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. 1993 Dec;92(6):2790–2795. doi: 10.1172/JCI116898

Corticotropin-releasing hormone, proopiomelanocortin, and glucocorticoid receptor gene expression in adrenocorticotropin-producing tumors in vitro.

T Suda 1, F Tozawa 1, I Dobashi 1, N Horiba 1, N Ohmori 1, M Yamakado 1, M Yamada 1, H Demura 1
PMCID: PMC288479  PMID: 8254033

Abstract

To differentiate between ectopic ACTH syndrome and Cushing's disease, gene expression of corticotropin-releasing hormone (CRH), proopiomelanocortin (POMC), and glucocorticoid receptor was examined in 10 pituitary adenomas (Cushing's disease) and in 10 ectopic ACTH-producing tumors. CRH increased plasma ACTH levels in all patients with Cushing's disease and in five patients with ectopic ACTH syndrome whose tumors contained CRH and CRH mRNA. In five CRH nonresponders, CRH was not detected in tumors that contained no CRH mRNA or that contained only long-size CRH mRNA. Dexamethasone (Dex) decreased plasma ACTH levels in all patients with Cushing's disease and in three patients with ectopic ACTH-producing bronchial carcinoid. These tumors contained glucocorticoid receptor mRNA. CRH increased and Dex decreased ACTH release and POMC mRNA levels in pituitary adenoma and bronchial carcinoid cells. PMA increased POMC mRNA levels only in carcinoid cells. These results reveal characteristics of ectopic ACTH-producing tumors: long-size CRH mRNA and PMA-induced POMC gene expression. In addition, there are two ectopic ACTH syndrome subtypes: tumors containing ACTH with CRH (CRH responder) and tumors without CRH. Dex decreases ACTH release and POMC mRNA levels in some bronchial carcinoids. Therefore, CRH and Dex tests have limited usefulness in differentiating between Cushing's disease and ectopic ACTH syndrome.

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Selected References

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

  1. Adler G. K., Rosen L. B., Fiandaca M. J., Majzoub J. A. Protein kinase-C activation increases the quantity and poly(A) tail length of corticotropin-releasing hormone messenger RNA in NPLC cells. Mol Endocrinol. 1992 Mar;6(3):476–484. doi: 10.1210/mend.6.3.1350054. [DOI] [PubMed] [Google Scholar]
  2. Adler G. K., Smas C. M., Fiandaca M., Frim D. M., Majzoub J. A. Regulated expression of the human corticotropin releasing hormone gene by cyclic AMP. Mol Cell Endocrinol. 1990 Apr 17;70(2):165–174. doi: 10.1016/0303-7207(90)90156-3. [DOI] [PubMed] [Google Scholar]
  3. Affolter H. U., Reisine T. Corticotropin releasing factor increases proopiomelanocortin messenger RNA in mouse anterior pituitary tumor cells. J Biol Chem. 1985 Dec 15;260(29):15477–15481. [PubMed] [Google Scholar]
  4. Bourgeois S., Newby R. F. Correlation between glucocorticoid receptor and cytolytic response of murine lymphoid cell lines. Cancer Res. 1979 Nov;39(11):4749–4751. [PubMed] [Google Scholar]
  5. Dave J. R., Eiden L. E., Lozovsky D., Waschek J. A., Eskay R. L. Calcium-independent and calcium-dependent mechanisms regulate corticotropin-releasing factor-stimulated proopiomelanocortin peptide secretion and messenger ribonucleic acid production. Endocrinology. 1987 Jan;120(1):305–310. doi: 10.1210/endo-120-1-305. [DOI] [PubMed] [Google Scholar]
  6. DeBold C. R., Schworer M. E., Connor T. B., Bird R. E., Orth D. N. Ectopic pro-opiolipomelanocortin: sequence of cDNA coding for beta-melanocyte-stimulating hormone and beta-endorphin. Science. 1983 May 13;220(4598):721–723. doi: 10.1126/science.6301015. [DOI] [PubMed] [Google Scholar]
  7. Dong Y., Aronsson M., Gustafsson J. A., Okret S. The mechanism of cAMP-induced glucocorticoid receptor expression. Correlation to cellular glucocorticoid response. J Biol Chem. 1989 Aug 15;264(23):13679–13683. [PubMed] [Google Scholar]
  8. Dong Y., Poellinger L., Gustafsson J. A., Okret S. Regulation of glucocorticoid receptor expression: evidence for transcriptional and posttranslational mechanisms. Mol Endocrinol. 1988 Dec;2(12):1256–1264. doi: 10.1210/mend-2-12-1256. [DOI] [PubMed] [Google Scholar]
  9. Hollenberg S. M., Weinberger C., Ong E. S., Cerelli G., Oro A., Lebo R., Thompson E. B., Rosenfeld M. G., Evans R. M. Primary structure and expression of a functional human glucocorticoid receptor cDNA. Nature. 1985 Dec 19;318(6047):635–641. doi: 10.1038/318635a0. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Liddle G. W. Cushing's syndrome. Ann N Y Acad Sci. 1977 Oct 28;297:594–602. doi: 10.1111/j.1749-6632.1977.tb41886.x. [DOI] [PubMed] [Google Scholar]
  11. Loeffler J. P., Kley N., Pittius C. W., Höllt V. Calcium ion and cyclic adenosine 3',5'-monophosphate regulate proopiomelanocortin messenger ribonucleic acid levels in rat intermediate and anterior pituitary lobes. Endocrinology. 1986 Dec;119(6):2840–2847. doi: 10.1210/endo-119-6-2840. [DOI] [PubMed] [Google Scholar]
  12. 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]
  13. 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]
  14. Nieman L. K., Chrousos G. P., Oldfield E. H., Avgerinos P. C., Cutler G. B., Jr, Loriaux D. L. The ovine corticotropin-releasing hormone stimulation test and the dexamethasone suppression test in the differential diagnosis of Cushing's syndrome. Ann Intern Med. 1986 Dec;105(6):862–867. doi: 10.7326/0003-4819-105-6-862. [DOI] [PubMed] [Google Scholar]
  15. Robinson B. G., Emanuel R. L., Frim D. M., Majzoub J. A. Glucocorticoid stimulates expression of corticotropin-releasing hormone gene in human placenta. Proc Natl Acad Sci U S A. 1988 Jul;85(14):5244–5248. doi: 10.1073/pnas.85.14.5244. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Robinson B. G., Frim D. M., Schwartz W. J., Majzoub J. A. Vasopressin mRNA in the suprachiasmatic nuclei: daily regulation of polyadenylate tail length. Science. 1988 Jul 15;241(4863):342–344. doi: 10.1126/science.3388044. [DOI] [PubMed] [Google Scholar]
  17. Sheppard K. E., Roberts J. L., Blum M. Adrenocorticotropin-releasing factor down-regulates glucocorticoid receptor expression in mouse corticotrope tumor cells via an adenylate cyclase-dependent mechanism. Endocrinology. 1991 Aug;129(2):663–670. doi: 10.1210/endo-129-2-663. [DOI] [PubMed] [Google Scholar]
  18. Strott C. A., Nugent C. A., Tyler F. H. Cushing's syndrome caused by bronchial adenomas. Am J Med. 1968 Jan;44(1):97–104. doi: 10.1016/0002-9343(68)90240-4. [DOI] [PubMed] [Google Scholar]
  19. Suda T., Kondo M., Totani R., Hashimoto N., Suzuki M., Imaki T., Oba Y., Tomori N., Yajima F., Sumitomo T. Ectopic adrenocorticotropin syndrome caused by lung cancer that responded to corticotropin-releasing hormone. J Clin Endocrinol Metab. 1986 Nov;63(5):1047–1051. doi: 10.1210/jcem-63-5-1047. [DOI] [PubMed] [Google Scholar]
  20. Suda T., Sumitomo T., Nakano Y., Tozawa F., Ushiyama T., Demura H. Glucocorticoids decrease a binding of corticotropin-releasing hormone-binding protein in human plasma. J Clin Endocrinol Metab. 1990 Oct;71(4):913–917. doi: 10.1210/jcem-71-4-913. [DOI] [PubMed] [Google Scholar]
  21. Suda T., Tomori N., Tozawa F., Demura H., Shizume K., Mouri T., Miura Y., Sasano N. Immunoreactive corticotropin and corticotropin-releasing factor in human hypothalamus, adrenal, lung cancer, and pheochromocytoma. J Clin Endocrinol Metab. 1984 May;58(5):919–924. doi: 10.1210/jcem-58-5-919. [DOI] [PubMed] [Google Scholar]
  22. Suda T., Tozawa F., Yamada M., Ushiyama T., Tomori N., Sumitomo T., Nakagami Y., Demura H., Shizume K. Effects of corticotropin-releasing hormone and dexamethasone on proopiomelanocortin messenger RNA level in human corticotroph adenoma cells in vitro. J Clin Invest. 1988 Jul;82(1):110–114. doi: 10.1172/JCI113557. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Suda T., Tozawa F., Yamada M., Ushiyama T., Tomori N., Sumitomo T., Nakagami Y., Demura H., Shizume K. Insulin-induced hypoglycemia increases corticotropin-releasing factor messenger ribonucleic acid levels in rat hypothalamus. Endocrinology. 1988 Sep;123(3):1371–1375. doi: 10.1210/endo-123-3-1371. [DOI] [PubMed] [Google Scholar]
  24. Thompson R. C., Seasholtz A. F., Herbert E. Rat corticotropin-releasing hormone gene: sequence and tissue-specific expression. Mol Endocrinol. 1987 May;1(5):363–370. doi: 10.1210/mend-1-5-363. [DOI] [PubMed] [Google Scholar]
  25. Tsukada T., Nakai Y., Jingami H., Imura H., Taii S., Nakanishi S., Numa S. Identification of the mRNA coding for the ACTH-beta-lipotropin precursor in a human ectopic ACTH-producing tumor. Biochem Biophys Res Commun. 1981 Jan 30;98(2):535–540. doi: 10.1016/0006-291x(81)90873-1. [DOI] [PubMed] [Google Scholar]
  26. Usui T., Nakai Y., Tsukada T., Jingami H., Takahashi H., Fukata J., Imura H. Expression of adrenocorticotropin-releasing hormone precursor gene in placenta and other nonhypothalamic tissues in man. Mol Endocrinol. 1988 Sep;2(9):871–875. doi: 10.1210/mend-2-9-871. [DOI] [PubMed] [Google Scholar]
  27. Vamvakopoulos N. C., Chrousos G. P. Regulated activity of the distal promoter-like element of the human corticotropin-releasing hormone gene and secondary structural features of its corresponding transcripts. Mol Cell Endocrinol. 1993 Jul;94(1):73–78. doi: 10.1016/0303-7207(93)90053-m. [DOI] [PubMed] [Google Scholar]
  28. 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]

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