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

信号转导子和转录激活子（STAT）蛋白调节细胞应答，所述细胞应答有助于人类和其他生物体（例如果蝇）中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发挥作用，以改变细胞表达的蛋白质的谱。STAT蛋白通过与细胞核中的DNA结合来做到这一点。在活化之前，STAT蛋白以非活性状态存在于细胞的细胞质中。当它们的独特受体在细胞质膜上受到刺激时，它们被激活。一旦激活，STAT蛋白进入细胞核以结合DNA并调节基因表达。 虽然最初认为活化的STAT蛋白在其活性期间留在细胞核中，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，在受体活化过程中，STAT蛋白在质膜上经历多轮活化，在细胞核中失活。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翻译成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）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。 这是一种小蛋白质，称为肽，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”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。我们的实验也将增加我们的基本机制的理解，这个家族的转录因子调节基因表达，并可能最终导致更好地了解这些蛋白质如何在正常和病理细胞反应的功能。

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.