ROLE OF SYNAPTOJANIN 2 IN MALIGNANT TRANSFORMATION

描述：（改编自研究者摘要）小型GTATRA Rac 1 是异常生长特性和入侵行为所必需的 转化细胞我们实验室的长期目标是阐明 由Rac 1控制的刺激细胞增殖的信号通路 和入侵。Rac 1调节许多细胞功能，这些功能可能 在恶性转化中发挥作用。这些包括抑制 受体介导的内吞作用和刺激片状伪足形成。 内吞作用有助于生长因子受体的下调， 已经显示抑制内吞运输可以增强细胞 增殖片状伪足被认为是重要的细胞运动。他 最近鉴定出磷脂酰肌醇5 '-磷酸酶synaptojanin 2为 一种新的Rac 1效应子。Synaptojanins参与了调节 受体介导的内吞作用和肌动蛋白的组织 细胞骨架，已知由磷脂酰肌醇调节的过程 新陈代谢. 本提案的总体目标是审查以下假设： synaptojanin 2在Rac 1下游调节细胞内吞 贩运和行动动态，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 Rac 1对synaptojanin 2的调控机制。在目标2中，他将 检查synaptojanin 2是否介导Rac 1对内吞作用的影响， 肌动蛋白细胞骨架动力学为了验证这些假设，他将使用两个不同的 反义策略来抑制突触连接蛋白2的表达。他将 作为补充，他将刺激细胞中synapotjanin 2的活性， 使用不依赖于Rac-1的synaptojanin 2的表达。在 目标3他将使用类似的策略来检验假设， synaptojanin 2在Rac 1下游调节细胞凋亡 扩散和入侵。 这些研究将有助于对肿瘤分子机制的认识。 确定synaptojanin 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.