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

信号换能器和转录激活器（STAT）蛋白调节细胞反应，促进人类和其他生物（如果蝇）的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。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蛋白在细胞的细胞质中以无活性状态存在。当它们独特的受体在细胞膜上受到刺激时，它们就会被激活。一旦被激活，STAT蛋白就会进入细胞核，与DNA结合并调节基因表达。虽然最初认为活化的STAT蛋白在其活动期间会留在细胞核中，但越来越多的证据表明，它们实际上只在细胞核中停留很短的时间。我们现在知道，在受体激活过程中，STAT蛋白在质膜处经历多轮激活，在细胞核内经历多轮失活。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细胞质穿梭调节STAT家族成员（称为STAT-6）诱导细胞核中基因表达的能力的机制。我们的研究将受益于我们开发的抑制STAT-6的独特工具。这是一种叫做肽的小蛋白质，它可以进入细胞，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”活化的STAT-6，阻止其在细胞核和细胞质之间循环。因此，我们将在实验中使用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。我们的实验也将增加我们对转录因子家族调节基因表达的基本机制的理解，并可能最终导致更好地理解这些蛋白质在正常和病理细胞反应中的作用。

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.