Novel functions of nuclear receptor coactivator 4 at the mitotic apparatus

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Nuclear receptor coactivators are proteins that act in the cell to increase the action of various hormones and growth factors and therefore play an important role in regulating normal development. Nuclear receptor coactivator 4 (NcoA4) is an unusual coactivator that was initially thought to specifically enhance androgen action. Subsequently, it was found to enhance the action of several hormones and dioxins. Most coactivators act in the cell nucleus to increase the expression of genes that are targeted by hormone action. Consistent with this, NcoA4 is found in the cell nucleus; however, it is also found in the cytoplasm, suggesting it may act differently to enhance hormone action. Moreover, NcoA4 is conserved among animal species ranging from sea urchins to humans, which suggests that it may have additional actions not yet discovered. We have found that NcoA4 associates with subcellular structures and organelles within the cytoplasm that are associated with cell division. We have also found that NcoA4 associates with several key proteins that regulate the equal separation of DNA material to the two daughter cells during cell division and with structures that are involved in separating the two cells. We have identified potential sites on the NcoA4 protein that may be phosphorylated by aurora kinase, a principal enzyme involved in orchestrating cell division. Phosphorylation of proteins often alters their ability to interact with various proteins. Based on these novel findings, we hypothesize that NcoA4 is a target of aurora kinase and that the phosphorylation state of NcoA4 is a key determinant of its activity during mitosis and regulates its function as a nuclear receptor coactivator. The studies outlined in this proposal will identify NcoA4 actions thereby enhancing our understanding of the impact of its altered expression that has been reported in several cancers and pathologies.