Skip to main content
NCBI home page
The Journal of Clinical Investigation logoLink to The Journal of Clinical Investigation
. 1996 Mar 1;97(5):1311–1318. doi: 10.1172/JCI118547

The pituitary V3 vasopressin receptor and the corticotroph phenotype in ectopic ACTH syndrome.

Y de Keyzer 1, F Lenne 1, C Auzan 1, S Jégou 1, P René 1, H Vaudry 1, J M Kuhn 1, J P Luton 1, E Clauser 1, X Bertagna 1
PMCID: PMC507185  PMID: 8636444

Abstract

Ectopic ACTH secretion occurs in highly differentiated and rather indolent tumors like bronchial carcinoids or, in contrast, in various types of aggressive and poorly differentiated neuroendocrine tumors. We explored this phenomenon using the recently cloned human pituitary V3 vasopressin receptor as an alternate molecular marker of the corticotroph phenotype. Expression of V3 receptor, corticotrophin releasing hormone (CRH) receptor, and proopiomelanocortin (POMC) genes was examined in tumors of pituitary and nonpituitary origin. A comparative RT-PCR approach revealed signals for both V3 receptor and CHR receptor mRNAs in 17 of 18 ACTH-secreting pituitary adenomas, and 6 of 6 normal pituitaries; in six growth hormone- or prolactin-secreting adenomas, a very faint V3 receptor signal was observed in three cases, and CRH receptor signal was undetected in all. Six of eight bronchial carcinoids responsible for the ectopic ACTH syndrome had both POMC and V3 receptor signals as high as those in ACTH-secreting pituitary adenomas; in contrast, no POMC signal and only a very faint V3 receptor signal were detected in six of eight nonsecreting bronchial carcinoids. Northern blot analysis showed V3 receptor mRNA of identical size in ACTH-secreting bronchial carcinoids and pituitary tumors. Other types of nonpituitary tumors responsible for ectopic ACTH syndrome presented much lower levels of both POMC and V3 receptor gene expression than those found in ACTH-secreting bronchial carcinoids. In contrast with the V3 receptor, CRH receptor mRNA was detected in the majority of neuroendocrine tumors irrespective of their POMC status. These results show that expression of the V3 receptor gene participates in the corticotroph phenotype. Its striking association with ACTH-secreting bronchial carcinoids defines a subset of nonpituitary tumors in which ectopic POMC gene expression is but one aspect of a wider process of corticotroph cell differentiation, and opens new possibilities of pharmacological investigations and even manipulations of this peculiar ACTH hypersecretory syndrome.

Full Text

The Full Text of this article is available as a PDF (352.9 KB).

Selected References

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

  1. Antoni F. A. Novel ligand specificity of pituitary vasopressin receptors in the rat. Neuroendocrinology. 1984 Aug;39(2):186–188. doi: 10.1159/000123976. [DOI] [PubMed] [Google Scholar]
  2. Antoni F. A. Receptors mediating the CRH effects of vasopressin and oxytocin. Ann N Y Acad Sci. 1987;512:195–204. doi: 10.1111/j.1749-6632.1987.tb24961.x. [DOI] [PubMed] [Google Scholar]
  3. Bertagna X. Y., Nicholson W. E., Sorenson G. D., Pettengill O. S., Mount C. D., Orth D. N. Corticotropin, lipotropin, and beta-endorphin production by a human nonpituitary tumor in culture: evidence for a common precursor. Proc Natl Acad Sci U S A. 1978 Oct;75(10):5160–5164. doi: 10.1073/pnas.75.10.5160. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Bertagna X. Proopiomelanocortin-derived peptides. Endocrinol Metab Clin North Am. 1994 Sep;23(3):467–485. [PubMed] [Google Scholar]
  5. Birnbaumer M., Seibold A., Gilbert S., Ishido M., Barberis C., Antaramian A., Brabet P., Rosenthal W. Molecular cloning of the receptor for human antidiuretic hormone. Nature. 1992 May 28;357(6376):333–335. doi: 10.1038/357333a0. [DOI] [PubMed] [Google Scholar]
  6. Case records of the Massachusetts General Hospital. Weekly clinicopathological exercises. 53-1981. Persistence of Cushing's syndrome after hypophysectomy. N Engl J Med. 1981 Dec 31;305(27):1637–1643. doi: 10.1056/NEJM198112313052707. [DOI] [PubMed] [Google Scholar]
  7. 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]
  8. Clark A. J., Lavender P. M., Besser G. M., Rees L. H. Pro-opiomelanocortin mRNA size heterogeneity in ACTH-dependent Cushing's syndrome. J Mol Endocrinol. 1989 Jan;2(1):3–9. doi: 10.1677/jme.0.0020003. [DOI] [PubMed] [Google Scholar]
  9. Creemers J. W., Roebroek A. J., Van de Ven W. J. Expression in human lung tumor cells of the proprotein processing enzyme PC1/PC3. Cloning and primary sequence of a 5 kb cDNA. FEBS Lett. 1992 Mar 23;300(1):82–88. doi: 10.1016/0014-5793(92)80169-h. [DOI] [PubMed] [Google Scholar]
  10. DeBold C. R., Mufson E. E., Menefee J. K., Orth D. N. Proopiomelanocortin gene expression in a pheochromocytoma using upstream transcription initiation sites. Biochem Biophys Res Commun. 1988 Sep 15;155(2):895–900. doi: 10.1016/s0006-291x(88)80580-1. [DOI] [PubMed] [Google Scholar]
  11. Findling J. W., Kehoe M. E., Shaker J. L., Raff H. Routine inferior petrosal sinus sampling in the differential diagnosis of adrenocorticotropin (ACTH)-dependent Cushing's syndrome: early recognition of the occult ectopic ACTH syndrome. J Clin Endocrinol Metab. 1991 Aug;73(2):408–413. doi: 10.1210/jcem-73-2-408. [DOI] [PubMed] [Google Scholar]
  12. Findling J. W., Tyrrell J. B. Occult ectopic secretion of corticotropin. Arch Intern Med. 1986 May;146(5):929–933. [PubMed] [Google Scholar]
  13. Gerrero M. R., McEvilly R. J., Turner E., Lin C. R., O'Connell S., Jenne K. J., Hobbs M. V., Rosenfeld M. G. Brn-3.0: a POU-domain protein expressed in the sensory, immune, and endocrine systems that functions on elements distinct from known octamer motifs. Proc Natl Acad Sci U S A. 1993 Nov 15;90(22):10841–10845. doi: 10.1073/pnas.90.22.10841. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Israel A., Cohen S. N. Hormonally mediated negative regulation of human pro-opiomelanocortin gene expression after transfection into mouse L cells. Mol Cell Biol. 1985 Sep;5(9):2443–2453. doi: 10.1128/mcb.5.9.2443. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Jard S., Gaillard R. C., Guillon G., Marie J., Schoenenberg P., Muller A. F., Manning M., Sawyer W. H. Vasopressin antagonists allow demonstration of a novel type of vasopressin receptor in the rat adenohypophysis. Mol Pharmacol. 1986 Aug;30(2):171–177. [PubMed] [Google Scholar]
  16. Kimura T., Tanizawa O., Mori K., Brownstein M. J., Okayama H. Structure and expression of a human oxytocin receptor. Nature. 1992 Apr 9;356(6369):526–529. doi: 10.1038/356526a0. [DOI] [PubMed] [Google Scholar]
  17. Kreisberg R. Clinical problem-solving. Half a loaf. N Engl J Med. 1994 May 5;330(18):1295–1299. doi: 10.1056/NEJM199405053301809. [DOI] [PubMed] [Google Scholar]
  18. Lacaze-Masmonteil T., de Keyzer Y., Luton J. P., Kahn A., Bertagna X. Characterization of proopiomelanocortin transcripts in human nonpituitary tissues. Proc Natl Acad Sci U S A. 1987 Oct;84(20):7261–7265. doi: 10.1073/pnas.84.20.7261. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Lefebvre H., Jégou S., Leroux P., Dero M., Vaudry H., Kuhn J. M. Characterization of the somatostatin receptor subtype in a bronchial carcinoid tumor responsible for Cushing's syndrome. J Clin Endocrinol Metab. 1995 Apr;80(4):1423–1428. doi: 10.1210/jcem.80.4.7714118. [DOI] [PubMed] [Google Scholar]
  20. Liddle G. W., Nicholson W. E., Island D. P., Orth D. N., Abe K., Lowder S. C. Clinical and laboratory studies of ectopic humoral syndromes. Recent Prog Horm Res. 1969;25:283–314. doi: 10.1016/b978-0-12-571125-8.50009-0. [DOI] [PubMed] [Google Scholar]
  21. Lolait S. J., O'Carroll A. M., Mahan L. C., Felder C. C., Button D. C., Young W. S., 3rd, Mezey E., Brownstein M. J. Extrapituitary expression of the rat V1b vasopressin receptor gene. Proc Natl Acad Sci U S A. 1995 Jul 18;92(15):6783–6787. doi: 10.1073/pnas.92.15.6783. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Lolait S. J., O'Carroll A. M., McBride O. W., Konig M., Morel A., Brownstein M. J. Cloning and characterization of a vasopressin V2 receptor and possible link to nephrogenic diabetes insipidus. Nature. 1992 May 28;357(6376):336–339. doi: 10.1038/357336a0. [DOI] [PubMed] [Google Scholar]
  23. Luton J. P., Mahoudeau J. A., Bouchard P., Thieblot P., Hautecouverture M., Simon D., Laudat M. H., Touitou Y., Bricaire H. Treatment of Cushing's disease by O,p'DDD. Survey of 62 cases. N Engl J Med. 1979 Mar 1;300(9):459–464. doi: 10.1056/NEJM197903013000903. [DOI] [PubMed] [Google Scholar]
  24. Mahlmann S., Meyerhof W., Hausmann H., Heierhorst J., Schönrock C., Zwiers H., Lederis K., Richter D. Structure, function, and phylogeny of [Arg8]vasotocin receptors from teleost fish and toad. Proc Natl Acad Sci U S A. 1994 Feb 15;91(4):1342–1345. doi: 10.1073/pnas.91.4.1342. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Malchoff C. D., Orth D. N., Abboud C., Carney J. A., Pairolero P. C., Carey R. M. Ectopic ACTH syndrome caused by a bronchial carcinoid tumor responsive to dexamethasone, metyrapone, and corticotropin-releasing factor. Am J Med. 1988 Apr;84(4):760–764. doi: 10.1016/0002-9343(88)90116-7. [DOI] [PubMed] [Google Scholar]
  26. Mason A. M., Ratcliffe J. G., Buckle R. M., Mason A. S. ACTH secretion by bronchial carcinoid tumours. Clin Endocrinol (Oxf) 1972 Jan;1(1):3–25. doi: 10.1111/j.1365-2265.1972.tb00374.x. [DOI] [PubMed] [Google Scholar]
  27. Milano C. A., Allen L. F., Rockman H. A., Dolber P. C., McMinn T. R., Chien K. R., Johnson T. D., Bond R. A., Lefkowitz R. J. Enhanced myocardial function in transgenic mice overexpressing the beta 2-adrenergic receptor. Science. 1994 Apr 22;264(5158):582–586. doi: 10.1126/science.8160017. [DOI] [PubMed] [Google Scholar]
  28. Morel A., O'Carroll A. M., Brownstein M. J., Lolait S. J. Molecular cloning and expression of a rat V1a arginine vasopressin receptor. Nature. 1992 Apr 9;356(6369):523–526. doi: 10.1038/356523a0. [DOI] [PubMed] [Google Scholar]
  29. Muglia L. J., Jenkins N. A., Gilbert D. J., Copeland N. G., Majzoub J. A. Expression of the mouse corticotropin-releasing hormone gene in vivo and targeted inactivation in embryonic stem cells. J Clin Invest. 1994 May;93(5):2066–2072. doi: 10.1172/JCI117201. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Orth D. N. Corticotropin-releasing hormone in humans. Endocr Rev. 1992 May;13(2):164–191. doi: 10.1210/edrv-13-2-164. [DOI] [PubMed] [Google Scholar]
  31. Parma J., Duprez L., Van Sande J., Cochaux P., Gervy C., Mockel J., Dumont J., Vassart G. Somatic mutations in the thyrotropin receptor gene cause hyperfunctioning thyroid adenomas. Nature. 1993 Oct 14;365(6447):649–651. doi: 10.1038/365649a0. [DOI] [PubMed] [Google Scholar]
  32. Phlipponneau M., Nocaudie M., Epelbaum J., De Keyzer Y., Lalau J. D., Marchandise X., Bertagna X. Somatostatin analogs for the localization and preoperative treatment of an adrenocorticotropin-secreting bronchial carcinoid tumor. J Clin Endocrinol Metab. 1994 Jan;78(1):20–24. doi: 10.1210/jcem.78.1.7904613. [DOI] [PubMed] [Google Scholar]
  33. Picon A., Leblond-Francillard M., Raffin-Sanson M. L., Lenne F., Bertagna X., de Keyzer Y. Functional analysis of the human pro-opiomelanocortin promoter in the small cell lung carcinoma cell line DMS-79. J Mol Endocrinol. 1995 Oct;15(2):187–194. doi: 10.1677/jme.0.0150187. [DOI] [PubMed] [Google Scholar]
  34. Raux M. C., Binoux M., Luton J. P., Gourmelen M., Girard F. Studies of ACTH secretion control in 116 cases of Cushing's syndrome. J Clin Endocrinol Metab. 1975 Feb;40(2):186–197. doi: 10.1210/jcem-40-2-186. [DOI] [PubMed] [Google Scholar]
  35. Rees L. H., Ratcliffe J. G. Ectopic hormone production by non-endocrine tumours. Clin Endocrinol (Oxf) 1974 Jul;3(3):263–299. doi: 10.1111/j.1365-2265.1974.tb01801.x. [DOI] [PubMed] [Google Scholar]
  36. Saito M., Sugimoto T., Tahara A., Kawashima H. Molecular cloning and characterization of rat V1b vasopressin receptor: evidence for its expression in extra-pituitary tissues. Biochem Biophys Res Commun. 1995 Jul 26;212(3):751–757. doi: 10.1006/bbrc.1995.2033. [DOI] [PubMed] [Google Scholar]
  37. Seidah N. G., Day R., Marcinkiewicz M., Benjannet S., Chrétien M. Mammalian neural and endocrine pro-protein and pro-hormone convertases belonging to the subtilisin family of serine proteinases. Enzyme. 1991;45(5-6):271–284. doi: 10.1159/000468901. [DOI] [PubMed] [Google Scholar]
  38. Stewart P. M., Gibson S., Crosby S. R., Penn R., Holder R., Ferry D., Thatcher N., Phillips P., London D. R., White A. ACTH precursors characterize the ectopic ACTH syndrome. Clin Endocrinol (Oxf) 1994 Feb;40(2):199–204. doi: 10.1111/j.1365-2265.1994.tb02468.x. [DOI] [PubMed] [Google Scholar]
  39. Suda T., Tozawa F., Dobashi I., Horiba N., Ohmori N., Yamakado M., Yamada M., Demura H. Corticotropin-releasing hormone, proopiomelanocortin, and glucocorticoid receptor gene expression in adrenocorticotropin-producing tumors in vitro. J Clin Invest. 1993 Dec;92(6):2790–2795. doi: 10.1172/JCI116898. [DOI] [PMC free article] [PubMed] [Google Scholar]
  40. Sugimoto T., Saito M., Mochizuki S., Watanabe Y., Hashimoto S., Kawashima H. Molecular cloning and functional expression of a cDNA encoding the human V1b vasopressin receptor. J Biol Chem. 1994 Oct 28;269(43):27088–27092. [PubMed] [Google Scholar]
  41. Texier P. L., de Keyzer Y., Lacave R., Vieau D., Lenne F., Rojas-Miranda A., Verley J. M., Luton J. P., Kahn A., Bertagna X. Proopiomelanocortin gene expression in normal and tumoral human lung. J Clin Endocrinol Metab. 1991 Aug;73(2):414–420. doi: 10.1210/jcem-73-2-414. [DOI] [PubMed] [Google Scholar]
  42. Therrien M., Drouin J. Cell-specific helix-loop-helix factor required for pituitary expression of the pro-opiomelanocortin gene. Mol Cell Biol. 1993 Apr;13(4):2342–2353. doi: 10.1128/mcb.13.4.2342. [DOI] [PMC free article] [PubMed] [Google Scholar]
  43. Thibonnier M., Auzan C., Madhun Z., Wilkins P., Berti-Mattera L., Clauser E. Molecular cloning, sequencing, and functional expression of a cDNA encoding the human V1a vasopressin receptor. J Biol Chem. 1994 Feb 4;269(5):3304–3310. [PubMed] [Google Scholar]
  44. Utiger R. D. Inappropriate antidiuresis and carcinoma of the lung: detection of arginine vasopressin in tumor extracts by immunoassay. J Clin Endocrinol Metab. 1966 Sep;26(9):970–974. doi: 10.1210/jcem-26-9-970. [DOI] [PubMed] [Google Scholar]
  45. Vieau D., Linard C. G., Mbikay M., Lenne F., Chretien M., Luton J. P., Bertagna X. Expression of the neuroendocrine cell marker 7B2 in human ACTH secreting tumours. Clin Endocrinol (Oxf) 1992 Jun;36(6):597–603. doi: 10.1111/j.1365-2265.1992.tb02271.x. [DOI] [PubMed] [Google Scholar]
  46. Vieau D., Massias J. F., Girard F., Luton J. P., Bertagna X. Corticotrophin-like intermediary lobe peptide as a marker of alternate pro-opiomelanocortin processing in ACTH-producing non-pituitary tumours. Clin Endocrinol (Oxf) 1989 Dec;31(6):691–700. doi: 10.1111/j.1365-2265.1989.tb01294.x. [DOI] [PubMed] [Google Scholar]
  47. Vieau D., Rojas-Miranda A., Verley J. M., Lenne F., Bertagna X. The secretory granule peptides 7B2 and CCB are sensitive biochemical markers of neuro-endocrine bronchial tumours in man. Clin Endocrinol (Oxf) 1991 Oct;35(4):319–325. doi: 10.1111/j.1365-2265.1991.tb03543.x. [DOI] [PubMed] [Google Scholar]
  48. Vieau D., Seidah N. G., Mbikay M., Chrétien M., Bertagna X. Expression of the prohormone convertase PC2 correlates with the presence of corticotropin-like intermediate lobe peptide in human adrenocorticotropin-secreting tumors. J Clin Endocrinol Metab. 1994 Nov;79(5):1503–1506. doi: 10.1210/jcem.79.5.7962350. [DOI] [PubMed] [Google Scholar]
  49. Warren W. H., Gould V. E., Faber L. P., Kittle C. F., Memoli V. A. Neuroendocrine neoplasms of the bronchopulmonary tract. A classification of the spectrum of carcinoid to small cell carcinoma and intervening variants. J Thorac Cardiovasc Surg. 1985 Jun;89(6):819–825. [PubMed] [Google Scholar]
  50. White A., Clark A. J. The cellular and molecular basis of the ectopic ACTH syndrome. Clin Endocrinol (Oxf) 1993 Aug;39(2):131–141. doi: 10.1111/j.1365-2265.1993.tb01765.x. [DOI] [PubMed] [Google Scholar]
  51. de Keyzer Y., Auzan C., Lenne F., Beldjord C., Thibonnier M., Bertagna X., Clauser E. Cloning and characterization of the human V3 pituitary vasopressin receptor. FEBS Lett. 1994 Dec 19;356(2-3):215–220. doi: 10.1016/0014-5793(94)01268-7. [DOI] [PubMed] [Google Scholar]
  52. de Keyzer Y., Bertagna X., Lenne F., Girard F., Luton J. P., Kahn A. Altered proopiomelanocortin gene expression in adrenocorticotropin-producing nonpituitary tumors. Comparative studies with corticotropic adenomas and normal pituitaries. J Clin Invest. 1985 Nov;76(5):1892–1898. doi: 10.1172/JCI112184. [DOI] [PMC free article] [PubMed] [Google Scholar]
  53. de Keyzer Y., Bertagna X., Luton J. P., Kahn A. Variable modes of proopiomelanocortin gene transcription in human tumors. Mol Endocrinol. 1989 Jan;3(1):215–223. doi: 10.1210/mend-3-1-215. [DOI] [PubMed] [Google Scholar]

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

RESOURCES