REGULATION OF CELL GROWTH BY NUCLEAR CALCIUM

$279,294P01FY2009DKNIH

Yale University, New Haven CT

Investigators

Linked publications & trials

Paper 38916955 Paper 35852334 Paper 35285892 Paper 35241781 Paper 34966448 Paper 34520633 Paper 34499766 Paper 34321341 Paper 34174909 Paper 34146542 Paper 33504822 Paper 33214166 Paper 33179019 Paper 32957029 Paper 32871457 Paper 32864536 Paper 32725890 Paper 32632005 Paper 32601203 Paper 32363317 Paper 32346964 Paper 32281947 Paper 32239615 Paper 32132708 Paper 31953394 Paper 31941974 Paper 31790953 Paper 31783290 Paper 31672932 Paper 31659121 Paper 31537645 Paper 31501520 Paper 31340446 Paper 31315944 Paper 31315892 Paper 31251815 Paper 31150626 Paper 31124786 Paper 31064883 Paper 30950790 Paper 30929953 Paper 30897078 Paper 30863489 Paper 30851876 Paper 30827936 Paper 30816253 Paper 30592625 Paper 30586711 Paper 30460472 Paper 30257990 Paper 30254023 Paper 30145376 Paper 30141207 Paper 30089263 Paper 30037904 Paper 29789326 Paper 29746899 Paper 29682902 Paper 29588368 Paper 29581527 Paper 29560416 Paper 29544874 Paper 29317435 Paper 29135333 Paper 29128158 Paper 29023819 Paper 28966992 Paper 28943284 Paper 28903979 Paper 28789925 Paper 28762163 Paper 28601384 Paper 28488703 Paper 28327356 Paper 28295353 Paper 28096466 Paper 27942593 Paper 27866221 Paper 27736153 Paper 27646831 Paper 27575489 Paper 27105115 Paper 27081851 Paper 26857659 Paper 26100660 Paper 25796361 Paper 25793639 Paper 25566193 Paper 25437447 Paper 25378392 Paper 25368166 Paper 25319894 Paper 25315698 Paper 25312648 Paper 25263013 Paper 25228769 Paper 24769077 Paper 24616106 Paper 24612866 Paper 24476518

Abstract

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.

View original record on NIH RePORTER →