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 liver regeneration, which results in hepatocellular carcinoma, one of the most common malignancies in the world. The hypothesis of the parent grant is that HGF, via c-met, regulates growth in the liver by inducing InsP3-mediated Ca2+ signals within the nucleus of hepatocytes. This FIRCA application would investigate whether this is a more general mechanism of action of receptor tyrosine kinases (RTKs) across a range of tissues. Specifically, the hypothesis of this FIRCA application is that the Epidermal Growth Factor receptor (EGFR), like c-met, regulates cell growth by inducing InsP3-mediated Ca2+ signals within the nucleus, and that this action of EGFR mediates cell proliferation in common malignancies. This hypothesis will be tested through the following specific aims: 1. whether and how the EGFR reaches the nucleus in common malignancies will be determined. We will test whether a sub-population of EGFRs in caveolae traffic to the nucleus. Intracellular movement of the receptor will be monitored by as well as by cell fractionation studies. Pathways identified in liver cells will be tested in cells derived from breast, lung, prostate, and colon cancers. 2. Whether and how EGF increases Ca2+ in the nucleus will be determined. Targeted InsP3 buffers will be used to determine whether EGF, like HGF, specifically induces InsP3 formation within the nucleus. RNA interference techniques will be used to compare PLC isoforms activated by EGF and HGF, and to determine whether these PLC isoforms vary among cell types. 3. The role of nuclear Ca2+ signals in EGF-induced cell growth will be determined. We will determine whether EGF-induced cell proliferation is disrupted by blocking either (a) movement of EGFR to the nucleus, (b) EGF-induced formation Ca2+ signals in the nucleus, or (c) activation of Ca2+-dependent proteins within the nucleus, such as CaMKII. 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 tumor growth. This research will be performed primarily at UFMG in Brazil in collaboration with Dawidson Gomes as an extension of Project 1 of NIH P01 DK57751.
Growth of cells within the liver and other organs is regulated by growth factors and their receptors, known as receptor tyrosine kinases. These studies will reveal how growth factors and their corresponding receptor tyrosine kinases control signaling within the cell nucleus, and identify the distinct role this signaling pathway may play in the abnormal growth that occurs in a wide variety of tumors.
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