title: Synthetic and partially-purified adenylate cyclase-stimulating proteins from tumors associated with humoral hypercalcemia of malignancy inhibit phosphate transport in a PTH-responsive renal cell line.
abstract: Hypophosphatemia and hyperphosphaturia characteristically occur in patients with humoral hypercalcemia of malignancy (HHM). To determine if a tumor product causes these abnormalities in phosphate metabolism, rather than, for example, hypercalcemia, we investigated the effect of partially-purified adenylate cyclase-stimulating activity (ACSA) from human and animal HHM-associated tumors on sodium-dependent phosphate transport (Na PiT) in a PTH-responsive renal epithelial cell line. Thirty minute exposure to 7 X 10(-10) MbPTH (1-34) equivalents of ACSA from the human and animal tumors, reduced NaPiT by 20% and 14%, respectively. We also recently isolated an adenylate cyclase-stimulating protein (hACSP) from two human tumors associated with HHM and identified a cDNA clone for this protein which encodes a 141 amino-acid peptide. Based on the deduced amino-acid sequence, we synthesized tyr36 (1-36) hACSP. This synthetic peptide induced a 22% decrease in the initial rate of NaPiT by the epithelial monolayer. Its inhibitory activity was roughly equipotent to that of bPTH (1-34). We conclude that the ACSP derived from HHM-associated tumors decreases phosphate transport in renal epithelial cells. This peptide appears to play a key role in mediating the changes in phosphate metabolism in this syndrome.
authors.affiliation: Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut 06510.
authors.forename: L
authors.initials: L
authors.lastname: Sartori
authors.forename: E C
authors.initials: EC
authors.lastname: Weir
authors.forename: A F
authors.initials: AF
authors.lastname: Stewart
authors.forename: A E
authors.initials: AE
authors.lastname: Broadus
authors.forename: M
authors.initials: M
authors.lastname: Mangin
authors.forename: P Q
authors.initials: PQ
authors.lastname: Barrett
authors.forename: K L
authors.initials: KL
authors.lastname: Insogna
mesh_terms: D000262:Adenylyl Cyclases / Q000378:metabolism*; D000818:Animals; D001692:Biological Transport; D002460:Cell Line; D004305:Dose-Response Relationship, Drug; D006801:Humans; D006934:Hypercalcemia / Q000201:enzymology*; D007668:Kidney / Q000187:drug effects* / Q000378:metabolism; D007984:Leydig Cell Tumor / Q000201:enzymology; D009893:Opossums; D010281:Parathyroid Hormone / Q000494:pharmacology*; D010710:Phosphates / Q000378:metabolism*; D012964:Sodium / Q000378:metabolism
chemical_list: D010281:Parathyroid Hormone; D010710:Phosphates; D012964:Sodium; D000262:Adenylyl Cyclases