Novel functions of nuclear receptor coactivator 4 at the mitotic apparatus

核受体共激活因子是在细胞内增强各种激素和生长因子作用的蛋白质，在调节正常发育中起重要作用。核受体辅助激活因子4 （NcoA4）是一种不寻常的辅助激活因子，最初被认为能特异性增强雄激素的作用。随后，人们发现它能增强几种激素和二恶英的作用。大多数共激活因子在细胞核中起作用，以增加激素作用的目标基因的表达。与此一致的是，NcoA4存在于细胞核中；然而，在细胞质中也发现了它，这表明它可能以不同的方式增强激素的作用。此外，NcoA4在从海胆到人类的动物物种中都是保守的，这表明它可能还有其他尚未发现的作用。我们发现NcoA4与细胞质内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与几个关键蛋白相关，这些蛋白在细胞分裂过程中调节DNA物质向两个子细胞的相等分离，并与分离两个细胞的结构相关。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点，极光激酶是一种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。基于这些新发现，我们假设NcoA4是极光激酶的靶标，NcoA4的磷酸化状态是其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。本提案中概述的研究将确定NcoA4的作用，从而增强我们对其在几种癌症和病理中已报道的表达改变的影响的理解。

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.