Humoral hypercalcemia of malignancy is a common paraneoplastic syndrome. The peptide factor or factors mediating this syndrome has not been previously identified. The two most active hypotheses at present are that the factor in question is a parathyroid hormone-like peptide or a growth factor-peptide. In ongoing studies, we have 1) fully characterized a number of animal models of the humoral syndrome and have identified a similar factor as a secretary product of normal keratinocytes, 2) purified and sequenced peptides from a human and a rat tumor, with the human tumor peptide revealing an aminoterminal region of striking homology to human parathyroid hormone, 3) constructed a cDNA library from a renal human carcinoma mRNA, and 4) begun to study the actions of the tumor-derived peptide at the level of its two key target tissues, bone and kidney. The principle goals of the present proposal include: 1) to continue our purification and sequencing efforts using tumors from humans and several other species, 2) to develop polyclonal and monoclonal antibodies to the human and rat peptides, 3) to identify and sequence a fulllength cDNA and initiate a broad range of molecular projects, and 4) to expand and refine out studies of the factor's actions on bone and renal cells.