REGULATION OF CELL GROWTH BY NUCLEAR CALCIUM

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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.