REGULATION OF CELL GROWTH BY NUCLEAR CALCIUM

肝脏显示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 可导致再生调节受损，从而导致肝细胞癌， 世界上最常见的恶性肿瘤尽管这个话题的临床意义，基本问题 保持。生长因子通过激活受体酪氨酸激酶刺激肝再生， 增加细胞质和细胞核内的游离Ca 2+，但细胞质和细胞核Ca 2+在 肝脏生长的调节尚不清楚。然而，我们现在知道，细胞核和胞浆Ca2+的变化， + 在肝细胞中是由1，4，5-三磷酸肌醇（InsPS）介导，不同InsPS受体 细胞核内的InsPSR能够局部增加Ca2+。此外，核Ca2+是 对生长因子介导的基因表达很重要。基于这些发现，Nathanson的项目将测试 受体酪氨酸激酶通过诱导InsP3介导Ca~（2+）信号调节细胞生长的假说 在细胞核内。肝细胞生长因子（HGF）受体将被用作模型来测试这一点 假设通过三个具体目标： 1.将确定磷酸化HGF受体到达细胞核的机制。 2.细胞核HGF受体局部产生InsPS从而产生细胞核钙的机制 信号将被识别。 3.将检查核Ca 2+调节细胞生长的过程。 这些研究将揭示生长因子及其相应的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 肝脏的连同埃利希和班尼特的项目，这项工作应该提供一个综合的理解，如何 生长因子通过丝裂原活化蛋白激酶（MAPK）和MAPK特异性磷酸酶起作用， 通过细胞核内的Ca2+信号调节肝细胞的生长。

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.