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

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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.