Novel functions of nuclear receptor coactivator 4 at the mitotic apparatus

核受体辅活化子是一种作用于细胞内的蛋白质，能增加各种激素和生长因子的作用，因此在调节正常发育中起着重要作用。核受体辅活化子4(NcoA4)是一种不寻常的辅活化子，最初被认为能特异性地增强雄激素的作用。随后，发现了几种激素和二恶英的增强作用。大多数共激活因子作用于细胞核，以增加荷尔蒙作用所针对的基因的表达。与此一致的是，NcoA4在细胞核中被发现；然而，它也在细胞质中被发现，这表明它在增强激素作用方面可能有不同的作用。此外，NcoA4在从海胆到人类的各种动物中都是保守的，这表明它可能还有其他尚未被发现的作用。我们发现NcoA4与细胞质中与细胞分裂相关的亚细胞结构和细胞器有关。我们还发现，NcoA4与几个关键蛋白质有关，这些蛋白质调节着细胞分裂过程中两个子细胞的DNA物质的平等分离，以及参与分离两个细胞的结构。我们已经确定了NcoA4蛋白上可能被极光激酶磷酸化的潜在位置，极光激酶是参与协调细胞分裂的主要酶。蛋白质的磷酸化通常会改变它们与各种蛋白质相互作用的能力。基于这些新的发现，我们假设NcoA4是极光激酶的靶标，并且NcoA4的磷酸化状态是其在有丝分裂过程中活性的关键决定因素，并调节其作为核受体辅助激活因子的功能。这项提案中概述的研究将确定NcoA4的作用，从而增强我们对其改变表达的影响的理解，据报道，它在几种癌症和病理中的影响。

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.