanin 2 in the regulation of either cell transformation or invasion would suggest novel avenues for cancer therapy.