|Ph.D Thesis||Department of Biology|
|Supervisor:||Prof. Neufeld Gera|
Lysyl oxidase related protein-1 (LOR-1) is a member of the lysyl-oxidases, which include lysyl oxidase (LO), lysyl oxidase-like protein (LOL), lysyl oxidase related proteins 1 and 2 (LOR-1 and LOR-2). LO is a copper-dependent enzyme that catalyses the formation of covalent cross-linkages between collagen monomers. However, the function of the other lysyl oxidases is less clear. We demonstrated a differential pattern of expression of the four oxidases in normal human tissues. The normal liver does not express LO, LOL, LOR-1 or LOR2 mRNA’s as determined by in-situ hybridization. However, in Wilson’s disease and in primary biliary cirrhosis, diseases characterized by copper accumulation, LOR-1 and LO were strongly expressed in hepatocytes and the expression was accompanied by collagen deposition around them. Such changes were not seen in liver fibrosis that is not associated with copper accumulation. Fibroblasts localized in fibrotic areas expressed the four lysyl oxidases regardless of the cause of fibrosis. We have found that LOR-1 can oxidize collagen type-I associated lysines, indicating that LOR-1 and LO probably cooperate to induce collagen polymerization between hepatocytes in Wilson’s disease. Furthermore, the copper chelator D-penicillamine, a drug that is used to treat Wilson’s disease, inhibited the activity of LOR-1. PF4, an angiogenesis inhibitor, also inhibited LOR-1 activity. LOR-1 also oxidized proteins of HepG2 cells, and strongly inhibited their proliferation, indicating that the LOR-1 over-expression seen in Wilson’s disease could contribute to the loss of liver function and fibrosis.
We also investigated another gene of the LO-family, the LOR-2. LOR-2 was found to be expressed in several melanoma cell-lines. In contrast, LOR-2 was not expressed in nevi derived melanocytes. A preliminary correlation was found between LOR-2 expression and collagen IV and laminin in malignant melanoma.