TY - JOUR
T1 - Identification of adenylate cyclase-stimulating activity and cytochemical glucose-6-phosphate dehydrogenase-stimulating activity in extracts of tumors from patients with humoral hypercalcemia of malignancy
AU - Stewart, A. F.
AU - Insogna, K. L.
AU - Goltzman, D.
AU - Broadus, A. E.
PY - 1983
Y1 - 1983
N2 - Humoral hypercalcemia of malignancy (HHM) most commonly results from secretion by tumors of an unidentified circulating calcemic factor that appears in clinical studies to stimulate both a parathyroid hormone (PTH)-sensitive proximal tubular adenylate cyclase and a distinct PTH-sensitive renal tubular glucose-6-phosphate dehydrogenase complex. In the present study, 8 M urea extracts of tumors from patients with HHM have been shown to contain both in vitro adenylate cyclase-stimulating activity and glucose-6-phosphate dehydrogenase-stimulating activity as detected in a sensitive cytochemical bioassay. Both the adenylate cyclase-stimulating activity and cytochemical bioactivity are due to specific binding of a substance in the tumor extracts to renal PTH receptors, as demonstrated by competitive inhibition studies, using the bovine PTH fragment analogue [Nle(8,18), Tyr34]bPTH-(3-34) amide. Preincubation with an antiserum to PTH results in no loss of activity in the tumor extract, and the activity appears both on gel filtration and ultrafiltration to be far larger than PTH (estimated M(r) 70,000). These studies demonstrate that extracts of tumors from patients with HHM contain a substance that binds to PTH receptors in the nephron responsible for activation of both the PTH-sensitive glucose-6-phosphate dehydrogenase and the PTH-sensitive adenylate cyclase. This substance is chromatographically and immunologically distinct from PTH. Its role in the genesis of HHM requires further study.
AB - Humoral hypercalcemia of malignancy (HHM) most commonly results from secretion by tumors of an unidentified circulating calcemic factor that appears in clinical studies to stimulate both a parathyroid hormone (PTH)-sensitive proximal tubular adenylate cyclase and a distinct PTH-sensitive renal tubular glucose-6-phosphate dehydrogenase complex. In the present study, 8 M urea extracts of tumors from patients with HHM have been shown to contain both in vitro adenylate cyclase-stimulating activity and glucose-6-phosphate dehydrogenase-stimulating activity as detected in a sensitive cytochemical bioassay. Both the adenylate cyclase-stimulating activity and cytochemical bioactivity are due to specific binding of a substance in the tumor extracts to renal PTH receptors, as demonstrated by competitive inhibition studies, using the bovine PTH fragment analogue [Nle(8,18), Tyr34]bPTH-(3-34) amide. Preincubation with an antiserum to PTH results in no loss of activity in the tumor extract, and the activity appears both on gel filtration and ultrafiltration to be far larger than PTH (estimated M(r) 70,000). These studies demonstrate that extracts of tumors from patients with HHM contain a substance that binds to PTH receptors in the nephron responsible for activation of both the PTH-sensitive glucose-6-phosphate dehydrogenase and the PTH-sensitive adenylate cyclase. This substance is chromatographically and immunologically distinct from PTH. Its role in the genesis of HHM requires further study.
UR - http://www.scopus.com/inward/record.url?scp=0020537387&partnerID=8YFLogxK
U2 - 10.1073/pnas.80.5.1454
DO - 10.1073/pnas.80.5.1454
M3 - Article
C2 - 6298791
AN - SCOPUS:0020537387
SN - 0027-8424
VL - 80
SP - 1454
EP - 1458
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
IS - 5 I
ER -