Skip to main content
NCBI home page
Molecular and Cellular Biology logoLink to Molecular and Cellular Biology
. 1994 May;14(5):2837–2848. doi: 10.1128/mcb.14.5.2837

Induction of the rat prodynorphin gene through Gs-coupled receptors may involve phosphorylation-dependent derepression and activation.

J Collins-Hicok 1, L Lin 1, C Spiro 1, P J Laybourn 1, R Tschumper 1, B Rapacz 1, C T McMurray 1
PMCID: PMC358652  PMID: 8164647

Abstract

Prodynorphin transcription is activated via Gs-coupled receptors through a cyclic AMP (cAMP)-dependent pathway. Four cAMP response elements (CREs) are present within the rat prodynorphin (RD) control region, and all four CREs appear to function in RD regulation. Three CREs located upstream between -1860 and -1504 are critical for receptor-responsive activity, but their function is distance dependent unless they act together with a fourth CRE found in exon 1. Regulation of RD also appears to involve multiple CRE-binding proteins. Both CRE-binding protein (CREB) and activator protein 1 (AP-1) can regulate RD, but their effects are in opposite directions; CREB represses and AP-1 activates RD. CREB-induced repression and AP-1 activation require distinct elements within the control region, but their binding and functions overlap at CRE-3. While CREB repression is dependent on CRE-3, AP-1 activation (and cAMP induction) of RD requires additional CREs (CRE-1, -2, and -4). CREB repression blocks AP-1 activation in unstimulated cells. However, phosphorylation relieves CREB-induced repression and enhances AP-1 activation. Gs-coupled receptor activation of RD may require phosphorylation-dependent derepression and activation steps.

Full text

PDF
2837

Images in this article

2841Image
on p.2841
2842Image
on p.2842

Selected References

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

  1. Abate C., Luk D., Curran T. Transcriptional regulation by Fos and Jun in vitro: interaction among multiple activator and regulatory domains. Mol Cell Biol. 1991 Jul;11(7):3624–3632. doi: 10.1128/mcb.11.7.3624. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Bading H., Ginty D. D., Greenberg M. E. Regulation of gene expression in hippocampal neurons by distinct calcium signaling pathways. Science. 1993 Apr 9;260(5105):181–186. doi: 10.1126/science.8097060. [DOI] [PubMed] [Google Scholar]
  3. Brindle P. K., Montminy M. R. The CREB family of transcription activators. Curr Opin Genet Dev. 1992 Apr;2(2):199–204. doi: 10.1016/s0959-437x(05)80274-6. [DOI] [PubMed] [Google Scholar]
  4. Comb M., Birnberg N. C., Seasholtz A., Herbert E., Goodman H. M. A cyclic AMP- and phorbol ester-inducible DNA element. 1986 Sep 25-Oct 1Nature. 323(6086):353–356. doi: 10.1038/323353a0. [DOI] [PubMed] [Google Scholar]
  5. Comb M., Mermod N., Hyman S. E., Pearlberg J., Ross M. E., Goodman H. M. Proteins bound at adjacent DNA elements act synergistically to regulate human proenkephalin cAMP inducible transcription. EMBO J. 1988 Dec 1;7(12):3793–3805. doi: 10.1002/j.1460-2075.1988.tb03264.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Dignam J. D., Martin P. L., Shastry B. S., Roeder R. G. Eukaryotic gene transcription with purified components. Methods Enzymol. 1983;101:582–598. doi: 10.1016/0076-6879(83)01039-3. [DOI] [PubMed] [Google Scholar]
  7. Douglass J. O., Iadarola M. J., Hong J. S., Garrett J. E., McMurray C. T. Transcriptional regulation of the rat prodynorphin gene. NIDA Res Monogr. 1991;111:133–148. [PubMed] [Google Scholar]
  8. Douglass J., McMurray C. T., Garrett J. E., Adelman J. P., Calavetta L. Characterization of the rat prodynorphin gene. Mol Endocrinol. 1989 Dec;3(12):2070–2078. doi: 10.1210/mend-3-12-2070. [DOI] [PubMed] [Google Scholar]
  9. Dwarki V. J., Montminy M., Verma I. M. Both the basic region and the 'leucine zipper' domain of the cyclic AMP response element binding (CREB) protein are essential for transcriptional activation. EMBO J. 1990 Jan;9(1):225–232. doi: 10.1002/j.1460-2075.1990.tb08099.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Frankel A. D., Kim P. S. Modular structure of transcription factors: implications for gene regulation. Cell. 1991 May 31;65(5):717–719. doi: 10.1016/0092-8674(91)90378-c. [DOI] [PubMed] [Google Scholar]
  11. 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]
  12. Goodman R. H. Regulation of neuropeptide gene expression. Annu Rev Neurosci. 1990;13:111–127. doi: 10.1146/annurev.ne.13.030190.000551. [DOI] [PubMed] [Google Scholar]
  13. Gorman C. M., Merlino G. T., Willingham M. C., Pastan I., Howard B. H. The Rous sarcoma virus long terminal repeat is a strong promoter when introduced into a variety of eukaryotic cells by DNA-mediated transfection. Proc Natl Acad Sci U S A. 1982 Nov;79(22):6777–6781. doi: 10.1073/pnas.79.22.6777. [DOI] [PMC free article] [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. Hattori K., Angel P., Le Beau M. M., Karin M. Structure and chromosomal localization of the functional intronless human JUN protooncogene. Proc Natl Acad Sci U S A. 1988 Dec;85(23):9148–9152. doi: 10.1073/pnas.85.23.9148. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. He X., Rosenfeld M. G. Mechanisms of complex transcriptional regulation: implications for brain development. Neuron. 1991 Aug;7(2):183–196. doi: 10.1016/0896-6273(91)90257-z. [DOI] [PubMed] [Google Scholar]
  17. Hille B. G protein-coupled mechanisms and nervous signaling. Neuron. 1992 Aug;9(2):187–195. doi: 10.1016/0896-6273(92)90158-a. [DOI] [PubMed] [Google Scholar]
  18. Ho S. N., Hunt H. D., Horton R. M., Pullen J. K., Pease L. R. Site-directed mutagenesis by overlap extension using the polymerase chain reaction. Gene. 1989 Apr 15;77(1):51–59. doi: 10.1016/0378-1119(89)90358-2. [DOI] [PubMed] [Google Scholar]
  19. Huggenvik J. I., Collard M. W., Stofko R. E., Seasholtz A. F., Uhler M. D. Regulation of the human enkephalin promoter by two isoforms of the catalytic subunit of cyclic adenosine 3',5'-monophosphate-dependent protein kinase. Mol Endocrinol. 1991 Jul;5(7):921–930. doi: 10.1210/mend-5-7-921. [DOI] [PubMed] [Google Scholar]
  20. Hunter T., Karin M. The regulation of transcription by phosphorylation. Cell. 1992 Aug 7;70(3):375–387. doi: 10.1016/0092-8674(92)90162-6. [DOI] [PubMed] [Google Scholar]
  21. Iadarola M. J., Douglass J., Civelli O., Naranjo J. R. Differential activation of spinal cord dynorphin and enkephalin neurons during hyperalgesia: evidence using cDNA hybridization. Brain Res. 1988 Jul 12;455(2):205–212. doi: 10.1016/0006-8993(88)90078-9. [DOI] [PubMed] [Google Scholar]
  22. Inagaki N., Maekawa T., Sudo T., Ishii S., Seino Y., Imura H. c-Jun represses the human insulin promoter activity that depends on multiple cAMP response elements. Proc Natl Acad Sci U S A. 1992 Feb 1;89(3):1045–1049. doi: 10.1073/pnas.89.3.1045. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Kaynard A. H., McMurray C. T., Douglass J., Curry T. E., Jr, Melner M. H. Regulation of prodynorphin gene expression in the ovary: distal DNA regulatory elements confer gonadotropin regulation of promoter activity. Mol Endocrinol. 1992 Dec;6(12):2244–2256. doi: 10.1210/mend.6.12.1337148. [DOI] [PubMed] [Google Scholar]
  24. Kerppola T. K., Curran T. DNA bending by Fos and Jun: the flexible hinge model. Science. 1991 Nov 22;254(5035):1210–1214. doi: 10.1126/science.1957173. [DOI] [PubMed] [Google Scholar]
  25. Knight J. D., Li R., Botchan M. The activation domain of the bovine papillomavirus E2 protein mediates association of DNA-bound dimers to form DNA loops. Proc Natl Acad Sci U S A. 1991 Apr 15;88(8):3204–3208. doi: 10.1073/pnas.88.8.3204. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Laybourn P. J., Kadonaga J. T. Role of nucleosomal cores and histone H1 in regulation of transcription by RNA polymerase II. Science. 1991 Oct 11;254(5029):238–245. doi: 10.1126/science.254.5029.238. [DOI] [PubMed] [Google Scholar]
  27. McMurray C. T., Devi L., Calavetta L., Douglass J. O. Regulated expression of the prodynorphin gene in the R2C Leydig tumor cell line. Endocrinology. 1989 Jan;124(1):49–59. doi: 10.1210/endo-124-1-49. [DOI] [PubMed] [Google Scholar]
  28. McMurray C. T., Pollock K. M., Douglass J. Cellular and molecular analysis of opioid peptide gene expression. NIDA Res Monogr. 1992;126:113–131. [PubMed] [Google Scholar]
  29. McMurray C. T., Wilson W. D., Douglass J. O. Hairpin formation within the enhancer region of the human enkephalin gene. Proc Natl Acad Sci U S A. 1991 Jan 15;88(2):666–670. doi: 10.1073/pnas.88.2.666. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Millan M. J., Członkowski A., Pilcher C. W., Almeida O. F., Millan M. H., Colpaert F. C., Herz A. A model of chronic pain in the rat: functional correlates of alterations in the activity of opioid systems. J Neurosci. 1987 Jan;7(1):77–87. doi: 10.1523/JNEUROSCI.07-01-00077.1987. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. Millan M. J., Millan M. H., Pilcher C. W., Członkowski A., Herz A., Colpaert F. C. Spinal cord dynorphin may modulate nociception via a kappa-opioid receptor in chronic arthritic rats. Brain Res. 1985 Aug 5;340(1):156–159. doi: 10.1016/0006-8993(85)90786-3. [DOI] [PubMed] [Google Scholar]
  32. Naranjo J. R., Mellström B., Achaval M., Sassone-Corsi P. Molecular pathways of pain: Fos/Jun-mediated activation of a noncanonical AP-1 site in the prodynorphin gene. Neuron. 1991 Apr;6(4):607–617. doi: 10.1016/0896-6273(91)90063-6. [DOI] [PubMed] [Google Scholar]
  33. Ofir R., Dwarki V. J., Rashid D., Verma I. M. CREB represses transcription of fos promoter: role of phosphorylation. Gene Expr. 1991 Apr;1(1):55–60. [PMC free article] [PubMed] [Google Scholar]
  34. 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]
  35. Ruda M. A., Iadarola M. J., Cohen L. V., Young W. S., 3rd In situ hybridization histochemistry and immunocytochemistry reveal an increase in spinal dynorphin biosynthesis in a rat model of peripheral inflammation and hyperalgesia. Proc Natl Acad Sci U S A. 1988 Jan;85(2):622–626. doi: 10.1073/pnas.85.2.622. [DOI] [PMC free article] [PubMed] [Google Scholar]
  36. Sassone-Corsi P., Visvader J., Ferland L., Mellon P. L., Verma I. M. Induction of proto-oncogene fos transcription through the adenylate cyclase pathway: characterization of a cAMP-responsive element. Genes Dev. 1988 Dec;2(12A):1529–1538. doi: 10.1101/gad.2.12a.1529. [DOI] [PubMed] [Google Scholar]
  37. Sheng M., Greenberg M. E. The regulation and function of c-fos and other immediate early genes in the nervous system. Neuron. 1990 Apr;4(4):477–485. doi: 10.1016/0896-6273(90)90106-p. [DOI] [PubMed] [Google Scholar]
  38. Sheng M., Thompson M. A., Greenberg M. E. CREB: a Ca(2+)-regulated transcription factor phosphorylated by calmodulin-dependent kinases. Science. 1991 Jun 7;252(5011):1427–1430. doi: 10.1126/science.1646483. [DOI] [PubMed] [Google Scholar]
  39. Silva A. J., Paylor R., Wehner J. M., Tonegawa S. Impaired spatial learning in alpha-calcium-calmodulin kinase II mutant mice. Science. 1992 Jul 10;257(5067):206–211. doi: 10.1126/science.1321493. [DOI] [PubMed] [Google Scholar]
  40. Silva A. J., Stevens C. F., Tonegawa S., Wang Y. Deficient hippocampal long-term potentiation in alpha-calcium-calmodulin kinase II mutant mice. Science. 1992 Jul 10;257(5067):201–206. doi: 10.1126/science.1378648. [DOI] [PubMed] [Google Scholar]
  41. Sonnenberg J. L., Rauscher F. J., 3rd, Morgan J. I., Curran T. Regulation of proenkephalin by Fos and Jun. Science. 1989 Dec 22;246(4937):1622–1625. doi: 10.1126/science.2512642. [DOI] [PubMed] [Google Scholar]
  42. Spiro C., Richards J. P., Chandrasekaran S., Brennan R. G., McMurray C. T. Secondary structure creates mismatched base pairs required for high-affinity binding of cAMP response element-binding protein to the human enkephalin enhancer. Proc Natl Acad Sci U S A. 1993 May 15;90(10):4606–4610. doi: 10.1073/pnas.90.10.4606. [DOI] [PMC free article] [PubMed] [Google Scholar]
  43. Studier F. W., Moffatt B. A. Use of bacteriophage T7 RNA polymerase to direct selective high-level expression of cloned genes. J Mol Biol. 1986 May 5;189(1):113–130. doi: 10.1016/0022-2836(86)90385-2. [DOI] [PubMed] [Google Scholar]
  44. Van Nguyen T., Kobierski L., Comb M., Hyman S. E. The effect of depolarization on expression of the human proenkephalin gene is synergistic with cAMP and dependent upon a cAMP-inducible enhancer. J Neurosci. 1990 Aug;10(8):2825–2833. doi: 10.1523/JNEUROSCI.10-08-02825.1990. [DOI] [PMC free article] [PubMed] [Google Scholar]
  45. Walton K. M., Rehfuss R. P. Molecular mechanisms of cAMP-regulated gene expression. Mol Neurobiol. 1990 Fall-Winter;4(3-4):197–210. doi: 10.1007/BF02780341. [DOI] [PubMed] [Google Scholar]
  46. Wampler S. L., Tyree C. M., Kadonaga J. T. Fractionation of the general RNA polymerase II transcription factors from Drosophila embryos. J Biol Chem. 1990 Dec 5;265(34):21223–21231. [PubMed] [Google Scholar]
  47. Xie C. W., Lee P. H., Douglass J., Crain B., Hong J. S. Deep prepyriform cortex kindling differentially alters the levels of prodynorphin mRNA in rat hippocampus and striatum. Brain Res. 1989 Aug 21;495(1):156–160. doi: 10.1016/0006-8993(89)91230-4. [DOI] [PubMed] [Google Scholar]
  48. Xie C. W., Lee P. H., Takeuchi K., Owyang V., Li S. J., Douglass J., Hong J. S. Single or repeated electroconvulsive shocks alter the levels of prodynorphin and proenkephalin mRNAs in rat brain. Brain Res Mol Brain Res. 1989 Jul;6(1):11–19. doi: 10.1016/0169-328x(89)90023-5. [DOI] [PubMed] [Google Scholar]
  49. van Straaten F., Müller R., Curran T., Van Beveren C., Verma I. M. Complete nucleotide sequence of a human c-onc gene: deduced amino acid sequence of the human c-fos protein. Proc Natl Acad Sci U S A. 1983 Jun;80(11):3183–3187. doi: 10.1073/pnas.80.11.3183. [DOI] [PMC free article] [PubMed] [Google Scholar]

Articles from Molecular and Cellular Biology are provided here courtesy of Taylor & Francis

RESOURCES