Novel functions of nuclear receptor coactivator 4 at the mitotic apparatus

核受体辅激活因子4在有丝分裂装置中的新功能

• 批准号: 312475-2011
• 负责人: Brown, Theodore
• 金额: $ 2.19万
• 依托单位: University of Toronto
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2013
• 资助国家: 加拿大
• 起止时间: 2013-01-01 至 2014-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=526528
• 关键词: Novel; functions; nuclear; receptor; coactivator

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.

核受体辅激活因子是在细胞中起作用以增加各种激素和生长因子的作用的蛋白质，因此在调节正常发育中起重要作用。核受体辅激活因子4（NcoA 4）是一种不寻常的辅激活因子，最初被认为是特异性增强雄激素作用。 随后，人们发现它可以增强几种激素和二恶英的作用。 大多数辅激活因子在细胞核中起作用，以增加激素作用靶向的基因的表达。 与此一致，NcoA 4存在于细胞核中;然而，它也存在于细胞质中，这表明它可能以不同的方式增强激素作用。 此外，NcoA 4在从海胆到人类的动物物种中是保守的，这表明它可能具有尚未发现的其他作用。 我们已经发现NcoA 4与细胞质内的亚细胞结构和细胞器相关，这些结构和细胞器与细胞分裂相关。 我们还发现，NcoA 4与几种关键蛋白相关，这些蛋白在细胞分裂期间调节DNA物质与两个子细胞的相等分离，并与参与分离两个细胞的结构相关。 我们已经确定了NcoA 4蛋白上可能被极光激酶磷酸化的潜在位点，极光激酶是参与协调细胞分裂的主要酶。 蛋白质的磷酸化常常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NcoA 4是极光激酶的靶点，NcoA 4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激活剂的功能。本提案中概述的研究将确定NcoA 4的作用，从而增强我们对其在几种癌症和病理学中报告的表达改变的影响的理解。