Advertisement

Regulation of Calcitonin Secretion and Calcitonin Gene Expression

  • F. Raue
  • A. Zink
  • H. Scherübl
Part of the Recent Results in Cancer Research book series (RECENTCANCER, volume 125)

Abstract

Medullary thyroid carcinoma (MTC) is a tumor of the calcitonin (CT)-secreting cells (C-cells or parafollicular cells). During embryogenesis C-cells migrate from the neural crest to the last branchial pouch and ultimately into the thyroid. In contrast to the follicular cells of the thyroid gland that produce the thyroid hormones under the control of thyroid-stimulating hormone (TSH), the C-cells secrete CT and related peptides under different control systems (Deftos and Roos 1989). CT helps to maintain the calcium homeostasis and as a feedback, physiological changes in blood-calcium concentration directly regulate CT secretion. In addition, 1,25 (OH)2D3 is involved in CT secretion and synthesis. CT release is also closely tied to feeding and gastrointestinal activity; gastrointestinal hormonal factors including gastrin, cholecystokinin (CCK), and glucagon participate in promoting CT release. Moreover neuroendocrine factors may be involved in the control of CT secretion. β-Adrenergic agonists stimulate CT secretion, while α-adrenergic agonists and dopamine inhibit it, which suggests a participation of the autonomic nervous system in the regulation of CT secretion. Somatostatin appears to have a paracrine or autocrine regulatory function as it is secreted by C-cells and it is able to inhibit CT secretion. While these phenomena can be studied in vivo, emphasizing their physiological relevance, the cellular and molecular mechanisms underlying regulation of CT secretion, synthesis, and transcription can only be studied in in vitro systems. The available in vitro systems include rat thyroid explants (Cooper et al. 1977), primary cell cultures of MTC (Raue et al. 1989), and permanent C-cell carcinoma cell lines (human TT: Leong et al. 1981; rMTC 6–23: Gagel et al. 1980). Cellular signaling processes thought to be involved in initiation of C-cell neoplasia and subsequent cellular changes during tumor progression are activation of adenylate cyclase, protein kinase C, and oncogenes.

Keywords

Medullary Thyroid Carcinoma Calcitonin Secretion Human Medullary Thyroid Carcinoma Medullary Thyroid Carcinoma Cell Line Human Medullary Thyroid Carcinoma Cell 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. Armstrong D, Eckert R (1987) Voltage-activated calcium channels that must be phosphorylated to respond to membrane depolarisation. Proc Natl Acad Sci USA 84: 2518–2624PubMedCrossRefGoogle Scholar
  2. Aron DC, Muszynski M, Birnbaum RS, Sabo SW, Roos BA (1981) Somatostatin elaboration by monolayer cell cultures derived from transplantable rat medullary thyroid carcinoma synergistic stimulatory effects of glucagon and calcium. Endocrinology 109: 1830–1834PubMedCrossRefGoogle Scholar
  3. Baier R, Lazaretti-Castro M, Grauer A, Raue F, Ziegler R (1991) 1,25 (OH)2D3 stimulates cell proliferation and C-myc oncogene transcription in a human C-cell carcinoma cell line (TT cell). Acta Endocrinol 124 [Suppl 11:Abstr 221Google Scholar
  4. Bean BP (1989) Neurotransmitter inhibition of neuronal calcium currents by changes in channel voltage dependence. Nature 340: 153–155PubMedCrossRefGoogle Scholar
  5. Besnard P, Jousset V, Garel JM (1989) Additive effects of dexamethasone and calcium on the calcitonin mRNA level in adrenalectomized rats. FEBS Lett 258: 293–296PubMedCrossRefGoogle Scholar
  6. Body JJ, Struelens M, Borkowski A, Mandrat G (1989) Effects of estrogens and calcium on calcitonin secretion in postmenopausal women. J Clin Endocrinol Metab 68: 223–226PubMedCrossRefGoogle Scholar
  7. Cooper CW, Borosky SA (1986) Inhibition of secretion of rat calcitonin by calmodulin inhibitors. Calcif Tissue Int 38: 103–108PubMedCrossRefGoogle Scholar
  8. Cooper CW, Ramp WK, Becker DI, Ontjes DA (1977) In vitro secretion of immunoreactive rat thyrocalcitonin. Endocrinology 101: 304–311PubMedCrossRefGoogle Scholar
  9. Cooper CW, Yi SJ, Seitz PK (1988) Inhibition by phenytoin of in vitro secretion of calcitonin from rat thyroid glands and cultured rat C-cells. J Bone Miner Res 3: 219–223PubMedCrossRefGoogle Scholar
  10. Cote GJ, Gagel RF (1986) Dexamethasone differentially affects the levels of calcitonin and clacitonin gene-related peptide mRNAs expressed in a human medullary thyroid carcinoma cell line. J Biol Chem 261: 15524–15528PubMedGoogle Scholar
  11. Cote GJ, Abruzze RV, Lips CJM, Gagel RF (1990) Transfection of calcitonin gene regulatory elements into a cell culture model of the C-Cell. J Bone Miner Res 5: 165–171PubMedCrossRefGoogle Scholar
  12. Cote GJ, Rodgers DG, Huang ESC, Gagel RF (1987) The effect of 1,25dihydroxyvitamin D3 treatment on calcitonin and calcitonin gene-related peptide mRNA levels in cultured human thyroid C-cells. Biochem Biophys Res Commun 149: 239–243PubMedCrossRefGoogle Scholar
  13. Croxton TL, Ben-Jonathan N, Armstrong WM (1988) Gonadotropin-releasing hormone induces oscillatory membrane current in rat gonadotrophes. Endocrinology 123: 1783–1799PubMedCrossRefGoogle Scholar
  14. De Bustros A, Baylin SB, Berger CL, Roos A, Leony SS, Nelkin BD (1985) Phorbol ester increase calcitonin gene transcription and decrease c-myc mRNA levels in cultured human medullary thyroid carcinoma. J Biol Chem 260: 98–104PubMedGoogle Scholar
  15. Deftos LJ, Roos BA (1989) Medullary thyroid carcinoma and calcitonin gene expression. In: Peck WA (eds) Bone and mineral research 6. Elsevier, Amsterdam, pp 267–316Google Scholar
  16. Eckert RW, Scherübl H, Petzelt C, Raue F, Ziegler R (1989) Rhythmic oscillations of cytosolic free calcium in rat C-cells. Mol Cell Endocrinol 64: 267–270PubMedCrossRefGoogle Scholar
  17. Endo T, Saito T, Uchida T, Onaga T (1988) Effects of somatostatin and serotonin on calcitonin secretion from cultured rat and parafollicular cells. Acta Endocrinol (Copenh) 117: 214–218Google Scholar
  18. Freake HC, McIntyre I (1982) Specific binding of 1,25 dihydroxycholecalciferol in human medullary thyroid carcinoma. Biochem J 206: 181–184PubMedGoogle Scholar
  19. Fried RM, Tashjian AH (1986) Unusual sensitivity of cytosolic free Cat+ to changes in extracellular Cat+ in rat C-cells. J Biol Chem 261: 7669–7674PubMedGoogle Scholar
  20. Fried RM, Tashjian AH (1987) Action of rat growth hormone-releasing factor and norepinephrine on cytosolic free calcium and inositol trisphosphate in rat C-cells. J Bone Miner Res 2: 579–585PubMedCrossRefGoogle Scholar
  21. Gagel RF, Zeytinoglu FN, Voelkel EF, Tashjian AH (1980) Establishment of a calcitonin-producing rat medullary carcinoma cell line. II. Secretory studies of the tumor and cells in culture. Endocrinology 107: 516–523Google Scholar
  22. Grauer A, Baier B, Lazaretti-Castro M, Raue F, Ziegler R (1991) 1,25 (OH)2D3 inhibits the dexamethasone induced stimulation of calcitonin gene expression in a human C-cell carcinoma cell line (TT-cell) (Abstr). Calcif Tissue Int 48 [Suppl]:26Google Scholar
  23. Greenberg C, Kukreja SC, Bowser EN, Hargis GK, Henderson WJ, William GA (1986) Effect of estradiol and progesterone on calcitonin secretion. Endocrinology 118: 2594–2598PubMedCrossRefGoogle Scholar
  24. Haller-Brem S, Muff R, Fischer JA (1988) Calcitonin gene-related peptide and calcitonin secretion from a human medullary thyroid carcinoma cell line: effects of ionomycin, phorbol ester and forskolin. J Endocrinol 119: 147–152PubMedCrossRefGoogle Scholar
  25. Haller-Brem S, Muff R, Petermann JB, Born W, Roos BA, Fischer JA (1987) Role of cytosolic free calcium concentration in the secretion of calcitonin gene-related peptide and calcitonin from medullary thyroid carcinoma cells. Endocrinology 121: 1272–1277PubMedCrossRefGoogle Scholar
  26. Hishikawa R, Fukase M, Takenaka M, Fujita T (1985) Effect of calcium channel agonist BAY K 8644 on calcitonin secretion from a rat C-cell line. Biochem Biophys Res Commun 130: 454–459PubMedCrossRefGoogle Scholar
  27. Höflich M, Scherübl H, Raue F, Hoffmann J, Ziegler R (1990) Regulation of adenylate cyclase in rat C-cells (Abstr). Acta Endocrinol (Copenh) 122 Suppl 1: 35Google Scholar
  28. Jaeger P, Jones W, Clemens TL, Haystett JP (1986) Evidence that calcitonin stimulates 1,25-dihydroxyvitamin D production and intestinal absorption of calcium in vivo, J Clin Invest 78: 456–461PubMedCrossRefGoogle Scholar
  29. Jousset U, Besnard P, Segond N, Julliene A, Garet JM (1988) Potassium administration and calcitonin mRNA levels in the rat. Mol Cell Endocrinol 59: 65–169CrossRefGoogle Scholar
  30. Koch BD, Schonbrunn A (1988) Characterization of cyclic AMP independent actions of somastatin in GH cells. II. An increase in potassium conductance initiates somatostatin-induced inhibition of prolactin secretion. J Biol Chem 263: 226–234Google Scholar
  31. Koch BD, Dorflinger LJ, Schonbrunn A (1985) Pertussis toxin blocks both cyclic AMP-mediated and cAMP-independent actions of somatostatin: evidence for coupling of Ni to decrease in intracellular free calcium. J Biol Chem 260: 13138–13145PubMedGoogle Scholar
  32. Koch BD, Blalock JB, Schonbrunn A (1988) Characterization of the cyclic AMP-independent actions of somatostatin in GH cells. I. An increase in potassium conductance is responsible for both the hyperpolarisation and the decrease in intracellular free calcium produced by somatostatin. J Biol Chem 263: 216–225Google Scholar
  33. Lazaretti-Castro M, Grauer A, Raue F, Ziegler R (1990) 1,25-dihydroxyvitamin D3 suppresses dexamethasone effects on calcitonin secretion. Mol Cell Endocrinol 71: R13 — R18Google Scholar
  34. Lazaretti-Castro M, Grauer A, Mekonnen Y, Raue F, Ziegler R (1991) 17ß-estradiol effects on calcitonin secretion and content in a human medullary thyroid carcinoma cell line. J Bone Miner Res 6: 1191–1195Google Scholar
  35. Leong SS, Horoszewicz JS, Shimoaka K, Friedmann M, Kawinski E, Song MJ, Zeigel R, Chu TM, Baylin S, Miraud EA (1981) A new cell line for study of human medullary thyroid carcinoma. In: Andreoli M, Monaco F, Robbind J (eds) Advances in thyroid neoplasia. Field Educational Italia, Rome, pp 95–108Google Scholar
  36. Lewis DL, Weight FF, Luini A (1986) A guanine nucleotide-binding protein mediates the inhibition of voltage-dependent calcium current by somatostatin in a pituitary cell line. Proc Natl Acad Sci USA 83: 9035–9045PubMedCrossRefGoogle Scholar
  37. Lussier BT, French MB, Moor BC, Kraicer J (1991a) Free intracellular CaZ+ concentration [CaZ+]; and growth hormone release from purified rat somatotrophs. I. GH-releasing factor-induced CaZ+ influx raises [Ca2+1,. Endocrinology 128: 570–582PubMedCrossRefGoogle Scholar
  38. Lussier BT, Wood DA, French MB, Moor BC, Kraicer J (1991b) Free-intracellular CaZ+ concentration [CaZ+]; and growth hormone release from purified rat somatotrophs. II. Somatostatin lowers CaZ+ by inhibiting influx. Endocrinology 128: 583–591PubMedCrossRefGoogle Scholar
  39. Mabry M, Nakagawa T, Baylin S, Pettengill O, Sorenson G, Nelkin B (1989) Insertion of the v-Ha-ras oncogene induces differentiation of calcitonin-producing human small cell lung cancer. J Clin Invest 84: 194–199PubMedCrossRefGoogle Scholar
  40. Mathew CGP, Chiu KS, Easton DF, Thorpe K, Carter C, Liou CI, Fong SL, Bridge CD, Haak H, Kruseman HC, Schifter S, Hansen HH, Telenius H, Telenius-Berg M, Ponder BAJ (1987) A linked genetic marker for multiple endocrine neoplasia type 2a on chromosome 10. Nature 328: 527–528PubMedCrossRefGoogle Scholar
  41. McDermott MT, Kidd GS (1987) The role of calcitonin in the development and treatment of osteoporosis. Endocr Rev 8: 377–390PubMedCrossRefGoogle Scholar
  42. Mekonnen Y, Lazaretti-Castro M, Raue F, Ziegler R (1990) Long term exposure to the calcium channel agonist BAY K 8644 inhibits calcitonin secretion and content in a rat C-cell carcinoma cell line (Abstr). J Endocrinol Invest 13 Suppl 2:P 316Google Scholar
  43. Murray SS, Burton DW, Deftos LJ (1988) The effects of forskolin and calcium ionophore A 23187 on secretion and cytoplasmic RNA levels of chromogranin-A and calcitonin. J Bone Miner Res 3: 447–452PubMedCrossRefGoogle Scholar
  44. Nakagawa T, Mabry M, de Bustros A, Ihle JN, Nelkin BD, Baylin SB (1987) Introduction of v-Ha-ras oncogene induces differentiation of cultured human medullary thyroid carcinoma cells. Proc Natl Acad Sci USA 84: 5923Google Scholar
  45. Naveh-Many T, Silver J (1988) Regulation of calcitonin gene transcription by vitamin D metabolites in vivo in the rat. J Clin Invest 81: 270–273PubMedCrossRefGoogle Scholar
  46. Naveh-Many T, Friedlaender M, Mayer H, Silver J (1988) Calcium regulates parathyroid hormone messenger ribonucleic acid (mRNA), but not calctionin mRNA in vivo in the rat; dominant role of 1,25 dihydroxyvitamin D. Endocrinology 125: 275–280CrossRefGoogle Scholar
  47. Nelkin BD, Chen YK, de Bustros A, Boos BA, Baylin SB (1989) Changes in calcitonin gene RNA processing during growth of a human medullary thyroid carcinoma cell line. Cancer Res 49: 6949Google Scholar
  48. Nelkin BD, de Bustros A, Mabry M, Baylin SB (1989) The molecular biology of medullary thyroid carcinoma, a model for cancer development and progression. JAMA 261: 3130–3135Google Scholar
  49. Raue F, Deutschle I, Ziegler R (1983) Acute effect of 1,25-dihydroxyvitamin D3 on calcitonin secretion in rats. Horm Metab Res 15: 208–209PubMedCrossRefGoogle Scholar
  50. Raue F, Deutschle I, Küntzel C, Ziegler R (1984) Reversible diminished calcitonin secretion in the rat during chronic hypercalcemia. Endocrinology 115: 2362–2367PubMedCrossRefGoogle Scholar
  51. Raue F, Wieland U, Weiler C, Ziegler R (1988) Enhanced calcitonin secretion in the rat after parathyroidectomy and during chronic calcium deprivation. Eur J Clin Invest 18: 284–289PubMedCrossRefGoogle Scholar
  52. Raue F, Serve H, Grauer A, Scherübl H, Schneider HG, Ziegler R (1989) Role of voltage-dependent calcium channels in secretion of calcitonin from human medullary thyroid carcinoma cells. Klin Wochenschr 67: 635–639PubMedCrossRefGoogle Scholar
  53. Raue F, Lazaretti-Castro M, Grauer A, Ziegler R (1990) Effect of estradiol on calcitonin secretion and storage in a human C-cell carcinoma cell line. 72nd Meeting of the Endocrine Society, Abstract 1432. Available from the Endocrine SocietyGoogle Scholar
  54. Reginster JY, Deroisy R, Albert A, Denis D, Lecart MP, Collette J, Franchimont P (1989) Relationship between whole plasma calcitonin levels, calcitonin secretory capacity, and plasma levels in estrone in healthy women and postmenopausal osteoporotics. J Clin Invest 83: 1073–1077PubMedCrossRefGoogle Scholar
  55. Reuter H, Scholz H (1977) The regulation of the calcium conductance of cardiac muscle by adrenaline. J Physiol (Lond) 264: 49Google Scholar
  56. Reynolds RK, Hoekzema GS, Vogel J, Hinrichs SH, Jay G (1988) Multiple endocrine neoplasia induced by the promiscuous expression of a viral oncogene. Proc Natl Acad Sci USA 85: 3135–3139PubMedCrossRefGoogle Scholar
  57. Rosenthal W, Hescheler J, Trautwein W, Schultz G (1988) Control of voltage dependent Cat+ channels by G protein-coupled receptors. FASEB J 2: 2784–2790PubMedGoogle Scholar
  58. Saad MF, Ordonez NG, Guido JJ, Samaan NA (1984) The prognostic value of immuno staining in medullary carcinoma of the thyroid. J Clin Endocrinol Metab 54: 233–239Google Scholar
  59. Scherübl H, Raue F, Zopf G, Hoffmann J, Ziegler R (1989) Reversible desensitization of calcitonin secretion by repetitive stimulation with calcium. Mol Cell Endocrinol 63: 263–266PubMedCrossRefGoogle Scholar
  60. Scherübl H, Raue F, Zopf G, Ziegler R (1989) Calcitonin secretion and cAMPefflux from C-cells, stimulated by glucagon and either calcium or BAY K 8644. Horm Metab Res Suppl 21: 18–21PubMedCrossRefGoogle Scholar
  61. Scherübl H, Schultz G, Hescheler J (1990) A slowly inactivating calcium current works as a calcium sensor in calcitonin-secreting cells. FEBS Lett 273: 51–54PubMedCrossRefGoogle Scholar
  62. Scherübl H, Hescheler J, Schultz G, Kliemann D, Zink A, Ziegler R, Raue F (1992) Inhibition of Cat+-induced calcitonin secretion by somatostatin: roles of voltage-dependent Cat+ channels and G proteins. Cell Signal 4: 77–85PubMedCrossRefGoogle Scholar
  63. Schulz N, Propst F, Westphal H, Rosenberg M, Vande Wounde F (1990) Pheochromocytomas and C-cell thyroid neoplasms in transgenic C-mos mice, a transgenic model for the human familial neoplasia syndrome MEN II (Abstr). J Cancer Res Clin Oncol 116 Suppl:A 106–103Google Scholar
  64. Segond N, Legendre B, Tahri EH, Besnard P, Jullienne A, Moukhtar MS, Garel JM (1985) Increased level of calcitonin mRNA after 1,25-dihydroxyvitamin D3 injection in the rat. FEBS Lett 184: 268–272PubMedCrossRefGoogle Scholar
  65. Segond N, Delehage MC, Jullienne A, Taboulet J, Minvielle S, Milhaud G, Moukhtar MS (1989) Actinomycin D inhibits the rapid increase in translatable calcitonin mRNA provoked by acute calcium stimulation. Horm Metab Res 21: 489–493PubMedCrossRefGoogle Scholar
  66. Seitz PK, Cooper CW (1989) Cosecretion of calcitonin and calcitonin gene-related peptide from cultured rat medullary thyroid C-Cells. J Bone Miner Res 4: 129–134PubMedCrossRefGoogle Scholar
  67. Simpson NE, Kidd KK, Goodfellow PJ, McDermid H, Myers S, Kidd JR, Jackson CE, Duncan AMV, Farrer LA, Brasch K, Castiglione C, Genel M, Gertner J, Greenberg CR, Gasella JF, Holden JJA, White GN (1987) Assignment of multiple endocrine neoplasia type 2A to chromosome 10 by linkage. Nature 328: 528PubMedCrossRefGoogle Scholar
  68. Stolarsky-Fredman L, Left SE, Klein ES, Crenshow EB, Yeakley J, Rosenfeld MG (1990) A tissue specific enhancer in the rat-calcitonin/CGRP gene is active in both neural and endocrine cell types. Mol Endocrinol 4: 497–504PubMedCrossRefGoogle Scholar
  69. Tiegs RD, Body JJ, Barta JM, Heath H III (1986) Plasma calcitonin in primary hyperparathyroidism: failure of C-cell response to sustained hypercalcemia. J Clin Endocrinol Metab 63: 785–788PubMedCrossRefGoogle Scholar
  70. Toning O, Bucht E, Sjöberg HE (1985) Decreased plasma calcitonin response to a calcium clamp in primary hyperparathyroidism. Acta Endocrinol (Copenh) 108: 372–376Google Scholar
  71. Yang K, Pearson CE, Samaan NA (1988) Estrongen receptor and hormone responsiveness of medullary thyroid carcinoma cells in continuous culture. Cancer Res 48: 2760–2763PubMedGoogle Scholar
  72. Yatani A, Codina J, Imoto Y, Reeves JP, Birnbaumer L, Brown AM (1987) A G protein directly regulates mammalian cardiac calcium channels. Science 238: 1288–1292PubMedCrossRefGoogle Scholar
  73. Zeytin FN, Rusk S, Leff SE (1987) Calcium, dexamethasone, and the anticorticoid RU-486 differentially regulate neuropeptide synthesis in a rat C-cell line. Endocrinology 121: 361–370PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin · Heidelberg 1992

Authors and Affiliations

  • F. Raue
    • 1
  • A. Zink
    • 1
  • H. Scherübl
    • 1
  1. 1.Abteilung für Innere Medizin I - Endokrinologie und StoffwechselUniversität HeidelbergHeidelberg 1Germany

Personalised recommendations