REGULATION OF CELL GROWTH BY NUCLEAR CALCIUM

核钙对细胞生长的调节

• 批准号: 7137082
• 负责人: MICHAEL H NATHANSON
• 金额: $ 21.86万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-05-01 至 2011-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7137082
• 关键词: calcium flux; calcium indicator; calcium ion; cell component structure /function; cell cycle; cell growth regulation; cell line; cell nucleus; chelating agents; confocal scanning microscopy; cytoplasm; flash photolysis; hepatocyte growth factor; hormone regulation /control mechanism; immunocytochemistry; inositol phosphates; intermolecular interaction; laboratory rat; liver cells; microinjections; peptide hormone; protein isoforms; protein localization; protein structure function; receptor; receptor expression; tissue /cell culture

The liver displays a unique ability to grow and regenerate. For example, complete hepatic regeneration occurs within days to weeks after two-thirds of the liver has been resected. Chronic hepatocellular damage can lead to impaired regulation of regeneration, which results in hepatocellular carcinoma, one of the most common malignancies in the world. Despite the clinical significance of this topic, fundamental questions remain. Growth factors stimulate liver regeneration by activation of receptor tyrosine kinases, which in turn increases free Ca2+ within the cytosol and nucleus, but the relative role of cytosolic and nuclear Ca2+ in the regulation of liver growth is unclear. However, we now know that changes in both nuclear and cytosolic Ca2 + in hepatocytes are mediated by inositol 1,4,5-trisphosphate (InsPS), and that distinct InsPS receptors (InsPSRs) within the nucleus are capable of locally increasing Ca2+. Furthermore, nuclear Ca2+ is important for growth factor-mediated gene expression. Based on these findings, Project by Nathanson will test the hypothesis that receptor tyrosine kinases regulate cell growth by inducing lnsP3-mediated Ca2+ signals within the nucleus. The hepatocyte growth factor (HGF) receptor will be used as a model to test this hypothesis through three specific aims: 1. The mechanism by which the phosphorylated HGF receptor reaches the nucleus will be determined. 2. The mechanism by which the nuclear HGF receptor locally generates InsPS and thus nuclear calcium signals will be identified. 3. The process through which nuclear Ca2+ regulates cell growth will be examined. These studies will reveal how growth factors and their corresponding receptor tyrosine kinases control nuclear Ca2+ in intact cells, and identify the distinct role this may play in regulating the growth and function of the liver. Together with Projects by Ehrlich and Bennett, this work should provide an integrated understanding of how growth factors act through mitogen-activated protein kinase (MAPK) and MAPK-specific phosphatases to regulate the growth of hepatocytes through Ca2+ signaling within the nucleus.

肝脏表现出独特的生长和再生能力。例如，完全肝再生 发生在三分之二的肝脏被切除后的几天到几周内。慢性肝细胞损伤 可能导致再生调节受损，从而导致肝细胞癌，这是最常见的癌症之一 世界上常见的恶性肿瘤。尽管这个主题具有临床意义，但基本问题 保持。生长因子通过激活受体酪氨酸激酶来刺激肝脏再生，从而反过来 增加细胞质和细胞核内的游离 Ca2+，但细胞质和细胞核 Ca2+ 的相对作用 肝脏生长的调节尚不清楚。然而，我们现在知道细胞核和细胞质 Ca2 的变化 + 肝细胞中的 + 由肌醇 1,4,5-三磷酸 (InsPS) 介导，并且不同的 InsPS 受体 细胞核内的 (InsPSR) 能够局部增加 Ca2+。此外，核Ca2+是 对于生长因子介导的基因表达很重要。基于这些发现，Nathanson 项目将测试 假设受体酪氨酸激酶通过诱导 lnsP3 介导的 Ca2+ 信号来调节细胞生长 核内。肝细胞生长因子（HGF）受体将被用作模型来测试这一点 通过三个具体目标的假设： 1.确定磷酸化HGF受体到达细胞核的机制。 2. 核HGF受体局部产生InsPS进而产生核钙的机制 信号将被识别。 3. 将检查核Ca2+调节细胞生长的过程。 这些研究将揭示生长因子及其相应受体酪氨酸激酶如何控制 完整细胞中的核 Ca2+，并确定其在调节生长和功能中可能发挥的独特作用 肝脏的。与埃利希和贝内特的项目一起，这项工作应该提供对如何 生长因子通过丝裂原激活蛋白激酶 (MAPK) 和 MAPK 特异性磷酸酶发挥作用， 通过细胞核内的 Ca2+ 信号传导调节肝细胞的生长。