Skip to main content
NCBI home page
Proceedings of the National Academy of Sciences of the United States of America logoLink to Proceedings of the National Academy of Sciences of the United States of America
. 1989 May;86(9):3036–3040. doi: 10.1073/pnas.86.9.3036

Regulation of the gastrin promoter by epidermal growth factor and neuropeptides.

J M Godley 1, S J Brand 1
PMCID: PMC287059  PMID: 2566164

Abstract

The regulation of gastrin gene transcription was studied in GH4 pituitary cells transfected with constructs comprised of the first exon of the human gastrin gene and various lengths of 5' regulatory sequences ligated upstream of the reporter gene chloramphenicol acetyltransferase. Gastrin reporter gene activity in GH4 cells was equal to the activity of a reporter gene transcribed from the endogenously expressed growth hormone promoter. The effect of a variety of peptides on gastrin gene transcription including epidermal growth factor (normally present in the gastric lumen), gastrin-releasing peptide, vasoactive intestinal peptide, and somatostatin (present in gastric nerves) was assessed. Epidermal growth factor increased the rate of gastrin transcription almost 3-fold, whereas thyrotropin-releasing hormone and vasoactive intestinal peptide increased gastrin transcription 2- and 1.5-fold, respectively. Gastrin-releasing peptide, a peptide that strongly stimulates gastrin release, weakly increased gastrin transcription (1.3-fold). Somatostatin inhibited the increase in gastrin transcription induced by epidermal growth factor, thyrotropin-releasing hormone, and vasoactive intestinal peptide. Constructs containing various lengths of 5' regulatory sequences defined a response element -40 to -82 base pairs (bp) 5' to the transcription initiation site. This 40-bp sequence contains Sp1 and AP2 binding sites, which suggests that epidermal growth factor and thyrotropin-releasing hormone stimulate gastrin gene transcription through transcription factors that bind to Sp1 and/or AP2 motifs.

Full text

PDF
3036

Images in this article

3037Image
on p.3037
3037Image
on p.3037
3037Image
on p.3037
3037Image
on p.3037
3038Image
on p.3038
3038Image
on p.3038
3039Image
on p.3039

Selected References

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

  1. Bachrach L. K., Eggo M. C., Mak W. W., Burrow G. N. Phorbol esters stimulate growth and inhibit differentiation in cultured thyroid cells. Endocrinology. 1985 Apr;116(4):1603–1609. doi: 10.1210/endo-116-4-1603. [DOI] [PubMed] [Google Scholar]
  2. Barinaga M., Bilezikjian L. M., Vale W. W., Rosenfeld M. G., Evans R. M. Independent effects of growth hormone releasing factor on growth hormone release and gene transcription. Nature. 1985 Mar 21;314(6008):279–281. doi: 10.1038/314279a0. [DOI] [PubMed] [Google Scholar]
  3. 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]
  4. Brand S. J., Fuller P. J. Differential gastrin gene expression in rat gastrointestinal tract and pancreas during neonatal development. J Biol Chem. 1988 Apr 15;263(11):5341–5347. [PubMed] [Google Scholar]
  5. Brand S. J., Stone D. Reciprocal regulation of antral gastrin and somatostatin gene expression by omeprazole-induced achlorhydria. J Clin Invest. 1988 Sep;82(3):1059–1066. doi: 10.1172/JCI113662. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Bunnett N. W., Clark B., Debas H. T., Del Milton R. C., Kovacs T. O., Orloff M. S., Pappas T. N., Reeve J. R., Jr, Rivier J. E., Walsh J. H. Canine bombesin-like gastrin releasing peptides stimulate gastrin release and acid secretion in the dog. J Physiol. 1985 Aug;365:121–130. doi: 10.1113/jphysiol.1985.sp015762. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Chen W. S., Lazar C. S., Poenie M., Tsien R. Y., Gill G. N., Rosenfeld M. G. Requirement for intrinsic protein tyrosine kinase in the immediate and late actions of the EGF receptor. 1987 Aug 27-Sep 2Nature. 328(6133):820–823. doi: 10.1038/328820a0. [DOI] [PubMed] [Google Scholar]
  8. Dannies P. S., Gautvik K. M., Tashjian A. H., Jr A possible role of cyclic AMP in mediating the effects of thyrotropin-releasing hormone on prolactin release and on prolactin and growth hormone synthesis in pituitary cells in culture. Endocrinology. 1976 May;98(5):1147–1159. doi: 10.1210/endo-98-5-1147. [DOI] [PubMed] [Google Scholar]
  9. Dockray G. J., Vaillant C., Walsh J. H. The neuronal origin of bombesin-like immunoreactivity in the rat gastrointestinal tract. Neuroscience. 1979;4(11):1561–1568. doi: 10.1016/0306-4522(79)90019-8. [DOI] [PubMed] [Google Scholar]
  10. Dorflinger L. J., Schonbrunn A. Somatostatin inhibits vasoactive intestinal peptide-stimulated cyclic adenosine monophosphate accumulation in GH pituitary cells. Endocrinology. 1983 Nov;113(5):1541–1550. doi: 10.1210/endo-113-5-1541. [DOI] [PubMed] [Google Scholar]
  11. Elsholtz H. P., Mangalam H. J., Potter E., Albert V. R., Supowit S., Evans R. M., Rosenfeld M. G. Two different cis-active elements transfer the transcriptional effects of both EGF and phorbol esters. Science. 1986 Dec 19;234(4783):1552–1557. doi: 10.1126/science.3491428. [DOI] [PubMed] [Google Scholar]
  12. Fearon C. W., Tashjian A. H., Jr Thyrotropin-releasing hormone induces redistribution of protein kinase C in GH4C1 rat pituitary cells. J Biol Chem. 1985 Jul 15;260(14):8366–8371. [PubMed] [Google Scholar]
  13. Giraud A. S., Soll A. H., Cuttitta F., Walsh J. H. Bombesin stimulation of gastrin release from canine gastrin cells in primary culture. Am J Physiol. 1987 Mar;252(3 Pt 1):G413–G420. doi: 10.1152/ajpgi.1987.252.3.G413. [DOI] [PubMed] [Google Scholar]
  14. 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]
  15. Gregory H., Walsh S., Hopkins C. R. The identification of urogastrone in serum, saliva, and gastric juice. Gastroenterology. 1979 Aug;77(2):313–318. [PubMed] [Google Scholar]
  16. Hepler J. R., Nakahata N., Lovenberg T. W., DiGuiseppi J., Herman B., Earp H. S., Harden T. K. Epidermal growth factor stimulates the rapid accumulation of inositol (1,4,5)-trisphosphate and a rise in cytosolic calcium mobilized from intracellular stores in A431 cells. J Biol Chem. 1987 Mar 5;262(7):2951–2956. [PubMed] [Google Scholar]
  17. Hinkle P. M., Tashjian A. H., Jr Receptors for thyrotropin-releasing hormone in prolactin producing rat pituitary cells in culture. J Biol Chem. 1973 Sep 10;248(17):6180–6186. [PubMed] [Google Scholar]
  18. Höller M., Westin G., Jiricny J., Schaffner W. Sp1 transcription factor binds DNA and activates transcription even when the binding site is CpG methylated. Genes Dev. 1988 Sep;2(9):1127–1135. doi: 10.1101/gad.2.9.1127. [DOI] [PubMed] [Google Scholar]
  19. Imagawa M., Chiu R., Karin M. Transcription factor AP-2 mediates induction by two different signal-transduction pathways: protein kinase C and cAMP. Cell. 1987 Oct 23;51(2):251–260. doi: 10.1016/0092-8674(87)90152-8. [DOI] [PubMed] [Google Scholar]
  20. Ito R., Sato K., Helmer T., Jay G., Agarwal K. Structural analysis of the gene encoding human gastrin: the large intron contains an Alu sequence. Proc Natl Acad Sci U S A. 1984 Aug;81(15):4662–4666. doi: 10.1073/pnas.81.15.4662. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Jameson J. L., Deutsch P. J., Gallagher G. D., Jaffe R. C., Habener J. F. trans-acting factors interact with a cyclic AMP response element to modulate expression of the human gonadotropin alpha gene. Mol Cell Biol. 1987 Sep;7(9):3032–3040. doi: 10.1128/mcb.7.9.3032. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Johnson L. R. New aspects of the trophic action of gastrointestinal hormones. Gastroenterology. 1977 Apr;72(4 PT2):788–792. [PubMed] [Google Scholar]
  23. Koch B. D., Dorflinger L. J., Schonbrunn A. Pertussis toxin blocks both cyclic AMP-mediated and cyclic AMP-independent actions of somatostatin. Evidence for coupling of Ni to decreases in intracellular free calcium. J Biol Chem. 1985 Oct 25;260(24):13138–13145. [PubMed] [Google Scholar]
  24. Larsen P. R., Harney J. W., Moore D. D. Repression mediates cell-type-specific expression of the rat growth hormone gene. Proc Natl Acad Sci U S A. 1986 Nov;83(21):8283–8287. doi: 10.1073/pnas.83.21.8283. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Larsson L. I. Peptide secretory pathways in GI tract: cytochemical contributions to regulatory physiology of the gut. Am J Physiol. 1980 Oct;239(4):G237–G246. doi: 10.1152/ajpgi.1980.239.4.G237. [DOI] [PubMed] [Google Scholar]
  26. Lewis E. J., Chikaraishi D. M. Regulated expression of the tyrosine hydroxylase gene by epidermal growth factor. Mol Cell Biol. 1987 Sep;7(9):3332–3336. doi: 10.1128/mcb.7.9.3332. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Lin M. C., Darfler F. J., Beckner S. K. Induction of glucagon sensitivity in a transformed kidney cell line by prostaglandin E2 and its inhibition by epidermal growth factor. Mol Cell Biol. 1987 Dec;7(12):4324–4328. doi: 10.1128/mcb.7.12.4324. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Lopata M. A., Cleveland D. W., Sollner-Webb B. High level transient expression of a chloramphenicol acetyl transferase gene by DEAE-dextran mediated DNA transfection coupled with a dimethyl sulfoxide or glycerol shock treatment. Nucleic Acids Res. 1984 Jul 25;12(14):5707–5717. doi: 10.1093/nar/12.14.5707. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Martin T. F., Lucas D. O., Bajjalieh S. M., Kowalchyk J. A. Thyrotropin-releasing hormone activates a Ca2+-dependent polyphosphoinositide phosphodiesterase in permeable GH3 cells. GTP gamma S potentiation by a cholera and pertussis toxin-insensitive mechanism. J Biol Chem. 1986 Feb 25;261(6):2918–2927. [PubMed] [Google Scholar]
  30. Miller L. R., Jacobson E. D., Johnson L. R. Effect of pentagastrin on gastric mucosal cells grown in tissue culture. Gastroenterology. 1973 Feb;64(2):254–267. [PubMed] [Google Scholar]
  31. Nishizuka Y. The molecular heterogeneity of protein kinase C and its implications for cellular regulation. Nature. 1988 Aug 25;334(6184):661–665. doi: 10.1038/334661a0. [DOI] [PubMed] [Google Scholar]
  32. Powell C. T., Ney C., Aran P., Agarwal K. A gastrin gene is expressed in both porcine pituitary and antral mucosal tissues. Nucleic Acids Res. 1985 Oct 25;13(20):7299–7305. doi: 10.1093/nar/13.20.7299. [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. Prost E., Moore D. D. CAT vectors for analysis of eukaryotic promoters and enhancers. Gene. 1986;45(1):107–111. doi: 10.1016/0378-1119(86)90138-1. [DOI] [PubMed] [Google Scholar]
  34. Ramsdell J. S., Tashjian A. H., Jr Thyrotropin-releasing hormone and epidermal growth factor stimulate prolactin synthesis by a pathway(s) that differs from that used by phorbol esters: dissociation of actions by calcium dependency and additivity. Endocrinology. 1985 Nov;117(5):2050–2060. doi: 10.1210/endo-117-5-2050. [DOI] [PubMed] [Google Scholar]
  35. Rehfeld J. F. Accumulation of nonamidated preprogastrin and preprocholecystokinin products in porcine pituitary corticotrophs. Evidence of post-translational control of cell differentiation. J Biol Chem. 1986 May 5;261(13):5841–5847. [PubMed] [Google Scholar]
  36. Roesler W. J., Vandenbark G. R., Hanson R. W. Cyclic AMP and the induction of eukaryotic gene transcription. J Biol Chem. 1988 Jul 5;263(19):9063–9066. [PubMed] [Google Scholar]
  37. Roger P. P., Van Heuverswyn B., Lambert C., Reuse S., Vassart G., Dumont J. E. Antagonistic effects of thyrotropin and epidermal growth factor on thyroglobulin mRNA level in cultured thyroid cells. Eur J Biochem. 1985 Oct 15;152(2):239–245. doi: 10.1111/j.1432-1033.1985.tb09189.x. [DOI] [PubMed] [Google Scholar]
  38. Schonbrunn A., Krasnoff M., Westendorf J. M., Tashjian A. H., Jr Epidermal growth factor and thyrotropin-releasing hormone act similarly on a clonal pituitary cell strain. Modulation of hormone production and inhbition of cell proliferation. J Cell Biol. 1980 Jun;85(3):786–797. doi: 10.1083/jcb.85.3.786. [DOI] [PMC free article] [PubMed] [Google Scholar]
  39. Schonbrunn A., Tashjian H., Jr Characterization of functional receptors for somatostatin in rat pituitary cells in culture. J Biol Chem. 1978 Sep 25;253(18):6473–6483. [PubMed] [Google Scholar]
  40. Sompayrac L. M., Danna K. J. Efficient infection of monkey cells with DNA of simian virus 40. Proc Natl Acad Sci U S A. 1981 Dec;78(12):7575–7578. doi: 10.1073/pnas.78.12.7575. [DOI] [PMC free article] [PubMed] [Google Scholar]
  41. St Hilaire R. J., Jones A. L. Epidermal growth factor: its biologic and metabolic effects with emphasis on the hepatocyte. Hepatology. 1982 Sep-Oct;2(5):601–613. doi: 10.1002/hep.1840020515. [DOI] [PubMed] [Google Scholar]
  42. Sugano K., Park J., Soll A. H., Yamada T. Stimulation of gastrin release by bombesin and canine gastrin-releasing peptides. Studies with isolated canine G cells in primary culture. J Clin Invest. 1987 Mar;79(3):935–942. doi: 10.1172/JCI112904. [DOI] [PMC free article] [PubMed] [Google Scholar]
  43. Supowit S. C., Potter E., Evans R. M., Rosenfeld M. G. Polypeptide hormone regulation of gene transcription: specific 5' genomic sequences are required for epidermal growth factor and phorbol ester regulation of prolactin gene expression. Proc Natl Acad Sci U S A. 1984 May;81(10):2975–2979. doi: 10.1073/pnas.81.10.2975. [DOI] [PMC free article] [PubMed] [Google Scholar]
  44. Takuwa N., Takuwa Y., Bollag W. E., Rasmussen H. The effects of bombesin on polyphosphoinositide and calcium metabolism in Swiss 3T3 cells. J Biol Chem. 1987 Jan 5;262(1):182–188. [PubMed] [Google Scholar]
  45. Tan K. N., Tashjian A. H., Jr Voltage-dependent calcium channels in pituitary cells in culture. II. Participation in thyrotropin-releasing hormone action on prolactin release. J Biol Chem. 1984 Jan 10;259(1):427–434. [PubMed] [Google Scholar]
  46. Thompson J. F. Specific receptors for epidermal growth factor in rat intestinal microvillus membranes. Am J Physiol. 1988 Mar;254(3 Pt 1):G429–G435. doi: 10.1152/ajpgi.1988.254.3.G429. [DOI] [PubMed] [Google Scholar]
  47. Ulshen M. H., Lyn-Cook L. E., Raasch R. H. Effects of intraluminal epidermal growth factor on mucosal proliferation in the small intestine of adult rats. Gastroenterology. 1986 Nov;91(5):1134–1140. doi: 10.1016/s0016-5085(86)80008-7. [DOI] [PubMed] [Google Scholar]
  48. Walsh J. H., Grossman M. I. Gastrin (first of two parts). N Engl J Med. 1975 Jun 19;292(25):1324–1334. doi: 10.1056/NEJM197506192922505. [DOI] [PubMed] [Google Scholar]
  49. Westendorf J. M., Schonbrunn A. Bombesin stimulates prolactin and growth hormone release by pituitary cells in culture. Endocrinology. 1982 Feb;110(2):352–358. doi: 10.1210/endo-110-2-352. [DOI] [PubMed] [Google Scholar]
  50. White B. A., Bancroft F. C. Epidermal growth factor and thyrotropin-releasing hormone interact synergistically with calcium to regulate prolactin mRNA levels. J Biol Chem. 1983 Apr 10;258(7):4618–4622. [PubMed] [Google Scholar]
  51. Whiteley B., Glaser L. Epidermal growth factor (EGF) promotes phosphorylation at threonine-654 of the EGF receptor: possible role of protein kinase C in homologous regulation of the EGF receptor. J Cell Biol. 1986 Oct;103(4):1355–1362. doi: 10.1083/jcb.103.4.1355. [DOI] [PMC free article] [PubMed] [Google Scholar]
  52. Wu L. C., Morley B. J., Campbell R. D. Cell-specific expression of the human complement protein factor B gene: evidence for the role of two distinct 5'-flanking elements. Cell. 1987 Jan 30;48(2):331–342. doi: 10.1016/0092-8674(87)90436-3. [DOI] [PubMed] [Google Scholar]
  53. Yajima Y., Akita Y., Saito T. Pertussis toxin blocks the inhibitory effects of somatostatin on cAMP-dependent vasoactive intestinal peptide and cAMP-independent thyrotropin releasing hormone-stimulated prolactin secretion of GH3 cells. J Biol Chem. 1986 Feb 25;261(6):2684–2689. [PubMed] [Google Scholar]

Articles from Proceedings of the National Academy of Sciences of the United States of America are provided here courtesy of National Academy of Sciences

RESOURCES