权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Mechanisms of TGFbeta-mediated fibroblastic transition

TGFβ介导的成纤维细胞转变机制

基本信息

批准号：
7007274
负责人：
Andrei V. Bakin
金额：
$ 33.01万
依托单位：
ROSWELL PARK CANCER INSTITUTE CORP
依托单位国家：
美国
项目类别：
财政年份：
2003
资助国家：
美国
起止时间：
2003-02-03 至 2008-01-31
项目状态：
已结题

项目摘要

The transforming growth factor beta (TGFbeta) family of secreted factors play important role(s) in development, homeostasis and functioning of biological systems. A number of human diseases are associated with abnormal operation of the TGFbeta signaling network. TGFbeta exhibits a tumor suppressor activity and components of its signaling pathway are frequently mutated or silenced in cancers. However, TGFbeta contributes to the progression and invasiveness of tumors by stimulating an epithelial to mesenchymal transition (EMT) and cell migration. EMT is a complex process associated with alterations in epithelial cell contacts, changes in cell morphology, reorganization of the cell cytoskeleton, expression of fibroblastic markers (fibronectin, vimentin) and enhancement of cell migration. These effects of TGFbeta are also involved in wound repair and fibrosis of various tissues. The mechanism(s) of TGFbeta-induced EMT and cell migration are not well understood. We made the important observation that TGFbeta- mediated EMT and cell migration are impaired by inhibitors of p38 mitogen activated protein kinase (p38Mapk), without inhibition of the antiproliferative activity of TGFbeta. Thus, the p38Mapk pathway may play a critical role in TGFbeta's tumor promoting activity. We also observed that p38Mapk activation is mediated by Rho-family GTPases. The mechanism by which TGFbeta signals to Rho-like GTPases and p38Mapk has not yet been defined. We hypothesize that activation of the p38Mapk pathway by kinase- active TGFbeta receptors mediated by Rho-family GTPases is required for setting up a program of changes in the cell phenotype leading to TGFbeta-induced fibroblastic transition and cell migration. This hypothesis will be tested by the following specific aims. Aim 1: To examine the role of kinase function of TGFbeta receptors in activation of Rho-like GTPases and the p38Mapk pathway. Aim 2: To examine in vitro the effect of dominant negative and constitutively active mutants of MKK3 and MKK6, p38Mapk activating kinases, on the TGFbeta-induced EMT and cell migration. Aim 3: To evaluate the role of the p38Mapk pathway in tumor cell motility, invasiveness and metastasis in mouse models. The proposed research will help to define the TGFbeta signaling network and will facilitate the design of novel selective inhibition of TGFbeta's tumor promoting activity.

分泌因子的转化生长因子β（TGF β）家族在生物系统的发育、稳态和功能中起重要作用。许多人类疾病与TGF β信号网络的异常操作有关。 TGF β表现出肿瘤抑制活性，并且其信号传导途径的组分在癌症中经常突变或沉默。然而，TGF β通过刺激上皮向间质转化（EMT）和细胞迁移而促进肿瘤的进展和侵袭。EMT是与上皮细胞接触的改变、细胞形态的改变、细胞骨架的重组、成纤维细胞标志物（纤连蛋白、波形蛋白）的表达和细胞迁移的增强相关的复杂过程。 TGF β的这些作用也涉及各种组织的伤口修复和纤维化。 TGF β诱导的EMT和细胞迁移的机制还不清楚。我们发现了一个重要的观察结果，即TGF β介导的EMT和细胞迁移受到p38有丝分裂原激活蛋白激酶（p38 Mapk）抑制剂的损害，而不抑制TGF β的抗增殖活性。因此，p38Mapk通路可能在TGF β的肿瘤促进活性中起关键作用。我们还观察到p38Mapk的激活是由Rho家族的GTP酶介导的。 TGF β信号传导至Rho样GTP酶和p38Mapk的机制尚未确定。我们假设，由Rho家族GTP酶介导的激酶活性TGF β受体激活p38 Mapk通路是建立细胞表型变化程序所必需的，导致TGF β诱导的成纤维细胞转化和细胞迁移。这一假设将通过以下具体目标进行检验。目的1：研究TGF β受体激酶功能在Rho样GTP酶和p38Mapk通路中的作用。目标二：在体外检测MKK 3和MKK 6的显性失活和组成型激活突变体p38Mapk激活激酶对TGF β诱导的EMT和细胞迁移的影响。目的3：探讨p38Mapk信号通路在肿瘤细胞运动、侵袭和转移中的作用。这项研究将有助于确定TGF β信号网络，并有助于设计新的选择性抑制TGF β促肿瘤活性的方法。