The broad goal of this research is to define the role of platelet derived growth factor (PDGF) in the regulation of growth of normal and transformed cells. The proposal has three aims: (1) To define the structures and the structure-function relationships of the A and B chains of PDGF and the related gene products p28?c-sis? and p28?v-sis?, with respect to receptor-binding activity and mitogenic activity. PDGF will be isolated from human platelets, p28?c-sis? from human osteosarcoma cells, and p28?v-sis? from simian sarcoma virus-infected NRK cells. Mitogenic activity and receptor-binding activity will be measured in NIH 3T3 mouse cells and human smooth muscle cells. (2) To isolate and characterize the PDGF receptor from mouse 3T3 cells, and to study its biochemistry and biological function in normal and transformed cells. Isolation of large amounts of receptor will permit preparation of polyclonal and monoclonal anti-bodies to the receptor, characterization of the tyrosine specific protein kinase activity of the receptor, and studies of the biosynthesis and degradation of the receptor in normal and transformed cells. (3) To study the relationship between the production and secretion of p28?csis? and p28?v-sis? and tumorigenicity in transformed cells which express these gene products. The gene products will be measured by radioimmunoassay and assay of mitogenic activity, and tumorigenicity measured by production of tumors following injection of transformed cells into nude mice. The effect of infused antibody to human PDGF on the production of tumors by injected transformed cells will also be examined. These studies should provide insight into the role of PDGF in the regulation of normal cell growth and may help understand the alterations in this growth regulation that lead to some forms of cancer. (J)
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