Regulation of cell transformation

在心脏发育期间，瓣膜祖细胞响应于心肌和内皮之间的TGF β介导的组织相互作用而从心脏内皮发育。内皮细胞的这种“上皮-间充质细胞转化”也被假定是由于“主基因”的调节，ECM或其受体变化的结果，或内皮细胞的细胞-细胞粘附的丧失。虽然这些假设的每个方面都可能涉及，但内皮细胞的粘附。虽然这些假设中的每一个方面都可能涉及，但本实验室获得的数据表明，在细胞转化过程中发生了复杂的调控过程。我们推测上皮细胞向间充质细胞转化是多种转录因子通过不同的信号转导途径协同调控的结果。为了探讨这个假设，我们将集中在两个关键事件的调节。第一种是以细胞形态变化为特征的活化过程，第二种是以细胞形态变化为特征的活化过程，第二种是细胞侵入下层ECM的过程。这些事件似乎与两种特异性转录因子Slug和Mox-1相关。Slug在细胞活化过程的早期起作用，而Mox-1在细胞侵袭期间起作用。在心脏中发现的第三种转录因子Snail将被研究，因为它可能与Slug具有冗余活性。我们以前表明，几个不同的转导途径介导内皮细胞的转化刺激的反应。下一阶段的工作是将信号转导与特定的基因调控联系起来。我们将使用各种试剂来确定Mox-1和Slug是否通过诱导刺激并行或串行调节。具体目标是：1。通过各种信号通路扩展表征内皮细胞和间充质细胞中的Mox-1和Slug调节。2.确定Mox 1和Slug上游序列中的启动子/增强子元件，介导对特定信号转导途径的反应。3.测试Smads通过TGF β参与Slug或Mox 1调节细胞转化时间。总之，这些目标将进一步表征心脏细胞发育的基本过程。

During cardiac development, valvular progenitors develop from cardiac endothelium in response to a TGFbeta-mediated tissue interaction between the myocardium and the endothelium. This "epithelial- mesenchymal cell transformation" of endothelial cells has been alternatively postulated to be due to the regulation of a "master gene", the result of changes in ECM or its receptors, or the loss of cell-cell adhesion by endothelial cells. While aspects of each of these hypotheses are likely to be involved, adhesion by endothelial cells. While aspects of each of these hypotheses are likely to be involved, data obtained in this laboratory suggest that a complex regulatory process takes place during cell transformation. It is our hypothesis that epithelial-mesenchymal cell transformation is the result of coordinate regulation of several transcription factors by different signal transduction pathways. To explore this hypothesize we will focus on the regulation of two critical events. The first is an activation process characterized by a change in cell morphology and the second is a process is an activation process characterized by a change in cell morphology and the second is a process wherein cells invade the underlying ECM. These events appear to correlate with two specific transcription factors, Slug and Mox-1. Slug functions early in the cell activation process while Mox-1 functions during cellular invasion. A third transcription factor found in the heart, Snail, will be investigated as it may have a redundant activity with Slug. We previously showed that several distinct transduction pathways mediate endothelial responses to the transforming stimulus. The next phase of the work is to link signal transduction with specific gene regulation. We will use a variety of reagents to determine whether Mox-1 and Slug are regulated in parallel or in serial by the inductive stimulus. Specific aims are: 1. Extend characterizing of Mox-1 and Slug regulation in endothelial and mesenchymal cells by various signal pathways. 2. Identify promoter/enhancer elements in Mox1 and Slug upstream sequences that mediate responses to specific signal transduction pathways. 3. Test involvement of Smads in the regulation of Slug, or Mox1 via a TGFbeta the time of cell transformation. Together, these aims will further the characterization of the fundamental process of cell development in the heart.