Nucleocytoplasmic shuttling of the stat-6 transcription factor and regulation of gene expression

信号转导和转录激活子(STAT)蛋白调节细胞反应，在人类和其他生物(如果蝇)中，这些反应有助于许多正常和病理过程。STAT蛋白通过改变特定基因的表达来改变细胞表达的蛋白质谱来发挥作用。STAT蛋白通过与细胞核中的DNA结合来实现这一点。在激活之前，STAT蛋白在细胞质中以不活跃的状态存在。当它们独特的受体在细胞质膜上受到刺激时，它们就会被激活。一旦被激活，STAT蛋白就会进入细胞核，以便与DNA结合并调节基因表达。虽然最初认为激活的STAT蛋白在其活动期间一直留在细胞核内，但越来越多的证据表明，它们实际上只在细胞核内停留了很短的时间。我们现在知道，在受体激活的过程中，STAT蛋白在质膜上经历了多轮激活，在细胞核中经历了多轮失活。这种进出细胞核的循环被认为允许STAT蛋白将质膜上的受体激活事件转化为细胞核中适当的基因表达反应。我们正在研究这种核质穿梭调节STAT家族成员(称为STAT-6)在细胞核中诱导基因表达的能力的机制。我们的研究将受益于我们开发的一种独特的工具，该工具可以抑制STAT-6。这是一种被称为多肽的小蛋白，它可以进入细胞，与STAT-6结合并抑制STAT-6。我们的初步数据表明，这种抑制剂有效地“捕获”激活的STAT-6，阻止它在细胞核和细胞质之间循环。因此，我们将在我们的实验中使用STAT-6抑制肽来了解STAT-6的核质穿梭如何调节其诱导靶基因表达的能力。我们的实验还将增加我们对这一转录因子家族调控基因表达的基本机制的理解，并最终可能导致更好地理解这些蛋白质在正常和病理细胞反应中的功能。

Signal transducer and activator of transcription (STAT) proteins regulate cellular responses that contribute to numerous processes, both normal and pathologic, in humans and other organisms, such as fruit flies. STAT proteins function by altering the expression of specific genes in order to modify the profile of proteins that a cell expresses. STAT proteins do this by binding to DNA in the nucleus. Prior to activation, the STAT proteins are present in an inactive state in the cytoplasm of a cell. They are activated when their unique receptors are stimulated at the plasma membrane of the cell. Once activated, STAT proteins go to the nucleus in order to bind to DNA and modulate gene expression. While it was thought originally that activated STAT proteins remained in the nucleus for the duration of their activity, increasing evidence indicates that they actually stay in the nucleus only a very short time. We now know that during the course of receptor activation, STAT proteins undergo multiple rounds of activation at the plasma membrane and inactivation in the nucleus. This cycling in and out of the nucleus is thought to allow STAT proteins to translate receptor activation events at the plasma membrane into appropriate gene expression responses in the nucleus. We are investigating the mechanism by which this nucleocytoplasmic shuttling regulates the ability of a STAT family member (called STAT-6) to induce expression of genes in the nucleus. Our studies will benefit from a unique tool that we have developed to inhibit STAT-6. This is a small protein, called a peptide, which can enter cells, and bind to and inhibit STAT-6. Our preliminary data suggest that this inhibitor effectively "traps" activated STAT-6, preventing it from cycling between the nucleus and the cytoplasm. Thus, we will use the STAT-6 inhibitory peptide in our experiments to understand how nucleocytoplasmic shuttling of STAT-6 regulates its ability to induce expression of target genes. Our experiments will also increase our understanding of the basic mechanisms by which this family of transcription factors regulates gene expression and may ultimately lead to a better understanding of how these proteins function in both normal and pathologic cellular responses.