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. 1995 Oct 10;92(21):9633–9637. doi: 10.1073/pnas.92.21.9633

Thyroid-stimulating hormone (TSH)-directed induction of the CREM gene in the thyroid gland participates in the long-term desensitization of the TSH receptor.

E Lalli 1, P Sassone-Corsi 1
PMCID: PMC40856  PMID: 7568187

Abstract

Thyroid gland function is regulated by the hypothalamic-pituitary axis via the secretion of TSH, according to environmental, developmental, and circadian stimuli. TSH modulates both the secretion of thyroid hormone and gland trophism through interaction with a specific guanine nucleotide-binding protein-coupled receptor (TSH receptor; TSH-R), which elicits the activation of the cAMP-dependent signaling pathway. After TSH stimulation, the levels of TSH-R RNA are known to decrease dramatically within a few hours. This phenomenon ultimately leads to homologous long-term desensitization of the TSH-R. Here we show that TSH drives the induction of the inducible cAMP early repressor (ICER) isoform of the cAMP response element (CRE) modulator gene both in rat thyroid gland and in the differentiated thyroid cell line FRTL-5. The kinetics of ICER protein induction mirrors the down-regulation of TSH-R mRNA. ICER binds to a CRE-like sequence in the TSH-R promoter and represses its expression. Thus, ICER induction by TSH in the thyroid gland represents a paradigm of the molecular mechanism by which pituitary hormones elicit homologous long-term desensitization.

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Selected References

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

  1. Akamizu T., Ikuyama S., Saji M., Kosugi S., Kozak C., McBride O. W., Kohn L. D. Cloning, chromosomal assignment, and regulation of the rat thyrotropin receptor: expression of the gene is regulated by thyrotropin, agents that increase cAMP levels, and thyroid autoantibodies. Proc Natl Acad Sci U S A. 1990 Aug;87(15):5677–5681. doi: 10.1073/pnas.87.15.5677. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Ambesi-Impiombato F. S., Parks L. A., Coon H. G. Culture of hormone-dependent functional epithelial cells from rat thyroids. Proc Natl Acad Sci U S A. 1980 Jun;77(6):3455–3459. doi: 10.1073/pnas.77.6.3455. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Andrews N. C., Faller D. V. A rapid micropreparation technique for extraction of DNA-binding proteins from limiting numbers of mammalian cells. Nucleic Acids Res. 1991 May 11;19(9):2499–2499. doi: 10.1093/nar/19.9.2499. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Avvedimento V. E., Musti A. M., Ueffing M., Obici S., Gallo A., Sanchez M., DeBrasi D., Gottesman M. E. Reversible inhibition of a thyroid-specific trans-acting factor by Ras. Genes Dev. 1991 Jan;5(1):22–28. doi: 10.1101/gad.5.1.22. [DOI] [PubMed] [Google Scholar]
  5. Chomczynski P., Sacchi N. Single-step method of RNA isolation by acid guanidinium thiocyanate-phenol-chloroform extraction. Anal Biochem. 1987 Apr;162(1):156–159. doi: 10.1006/abio.1987.9999. [DOI] [PubMed] [Google Scholar]
  6. Civitareale D., Castelli M. P., Falasca P., Saiardi A. Thyroid transcription factor 1 activates the promoter of the thyrotropin receptor gene. Mol Endocrinol. 1993 Dec;7(12):1589–1595. doi: 10.1210/mend.7.12.8145764. [DOI] [PubMed] [Google Scholar]
  7. Civitareale D., Lonigro R., Sinclair A. J., Di Lauro R. A thyroid-specific nuclear protein essential for tissue-specific expression of the thyroglobulin promoter. EMBO J. 1989 Sep;8(9):2537–2542. doi: 10.1002/j.1460-2075.1989.tb08391.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Delmas V., van der Hoorn F., Mellström B., Jégou B., Sassone-Corsi P. Induction of CREM activator proteins in spermatids: down-stream targets and implications for haploid germ cell differentiation. Mol Endocrinol. 1993 Nov;7(11):1502–1514. doi: 10.1210/mend.7.11.8114765. [DOI] [PubMed] [Google Scholar]
  9. Foti D., Catalfamo R., Russo D., Costante G., Filetti S. Lack of relationship between 3',5'cyclic adenosine monophosphate desensitization and thyrotropin receptor down regulation in the rat thyroid cell line FRTL5. J Endocrinol Invest. 1991 Mar;14(3):213–218. doi: 10.1007/BF03346791. [DOI] [PubMed] [Google Scholar]
  10. Foulkes N. S., Borrelli E., Sassone-Corsi P. CREM gene: use of alternative DNA-binding domains generates multiple antagonists of cAMP-induced transcription. Cell. 1991 Feb 22;64(4):739–749. doi: 10.1016/0092-8674(91)90503-q. [DOI] [PubMed] [Google Scholar]
  11. Foulkes N. S., Schlotter F., Pévet P., Sassone-Corsi P. Pituitary hormone FSH directs the CREM functional switch during spermatogenesis. Nature. 1993 Mar 18;362(6417):264–267. doi: 10.1038/362264a0. [DOI] [PubMed] [Google Scholar]
  12. Francis-Lang H., Price M., Polycarpou-Schwarz M., Di Lauro R. Cell-type-specific expression of the rat thyroperoxidase promoter indicates common mechanisms for thyroid-specific gene expression. Mol Cell Biol. 1992 Feb;12(2):576–588. doi: 10.1128/mcb.12.2.576. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Hansen C., Javaux F., Juvenal G., Vassart G., Christophe D. cAMP-dependent binding of a trans-acting factor to the thyroglobulin promoter. Biochem Biophys Res Commun. 1989 Apr 28;160(2):722–731. doi: 10.1016/0006-291x(89)92493-5. [DOI] [PubMed] [Google Scholar]
  14. Hen R., Axel R., Obici S. Activation of the beta 2-adrenergic receptor promotes growth and differentiation in thyroid cells. Proc Natl Acad Sci U S A. 1989 Jun;86(12):4785–4788. doi: 10.1073/pnas.86.12.4785. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Holmes S. D., Field J. B. Effect of endogenous TSH on the in vitro responsiveness and binding of TSH in rat thyroid tissue. Endocr Res Commun. 1980;7(4):205–219. doi: 10.3109/07435808009065973. [DOI] [PubMed] [Google Scholar]
  16. Ikuyama S., Niller H. H., Shimura H., Akamizu T., Kohn L. D. Characterization of the 5'-flanking region of the rat thyrotropin receptor gene. Mol Endocrinol. 1992 May;6(5):793–804. doi: 10.1210/mend.6.5.1318504. [DOI] [PubMed] [Google Scholar]
  17. Ikuyama S., Shimura H., Hoeffler J. P., Kohn L. D. Role of the cyclic adenosine 3',5'-monophosphate response element in efficient expression of the rat thyrotropin receptor promoter. Mol Endocrinol. 1992 Oct;6(10):1701–1715. doi: 10.1210/mend.6.10.1333054. [DOI] [PubMed] [Google Scholar]
  18. Kopp P., van Sande J., Parma J., Duprez L., Gerber H., Joss E., Jameson J. L., Dumont J. E., Vassart G. Brief report: congenital hyperthyroidism caused by a mutation in the thyrotropin-receptor gene. N Engl J Med. 1995 Jan 19;332(3):150–154. doi: 10.1056/NEJM199501193320304. [DOI] [PubMed] [Google Scholar]
  19. Lalli E., Sassone-Corsi P. Signal transduction and gene regulation: the nuclear response to cAMP. J Biol Chem. 1994 Jul 1;269(26):17359–17362. [PubMed] [Google Scholar]
  20. Ledent C., Dumont J. E., Vassart G., Parmentier M. Thyroid expression of an A2 adenosine receptor transgene induces thyroid hyperplasia and hyperthyroidism. EMBO J. 1992 Feb;11(2):537–542. doi: 10.1002/j.1460-2075.1992.tb05084.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Lefkowitz R. J., Cotecchia S., Kjelsberg M. A., Pitcher J., Koch W. J., Inglese J., Caron M. G. Adrenergic receptors: recent insights into their mechanism of activation and desensitization. Adv Second Messenger Phosphoprotein Res. 1993;28:1–9. [PubMed] [Google Scholar]
  22. Molina C. A., Foulkes N. S., Lalli E., Sassone-Corsi P. Inducibility and negative autoregulation of CREM: an alternative promoter directs the expression of ICER, an early response repressor. Cell. 1993 Dec 3;75(5):875–886. doi: 10.1016/0092-8674(93)90532-u. [DOI] [PubMed] [Google Scholar]
  23. Nagayama Y., Rapoport B. The thyrotropin receptor 25 years after its discovery: new insight after its molecular cloning. Mol Endocrinol. 1992 Feb;6(2):145–156. doi: 10.1210/mend.6.2.1569961. [DOI] [PubMed] [Google Scholar]
  24. 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]
  25. Rapoport B., Adams R. J. Induction of refractoriness to thyrotropin stimulation in cultured thyroid cells. Dependence on new protein synthesis. J Biol Chem. 1976 Nov 10;251(21):6653–6661. [PubMed] [Google Scholar]
  26. Rapoport B., Filetti S., Takai N., Seto P. Studies on the desensitization of the cyclic AMP response to thyrotropin in thyroid tissue. FEBS Lett. 1982 Sep 6;146(1):23–27. doi: 10.1016/0014-5793(82)80697-2. [DOI] [PubMed] [Google Scholar]
  27. Saji M., Akamizu T., Sanchez M., Obici S., Avvedimento E., Gottesman M. E., Kohn L. D. Regulation of thyrotropin receptor gene expression in rat FRTL-5 thyroid cells. Endocrinology. 1992 Jan;130(1):520–533. doi: 10.1210/endo.130.1.1309347. [DOI] [PubMed] [Google Scholar]
  28. Shimura H., Okajima F., Ikuyama S., Shimura Y., Kimura S., Saji M., Kohn L. D. Thyroid-specific expression and cyclic adenosine 3',5'-monophosphate autoregulation of the thyrotropin receptor gene involves thyroid transcription factor-1. Mol Endocrinol. 1994 Aug;8(8):1049–1069. doi: 10.1210/mend.8.8.7997232. [DOI] [PubMed] [Google Scholar]
  29. Shuman S. J., Zor U., Chayoth R., Field J. B. Exposure of thyroid slices to thyroid-stimulating hormone induces refractoriness of the cyclic AMP system to subsequent hormone stimulation. J Clin Invest. 1976 May;57(5):1132–1141. doi: 10.1172/JCI108380. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Stehle J. H., Foulkes N. S., Molina C. A., Simonneaux V., Pévet P., Sassone-Corsi P. Adrenergic signals direct rhythmic expression of transcriptional repressor CREM in the pineal gland. Nature. 1993 Sep 23;365(6444):314–320. doi: 10.1038/365314a0. [DOI] [PubMed] [Google Scholar]
  31. Van Heuverswyn B., Streydio C., Brocas H., Refetoff S., Dumont J., Vassart G. Thyrotropin controls transcription of the thyroglobulin gene. Proc Natl Acad Sci U S A. 1984 Oct;81(19):5941–5945. doi: 10.1073/pnas.81.19.5941. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. Witte A., Henderson B., Zakarija M., McKenzie J. M. Thyrotropin binding to rat thyroid membranes: reduced capacity associated with goitrogenesis. Endocrinology. 1980 May;106(5):1489–1497. doi: 10.1210/endo-106-5-1489. [DOI] [PubMed] [Google Scholar]
  33. Wong C. C., Döhler K. D., Atkinson M. J., Geerlings H., Hesch R. D., von zur Mühlen A. Influence of age, strain and season on diurnal periodicity of thyroid stimulating hormone, thyroxine, triiodothyronine and parathyroid hormone in the serum of male laboratory rats. Acta Endocrinol (Copenh) 1983 Mar;102(3):377–385. doi: 10.1530/acta.0.1020377. [DOI] [PubMed] [Google Scholar]
  34. de Wet J. R., Wood K. V., DeLuca M., Helinski D. R., Subramani S. Firefly luciferase gene: structure and expression in mammalian cells. Mol Cell Biol. 1987 Feb;7(2):725–737. doi: 10.1128/mcb.7.2.725. [DOI] [PMC free article] [PubMed] [Google Scholar]

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