Skip to main content
PMC home page
The Journal of Clinical Investigation logoLink to The Journal of Clinical Investigation
. 1988 Jun;81(6):2010–2014. doi: 10.1172/JCI113551

Identification of transcripts encoding a parathyroid hormone-like peptide in messenger RNAs from a variety of human and animal tumors associated with humoral hypercalcemia of malignancy.

K Ikeda 1, M Mangin 1, B E Dreyer 1, A C Webb 1, J T Posillico 1, A F Stewart 1, N H Bander 1, E C Weir 1, K L Insogna 1, A E Broadus 1
PMCID: PMC442656  PMID: 2454953

Abstract

The syndrome of humoral hypercalcemia of malignancy (HHM) appears to be mediated in many instances by a parathyroid hormone-like peptide, which has recently been purified, sequenced, and cloned. Using a probe representing the coding region of the human PTH-like peptide, we examined by Northern analysis poly (A)+ RNA from a variety of human and animal tumors associated with HHM. Hybridizing transcripts were identified in mRNA from each of 12 human and each of four animal HHM-associated tumors, with a complex hybridization pattern observed in the human mRNAs and a relatively simple pattern observed in the animal mRNAs. Poly (A)+ RNA prepared from tumors of similar histological types unassociated with HHM failed to hybridize with the probe. Messenger RNA-dependent biological activity from the animal tumors was entirely eliminated in a hybridization-arrest experiment using a complementary oligonucleotide spanning the region of homology between human PTH and the PTH-like peptide. These findings indicate that the PTH-like peptide is associated with the syndrome of HHM in a wide spectrum of tumor types from a variety of mammalian species and that the PTH-like sequence in the proximal amino terminus of the peptide is highly conserved.

Full text

PDF
2011

Images in this article

2011Image
on p.2011
2011Image
on p.2011
2012Image
on p.2012
2012Image
on p.2012

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Broadus A. E., Goltzman D., Webb A. C., Kronenberg H. M. Messenger ribonucleic acid from tumors associated with humoral hypercalcemia of malignancy directs the synthesis of a secretory parathyroid hormone-like peptide. Endocrinology. 1985 Oct;117(4):1661–1666. doi: 10.1210/endo-117-4-1661. [DOI] [PubMed] [Google Scholar]
  2. Burtis W. J., Wu T., Bunch C., Wysolmerski J. J., Insogna K. L., Weir E. C., Broadus A. E., Stewart A. F. Identification of a novel 17,000-dalton parathyroid hormone-like adenylate cyclase-stimulating protein from a tumor associated with humoral hypercalcemia of malignancy. J Biol Chem. 1987 May 25;262(15):7151–7156. [PubMed] [Google Scholar]
  3. Chirgwin J. M., Przybyla A. E., MacDonald R. J., Rutter W. J. Isolation of biologically active ribonucleic acid from sources enriched in ribonuclease. Biochemistry. 1979 Nov 27;18(24):5294–5299. doi: 10.1021/bi00591a005. [DOI] [PubMed] [Google Scholar]
  4. Cooke B. A., Lindh L. M., Janszen F. H., van Driel M. J., Bakker C. P., van der Plank M. P., van der Molen H. J. A Leydig cell tumour: a model for the study of lutropin action. Biochim Biophys Acta. 1979 Mar 22;583(3):320–331. doi: 10.1016/0304-4165(79)90456-2. [DOI] [PubMed] [Google Scholar]
  5. Gkonos P. J., Hayes T., Burtis W., Jacoby R., McGuire J., Baron R., Stewart A. F. Squamous carcinoma model of humoral hypercalcemia of malignancy. Endocrinology. 1984 Dec;115(6):2384–2390. doi: 10.1210/endo-115-6-2384. [DOI] [PubMed] [Google Scholar]
  6. Grima B., Lamouroux A., Boni C., Julien J. F., Javoy-Agid F., Mallet J. A single human gene encoding multiple tyrosine hydroxylases with different predicted functional characteristics. Nature. 1987 Apr 16;326(6114):707–711. doi: 10.1038/326707a0. [DOI] [PubMed] [Google Scholar]
  7. Horiuchi N., Caulfield M. P., Fisher J. E., Goldman M. E., McKee R. L., Reagan J. E., Levy J. J., Nutt R. F., Rodan S. B., Schofield T. L. Similarity of synthetic peptide from human tumor to parathyroid hormone in vivo and in vitro. Science. 1987 Dec 11;238(4833):1566–1568. doi: 10.1126/science.3685994. [DOI] [PubMed] [Google Scholar]
  8. Insogna K. L., Stewart A. F., Vignery A. M., Weir E. C., Namnum P. A., Baron R. E., Kirkwood J. M., Deftos L. M., Broadus A. E. Biochemical and histomorphometric characterization of a rat model for humoral hypercalcemia of malignancy. Endocrinology. 1984 Mar;114(3):888–896. doi: 10.1210/endo-114-3-888. [DOI] [PubMed] [Google Scholar]
  9. Isales C., Carcangiu M. L., Stewart A. F. Hypercalcemia in breast cancer. Reassessment of the mechanism. Am J Med. 1987 Jun;82(6):1143–1147. doi: 10.1016/0002-9343(87)90216-6. [DOI] [PubMed] [Google Scholar]
  10. Kawasaki E. S. Quantitative hybridization-arrest of mRNA in Xenopus oocytes using single-stranded complementary DNA or oligonucleotide probes. Nucleic Acids Res. 1985 Jul 11;13(13):4991–5004. doi: 10.1093/nar/13.13.4991. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Kemp B. E., Moseley J. M., Rodda C. P., Ebeling P. R., Wettenhall R. E., Stapleton D., Diefenbach-Jagger H., Ure F., Michelangeli V. P., Simmons H. A. Parathyroid hormone-related protein of malignancy: active synthetic fragments. Science. 1987 Dec 11;238(4833):1568–1570. doi: 10.1126/science.3685995. [DOI] [PubMed] [Google Scholar]
  12. Mangin M., Webb A. C., Dreyer B. E., Posillico J. T., Ikeda K., Weir E. C., Stewart A. F., Bander N. H., Milstone L., Barton D. E. Identification of a cDNA encoding a parathyroid hormone-like peptide from a human tumor associated with humoral hypercalcemia of malignancy. Proc Natl Acad Sci U S A. 1988 Jan;85(2):597–601. doi: 10.1073/pnas.85.2.597. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Melton D. A., Krieg P. A., Rebagliati M. R., Maniatis T., Zinn K., Green M. R. Efficient in vitro synthesis of biologically active RNA and RNA hybridization probes from plasmids containing a bacteriophage SP6 promoter. Nucleic Acids Res. 1984 Sep 25;12(18):7035–7056. doi: 10.1093/nar/12.18.7035. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Meuten D. J., Segre G. V., Capen C. C., Kociba G. J., Voelkel E. F., Levine L., Tashjian A. H., Jr, Chew D. J., Nagode L. A. Hypercalcemia in dogs with adenocarcinoma derived from apocrine glands of the anal sac. Biochemical and histomorphometric investigations. Lab Invest. 1983 Apr;48(4):428–435. [PubMed] [Google Scholar]
  15. Moseley J. M., Kubota M., Diefenbach-Jagger H., Wettenhall R. E., Kemp B. E., Suva L. J., Rodda C. P., Ebeling P. R., Hudson P. J., Zajac J. D. Parathyroid hormone-related protein purified from a human lung cancer cell line. Proc Natl Acad Sci U S A. 1987 Jul;84(14):5048–5052. doi: 10.1073/pnas.84.14.5048. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Pelham H. R., Jackson R. J. An efficient mRNA-dependent translation system from reticulocyte lysates. Eur J Biochem. 1976 Aug 1;67(1):247–256. doi: 10.1111/j.1432-1033.1976.tb10656.x. [DOI] [PubMed] [Google Scholar]
  17. Peng T. C., Garner S. C., Hirsch P. F., Posillico J. T. Cytochemical bioassay of circulating concentrations of rat parathyroid hormone: application to a study of age and sex. J Bone Miner Res. 1986 Aug;1(4):351–357. doi: 10.1002/jbmr.5650010408. [DOI] [PubMed] [Google Scholar]
  18. Rodan S. B., Insogna K. L., Vignery A. M., Stewart A. F., Broadus A. E., D'Souza S. M., Bertolini D. R., Mundy G. R., Rodan G. A. Factors associated with humoral hypercalcemia of malignancy stimulate adenylate cyclase in osteoblastic cells. J Clin Invest. 1983 Oct;72(4):1511–1515. doi: 10.1172/JCI111108. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Rosenthal N., Insogna K. L., Godsall J. W., Smaldone L., Waldron J. A., Stewart A. F. Elevations in circulating 1,25-dihydroxyvitamin D in three patients with lymphoma-associated hypercalcemia. J Clin Endocrinol Metab. 1985 Jan;60(1):29–33. doi: 10.1210/jcem-60-1-29. [DOI] [PubMed] [Google Scholar]
  20. Stewart A. F., Burtis W. J., Wu T., Goumas D., Broadus A. E. Two forms of parathyroid hormone-like adenylate cyclase-stimulating protein derived from tumors associated with humoral hypercalcemia of malignancy. J Bone Miner Res. 1987 Dec;2(6):587–593. doi: 10.1002/jbmr.5650020616. [DOI] [PubMed] [Google Scholar]
  21. Stewart A. F., Hoecker J. L., Mallette L. E., Segre G. V., Amatruda T. T., Jr, Vignery A. Hypercalcemia in pheochromocytoma. Evidence for a novel mechanism. Ann Intern Med. 1985 Jun;102(6):776–779. doi: 10.7326/0003-4819-102-6-776. [DOI] [PubMed] [Google Scholar]
  22. Stewart A. F., Horst R., Deftos L. J., Cadman E. C., Lang R., Broadus A. E. Biochemical evaluation of patients with cancer-associated hypercalcemia: evidence for humoral and nonhumoral groups. N Engl J Med. 1980 Dec 11;303(24):1377–1383. doi: 10.1056/NEJM198012113032401. [DOI] [PubMed] [Google Scholar]
  23. Stewart A. F., Insogna K. L., Burtis W. J., Aminiafshar A., Wu T., Weir E. C., Broadus A. E. Frequency and partial characterization of adenylate cyclase-stimulating activity in tumors associated with humoral hypercalcemia of malignancy. J Bone Miner Res. 1986 Jun;1(3):267–276. doi: 10.1002/jbmr.5650010305. [DOI] [PubMed] [Google Scholar]
  24. Stewart A. F., Insogna K. L., Goltzman D., Broadus A. E. 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. Proc Natl Acad Sci U S A. 1983 Mar;80(5):1454–1458. doi: 10.1073/pnas.80.5.1454. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Stewart A. F., Mangin M., Wu T., Goumas D., Insogna K. L., Burtis W. J., Broadus A. E. Synthetic human parathyroid hormone-like protein stimulates bone resorption and causes hypercalcemia in rats. J Clin Invest. 1988 Feb;81(2):596–600. doi: 10.1172/JCI113358. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Stewart A. F., Wu T., Goumas D., Burtis W. J., Broadus A. E. N-terminal amino acid sequence of two novel tumor-derived adenylate cyclase-stimulating proteins: identification of parathyroid hormone-like and parathyroid hormone-unlike domains. Biochem Biophys Res Commun. 1987 Jul 31;146(2):672–678. doi: 10.1016/0006-291x(87)90581-x. [DOI] [PubMed] [Google Scholar]
  27. Strewler G. J., Stern P. H., Jacobs J. W., Eveloff J., Klein R. F., Leung S. C., Rosenblatt M., Nissenson R. A. Parathyroid hormonelike protein from human renal carcinoma cells. Structural and functional homology with parathyroid hormone. J Clin Invest. 1987 Dec;80(6):1803–1807. doi: 10.1172/JCI113275. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Strewler G. J., Williams R. D., Nissenson R. A. Human renal carcinoma cells produce hypercalcemia in the nude mouse and a novel protein recognized by parathyroid hormone receptors. J Clin Invest. 1983 Mar;71(3):769–774. doi: 10.1172/JCI110825. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Suva L. J., Winslow G. A., Wettenhall R. E., Hammonds R. G., Moseley J. M., Diefenbach-Jagger H., Rodda C. P., Kemp B. E., Rodriguez H., Chen E. Y. A parathyroid hormone-related protein implicated in malignant hypercalcemia: cloning and expression. Science. 1987 Aug 21;237(4817):893–896. doi: 10.1126/science.3616618. [DOI] [PubMed] [Google Scholar]
  30. Thomas P. S. Hybridization of denatured RNA and small DNA fragments transferred to nitrocellulose. Proc Natl Acad Sci U S A. 1980 Sep;77(9):5201–5205. doi: 10.1073/pnas.77.9.5201. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. Weir E. C., Insogna K. L., Brownstein D. G., Bander N. H., Broadus A. E. In vitro adenylate cyclase-stimulating activity predicts the occurrence of humoral hypercalcemia of malignancy in nude mice. J Clin Invest. 1988 Mar;81(3):818–821. doi: 10.1172/JCI113389. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. Weir E. C., Norrdin R. W., Matus R. E., Brooks M. B., Broadus A. E., Mitnick M., Johnston S. D., Insogna K. L. Humoral hypercalcemia of malignancy in canine lymphosarcoma. Endocrinology. 1988 Feb;122(2):602–608. doi: 10.1210/endo-122-2-602. [DOI] [PubMed] [Google Scholar]

Articles from Journal of Clinical Investigation are provided here courtesy of American Society for Clinical Investigation

RESOURCES