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. 1990 Oct 11;18(19):5677–5683. doi: 10.1093/nar/18.19.5677

The promoter of the human parathyroid hormone gene contains a functional cyclic AMP-response element.

E Rupp 1, H Mayer 1, E Wingender 1
PMCID: PMC332300  PMID: 1977134

Abstract

We have screened the sequence of the 394 base pairs upstream of the main transcriptional start site of the promoter of the human parathyroid hormone (PTH) gene for well-known protein recognition motifs with the aim to identify potential positive or negative regulatory elements. Within this region we found a potential cAMP-response element (CRE) besides several other putative binding sites for transcription factors. We fused promoter regions that contain this element and extend beyond the transcription start site to an appropriate reporter gene (CAT) and transfected different cell lines with these constructs. Transient expression of the CAT gene from these hybrid genes could be shown to be significantly stimulated by forskolin or isoproterenol thus proving the responsiveness of the whole promoter region towards elevated cAMP levels. DNase I protection studies revealed protein binding around the putative CRE (PTH-CRE) and an adjacent CCAAT element. Gel retardation assays with the PTH-CRE as well as the well-characterized CRE from the rat somatostatin promoter indicated specific binding of the same protein to both elements, although with a slightly reduced affinity of the PTH-CRE. Both of these elements were also able to confer cAMP-responsiveness to a heterologous promoter.

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Selected References

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

  1. Andrisani O. M., Dixon J. E. Somatostatin gene regulation. Annu Rev Physiol. 1990;52:793–806. doi: 10.1146/annurev.ph.52.030190.004045. [DOI] [PubMed] [Google Scholar]
  2. Angel P., Imagawa M., Chiu R., Stein B., Imbra R. J., Rahmsdorf H. J., Jonat C., Herrlich P., Karin M. Phorbol ester-inducible genes contain a common cis element recognized by a TPA-modulated trans-acting factor. Cell. 1987 Jun 19;49(6):729–739. doi: 10.1016/0092-8674(87)90611-8. [DOI] [PubMed] [Google Scholar]
  3. Berkowitz L. A., Gilman M. Z. Two distinct forms of active transcription factor CREB (cAMP response element binding protein). Proc Natl Acad Sci U S A. 1990 Jul;87(14):5258–5262. doi: 10.1073/pnas.87.14.5258. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Birnbaumer L. Hormone-sensitive adenylyl cyclases. Useful models for studying hormone receptor functions in cell-free systems. Biochim Biophys Acta. 1973 Sep 10;300(2):129–158. doi: 10.1016/0304-4157(73)90002-6. [DOI] [PubMed] [Google Scholar]
  5. Bokar J. A., Roesler W. J., Vandenbark G. R., Kaetzel D. M., Hanson R. W., Nilson J. H. Characterization of the cAMP responsive elements from the genes for the alpha-subunit of glycoprotein hormones and phosphoenolpyruvate carboxykinase (GTP). Conserved features of nuclear protein binding between tissues and species. J Biol Chem. 1988 Dec 25;263(36):19740–19747. [PubMed] [Google Scholar]
  6. Bradford M. M. A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding. Anal Biochem. 1976 May 7;72:248–254. doi: 10.1016/0003-2697(76)90527-3. [DOI] [PubMed] [Google Scholar]
  7. Brown E. M., Hurwitz S. H., Aurbach G. D. alpha-Adrenergic inhibition of adenosine 3',5'-monophosphate accumulation and parathyroid hormone release from dispersed bovine parathyroid cells. Endocrinology. 1978 Sep;103(3):893–899. doi: 10.1210/endo-103-3-893. [DOI] [PubMed] [Google Scholar]
  8. Dean D. C., Blakeley M. S., Newby R. F., Ghazal P., Hennighausen L., Bourgeois S. Forskolin inducibility and tissue-specific expression of the fibronectin promoter. Mol Cell Biol. 1989 Apr;9(4):1498–1506. doi: 10.1128/mcb.9.4.1498. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Deutsch P. J., Hoeffler J. P., Jameson J. L., Lin J. C., Habener J. F. Structural determinants for transcriptional activation by cAMP-responsive DNA elements. J Biol Chem. 1988 Dec 5;263(34):18466–18472. [PubMed] [Google Scholar]
  10. Dignam J. D., Lebovitz R. M., Roeder R. G. Accurate transcription initiation by RNA polymerase II in a soluble extract from isolated mammalian nuclei. Nucleic Acids Res. 1983 Mar 11;11(5):1475–1489. doi: 10.1093/nar/11.5.1475. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Duarte B., Hargis G. K., Kukreja S. C. Effects of estradiol and progesterone on parathyroid hormone secretion from human parathyroid tissue. J Clin Endocrinol Metab. 1988 Mar;66(3):584–587. doi: 10.1210/jcem-66-3-584. [DOI] [PubMed] [Google Scholar]
  12. Edlund T., Walker M. D., Barr P. J., Rutter W. J. Cell-specific expression of the rat insulin gene: evidence for role of two distinct 5' flanking elements. Science. 1985 Nov 22;230(4728):912–916. doi: 10.1126/science.3904002. [DOI] [PubMed] [Google Scholar]
  13. Englander E. W., Wilson S. H. Protein binding elements in the human beta-polymerase promoter. Nucleic Acids Res. 1990 Feb 25;18(4):919–928. doi: 10.1093/nar/18.4.919. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Gonzalez G. A., Montminy M. R. Cyclic AMP stimulates somatostatin gene transcription by phosphorylation of CREB at serine 133. Cell. 1989 Nov 17;59(4):675–680. doi: 10.1016/0092-8674(89)90013-5. [DOI] [PubMed] [Google Scholar]
  15. Gonzalez G. A., Yamamoto K. K., Fischer W. H., Karr D., Menzel P., Biggs W., 3rd, Vale W. W., Montminy M. R. A cluster of phosphorylation sites on the cyclic AMP-regulated nuclear factor CREB predicted by its sequence. Nature. 1989 Feb 23;337(6209):749–752. doi: 10.1038/337749a0. [DOI] [PubMed] [Google Scholar]
  16. Gorman C. M., Moffat L. F., Howard B. H. Recombinant genomes which express chloramphenicol acetyltransferase in mammalian cells. Mol Cell Biol. 1982 Sep;2(9):1044–1051. doi: 10.1128/mcb.2.9.1044. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Graham F. L., van der Eb A. J. A new technique for the assay of infectivity of human adenovirus 5 DNA. Virology. 1973 Apr;52(2):456–467. doi: 10.1016/0042-6822(73)90341-3. [DOI] [PubMed] [Google Scholar]
  18. Greenberg C., Kukreja S. C., Bowser E. N., Hargis G. K., Henderson W. J., Williams G. A. Parathyroid hormone secretion: effect of estradiol and progesterone. Metabolism. 1987 Feb;36(2):151–154. doi: 10.1016/0026-0495(87)90009-6. [DOI] [PubMed] [Google Scholar]
  19. Hai T. W., Liu F., Coukos W. J., Green M. R. Transcription factor ATF cDNA clones: an extensive family of leucine zipper proteins able to selectively form DNA-binding heterodimers. Genes Dev. 1989 Dec;3(12B):2083–2090. doi: 10.1101/gad.3.12b.2083. [DOI] [PubMed] [Google Scholar]
  20. Hardy S., Shenk T. Adenoviral control regions activated by E1A and the cAMP response element bind to the same factor. Proc Natl Acad Sci U S A. 1988 Jun;85(12):4171–4175. doi: 10.1073/pnas.85.12.4171. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Heinrich G., Kronenberg H. M., Potts J. T., Jr, Habener J. F. Gene encoding parathyroid hormone. Nucleotide sequence of the rat gene and deduced amino acid sequence of rat preproparathyroid hormone. J Biol Chem. 1984 Mar 10;259(5):3320–3329. [PubMed] [Google Scholar]
  22. Heinrich G., Kronenberg H. M., Potts J. T., Jr, Habener J. F. Parathyroid hormone messenger ribonucleic acid: effects of calcium on cellular regulation in vitro. Endocrinology. 1983 Feb;112(2):449–458. doi: 10.1210/endo-112-2-449. [DOI] [PubMed] [Google Scholar]
  23. Herbomel P., Bourachot B., Yaniv M. Two distinct enhancers with different cell specificities coexist in the regulatory region of polyoma. Cell. 1984 Dec;39(3 Pt 2):653–662. doi: 10.1016/0092-8674(84)90472-0. [DOI] [PubMed] [Google Scholar]
  24. Hoeffler J. P., Meyer T. E., Yun Y., Jameson J. L., Habener J. F. Cyclic AMP-responsive DNA-binding protein: structure based on a cloned placental cDNA. Science. 1988 Dec 9;242(4884):1430–1433. doi: 10.1126/science.2974179. [DOI] [PubMed] [Google Scholar]
  25. Igarashi T., Okazaki T., Potter H., Gaz R., Kronenberg H. M. Cell-specific expression of the human parathyroid hormone gene in rat pituitary cells. Mol Cell Biol. 1986 May;6(5):1830–1833. doi: 10.1128/mcb.6.5.1830. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Ivashkiv L. B., Liou H. C., Kara C. J., Lamph W. W., Verma I. M., Glimcher L. H. mXBP/CRE-BP2 and c-Jun form a complex which binds to the cyclic AMP, but not to the 12-O-tetradecanoylphorbol-13-acetate, response element. Mol Cell Biol. 1990 Apr;10(4):1609–1621. doi: 10.1128/mcb.10.4.1609. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Johnson P. F., McKnight S. L. Eukaryotic transcriptional regulatory proteins. Annu Rev Biochem. 1989;58:799–839. doi: 10.1146/annurev.bi.58.070189.004055. [DOI] [PubMed] [Google Scholar]
  28. Kara C. J., Liou H. C., Ivashkiv L. B., Glimcher L. H. A cDNA for a human cyclic AMP response element-binding protein which is distinct from CREB and expressed preferentially in brain. Mol Cell Biol. 1990 Apr;10(4):1347–1357. doi: 10.1128/mcb.10.4.1347. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Kobayashi N., Russell J., Lettieri D., Sherwood L. M. Regulation of protein kinase C by extracellular calcium in bovine parathyroid cells. Proc Natl Acad Sci U S A. 1988 Jul;85(13):4857–4860. doi: 10.1073/pnas.85.13.4857. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Laimins L. A., Gruss P., Pozzatti R., Khoury G. Characterization of enhancer elements in the long terminal repeat of Moloney murine sarcoma virus. J Virol. 1984 Jan;49(1):183–189. doi: 10.1128/jvi.49.1.183-189.1984. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. Lee W., Haslinger A., Karin M., Tjian R. Activation of transcription by two factors that bind promoter and enhancer sequences of the human metallothionein gene and SV40. Nature. 1987 Jan 22;325(6102):368–372. doi: 10.1038/325368a0. [DOI] [PubMed] [Google Scholar]
  32. Luckow B., Schütz G. CAT constructions with multiple unique restriction sites for the functional analysis of eukaryotic promoters and regulatory elements. Nucleic Acids Res. 1987 Jul 10;15(13):5490–5490. doi: 10.1093/nar/15.13.5490. [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. Maekawa T., Sakura H., Kanei-Ishii C., Sudo T., Yoshimura T., Fujisawa J., Yoshida M., Ishii S. Leucine zipper structure of the protein CRE-BP1 binding to the cyclic AMP response element in brain. EMBO J. 1989 Jul;8(7):2023–2028. doi: 10.1002/j.1460-2075.1989.tb03610.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  34. Mitchell P. J., Wang C., Tjian R. Positive and negative regulation of transcription in vitro: enhancer-binding protein AP-2 is inhibited by SV40 T antigen. Cell. 1987 Sep 11;50(6):847–861. doi: 10.1016/0092-8674(87)90512-5. [DOI] [PubMed] [Google Scholar]
  35. Montminy M. R., Bilezikjian L. M. Binding of a nuclear protein to the cyclic-AMP response element of the somatostatin gene. Nature. 1987 Jul 9;328(6126):175–178. doi: 10.1038/328175a0. [DOI] [PubMed] [Google Scholar]
  36. Montminy M. R., Sevarino K. A., Wagner J. A., Mandel G., Goodman R. H. Identification of a cyclic-AMP-responsive element within the rat somatostatin gene. Proc Natl Acad Sci U S A. 1986 Sep;83(18):6682–6686. doi: 10.1073/pnas.83.18.6682. [DOI] [PMC free article] [PubMed] [Google Scholar]
  37. Morrissey J. J., Cohn D. V. Regulation of secretion of parathormone and secretory protein-I from separate intracellular pools by calcium, dibutyryl cyclic AMP, and (1)-isoproterenol. J Cell Biol. 1979 Jul;82(1):93–102. doi: 10.1083/jcb.82.1.93. [DOI] [PMC free article] [PubMed] [Google Scholar]
  38. Muff R., Fischer J. A. Parathyroid hormone secretion does not respond to changes of free calcium in electropermeabilized bovine parathyroid cells, but is stimulated with phorbol ester and cyclic AMP. Biochem Biophys Res Commun. 1986 Sep 30;139(3):1233–1238. doi: 10.1016/s0006-291x(86)80309-6. [DOI] [PubMed] [Google Scholar]
  39. Naveh-Many T., Friedlaender M. M., Mayer H., Silver J. Calcium regulates parathyroid hormone messenger ribonucleic acid (mRNA), but not calcitonin mRNA in vivo in the rat. Dominant role of 1,25-dihydroxyvitamin D. Endocrinology. 1989 Jul;125(1):275–280. doi: 10.1210/endo-125-1-275. [DOI] [PubMed] [Google Scholar]
  40. Reis A., Hecht W., Gröger R., Böhm I., Cooper D. N., Lindenmaier W., Mayer H., Schmidtke J. Cloning and sequence analysis of the human parathyroid hormone gene region. Hum Genet. 1990 Jan;84(2):119–124. doi: 10.1007/BF00208924. [DOI] [PubMed] [Google Scholar]
  41. Rickles R. J., Darrow A. L., Strickland S. Differentiation-responsive elements in the 5' region of the mouse tissue plasminogen activator gene confer two-stage regulation by retinoic acid and cyclic AMP in teratocarcinoma cells. Mol Cell Biol. 1989 Apr;9(4):1691–1704. doi: 10.1128/mcb.9.4.1691. [DOI] [PMC free article] [PubMed] [Google Scholar]
  42. Russell J., Lettieri D., Sherwood L. M. Direct regulation by calcium of cytoplasmic messenger ribonucleic acid coding for pre-proparathyroid hormone in isolated bovine parathyroid cells. J Clin Invest. 1983 Nov;72(5):1851–1855. doi: 10.1172/JCI111146. [DOI] [PMC free article] [PubMed] [Google Scholar]
  43. Sanger F., Nicklen S., Coulson A. R. DNA sequencing with chain-terminating inhibitors. Proc Natl Acad Sci U S A. 1977 Dec;74(12):5463–5467. doi: 10.1073/pnas.74.12.5463. [DOI] [PMC free article] [PubMed] [Google Scholar]
  44. Savagner P., Miyashita T., Yamada Y. Two silencers regulate the tissue-specific expression of the collagen II gene. J Biol Chem. 1990 Apr 25;265(12):6669–6674. [PubMed] [Google Scholar]
  45. Schreiber E., Matthias P., Müller M. M., Schaffner W. Rapid detection of octamer binding proteins with 'mini-extracts', prepared from a small number of cells. Nucleic Acids Res. 1989 Aug 11;17(15):6419–6419. doi: 10.1093/nar/17.15.6419. [DOI] [PMC free article] [PubMed] [Google Scholar]
  46. Seamon K. B., Padgett W., Daly J. W. Forskolin: unique diterpene activator of adenylate cyclase in membranes and in intact cells. Proc Natl Acad Sci U S A. 1981 Jun;78(6):3363–3367. doi: 10.1073/pnas.78.6.3363. [DOI] [PMC free article] [PubMed] [Google Scholar]
  47. Silver J., Naveh-Many T., Mayer H., Schmelzer H. J., Popovtzer M. M. Regulation by vitamin D metabolites of parathyroid hormone gene transcription in vivo in the rat. J Clin Invest. 1986 Nov;78(5):1296–1301. doi: 10.1172/JCI112714. [DOI] [PMC free article] [PubMed] [Google Scholar]
  48. Silver J., Russell J., Sherwood L. M. Regulation by vitamin D metabolites of messenger ribonucleic acid for preproparathyroid hormone in isolated bovine parathyroid cells. Proc Natl Acad Sci U S A. 1985 Jun;82(12):4270–4273. doi: 10.1073/pnas.82.12.4270. [DOI] [PMC free article] [PubMed] [Google Scholar]
  49. Tabor S., Richardson C. C. DNA sequence analysis with a modified bacteriophage T7 DNA polymerase. Proc Natl Acad Sci U S A. 1987 Jul;84(14):4767–4771. doi: 10.1073/pnas.84.14.4767. [DOI] [PMC free article] [PubMed] [Google Scholar]
  50. Vasicek T. J., McDevitt B. E., Freeman M. W., Fennick B. J., Hendy G. N., Potts J. T., Jr, Rich A., Kronenberg H. M. Nucleotide sequence of the human parathyroid hormone gene. Proc Natl Acad Sci U S A. 1983 Apr;80(8):2127–2131. doi: 10.1073/pnas.80.8.2127. [DOI] [PMC free article] [PubMed] [Google Scholar]
  51. Wang L. H., Tsai S. Y., Cook R. G., Beattie W. G., Tsai M. J., O'Malley B. W. COUP transcription factor is a member of the steroid receptor superfamily. Nature. 1989 Jul 13;340(6229):163–166. doi: 10.1038/340163a0. [DOI] [PubMed] [Google Scholar]
  52. Weaver C. A., Gordon D. F., Kissil M. S., Mead D. A., Kemper B. Isolation and complete nucleotide sequence of the gene for bovine parathyroid hormone. Gene. 1984 Jun;28(3):319–329. doi: 10.1016/0378-1119(84)90149-5. [DOI] [PubMed] [Google Scholar]
  53. Williams G. A., Hargis G. K., Bowser E. N., Henderson W. J., Martinez N. J. Evidence for a role of adenosine 3',5'-monophosphate in parathyroid hormone release. Endocrinology. 1973 Mar;92(3):687–691. doi: 10.1210/endo-92-3-687. [DOI] [PubMed] [Google Scholar]
  54. Wingender E. Compilation of transcription regulating proteins. Nucleic Acids Res. 1988 Mar 25;16(5):1879–1902. doi: 10.1093/nar/16.5.1879. [DOI] [PMC free article] [PubMed] [Google Scholar]
  55. Yamamoto K. K., Gonzalez G. A., Biggs W. H., 3rd, Montminy M. R. Phosphorylation-induced binding and transcriptional efficacy of nuclear factor CREB. Nature. 1988 Aug 11;334(6182):494–498. doi: 10.1038/334494a0. [DOI] [PubMed] [Google Scholar]
  56. Ziff E. B. Transcription factors: a new family gathers at the cAMP response site. Trends Genet. 1990 Mar;6(3):69–72. doi: 10.1016/0168-9525(90)90081-g. [DOI] [PubMed] [Google Scholar]

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