We have isolated and characterized a human gene that is located at the D3F15S2 locus on human chromosome 3 (3p21), a region believed to code for one or more tumor suppressor genes since this region is deleted in DNA from small cell lung carcinomas, renal carcinomas and other forms of cancer. The corresponding cDNA for our recently discovered gene codes for a protein with a domain structure similar to hepatocyte growth factor (HGF) in that it contains four kringle domains followed by a serine protease-like domain. Based on this similarity we have called the protein encoded by our cDNA """"""""HGF-like protein"""""""". HGF itself can act as either a growth factor, morphogen, a tumor suppressor or a scatter factor depending on the target tissue or cell type. However, the biological activities of our newly discovered HGF-like protein remain to be determined. We have extensively characterized the human and mouse genes and cDNAs coding for HGF-like protein. We have determined that the major site of synthesis of this protein is in the liver and is specifically localized to hepatocytes. This is in contrast to HGF which is expressed in a broad range of tissues and is localized to the fat storage cells in the liver. Recently we noted that the amino acid sequence of HGF-like protein is almost identical to the partial amino acid sequence determined for macrophage stimulating protein (MSP). Based on the fact that HGF-like protein is expressed primarily in hepatocytes and based on its similarity to a known growth factor and MSP, we hypothesize that HGF-like protein is a liver-specific growth factor that may be involved in the development, differentiation and/or regulation of growth of the liver and plays an important role in inflammation acting as a cytokine to macrophages. We will test HGF-like protein for growth factor or growth inhibitory activity by measuring the stimulation or inhibition of DNA synthesis in primary rat hepatocytes, as well as, cell lines derived from hepatocarcinomas. Mitogenic, comitogenic of growth inhibitory activity by measuring the stimulation or inhibiting of DNA synthesis in primary rat hepatocytes, as well as, cell lines derived from hepatocarcinomas. Mitogenic, comitogenic of growth inhibitory activity will be determined in conjunction with other known modulators of DNA synthesis in primary rat hepatocytes. HGF-like protein will be tested in a similar manner on tissue macrophages as well as other cell lines since it has a secreted protein that may have growth promoting or growth inhibitory effects on other systems. We will determine whether HGF-like protein has the same properties as MSP with respect to tissue macrophages from different sources. We will determine whether changes in expression of the mRNA coding for HGF-like proteins occurs during liver regeneration induced by hepatotoxins and during the inflammatory response induced by treatment with turpentine or thioglycolate as a test for an in vivo function for this protein. We also propose to identify additional cell populations that synthesize HGF- like protein which could give us insight into other potential biological functions for this protein that can be addressed in future experiments.
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