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. 1992 Jan;12(1):292–301. doi: 10.1128/mcb.12.1.292

Divergent regulation of the human atrial natriuretic peptide gene by c-jun and c-fos.

B Kovacic-Milivojević 1, D G Gardner 1
PMCID: PMC364109  PMID: 1530876

Abstract

Employing transient transfection analysis in neonatal rat cardiocytes, we have demonstrated that overexpression of c-jun results in a dose-dependent induction of the human atrial natriuretic peptide (hANP) gene promoter. Studies using a series of mutations in the hANP gene promoter identified a TRE-like, cis-acting regulatory sequence which conferred c-jun sensitivity. This same region was shown to interact with the c-jun/c-fos complex in an in vitro gel mobility shift assay. Selective mutation of this site suppressed basal activity of the hANP promoter and significantly reduced c-jun-dependent activation. Overexpression of c-fos had a biphasic effect on hANP gene promoter activity. At low levels, in concert with c-jun, it activated, while at higher levels it suppressed, transcription from the hANP gene promoter. This inhibition was both cell and promoter specific. hANP gene promoter sequences which mediate c-fos-dependent inhibition appear to be separable from those responsible for the induction. In addition, the protein domains on c-fos responsible for transcriptional activation and repression can be segregated topographically, with the inhibitory activity being localized to the carboxy-terminal domain. Thus, c-fos can activate or repress hANP gene expression through two separate functional domains that act on distinct regulatory elements in the hANP gene promoter. These data imply that the ANP gene may be a physiological target for c-fos- and c-jun-dependent activity in the heart and suggest a potential mechanism linking environmental stimuli to its expression.

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Selected References

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  1. Abate C., Luk D., Gentz R., Rauscher F. J., 3rd, Curran T. Expression and purification of the leucine zipper and DNA-binding domains of Fos and Jun: both Fos and Jun contact DNA directly. Proc Natl Acad Sci U S A. 1990 Feb;87(3):1032–1036. doi: 10.1073/pnas.87.3.1032. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Angel P., Hattori K., Smeal T., Karin M. The jun proto-oncogene is positively autoregulated by its product, Jun/AP-1. Cell. 1988 Dec 2;55(5):875–885. doi: 10.1016/0092-8674(88)90143-2. [DOI] [PubMed] [Google Scholar]
  3. 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]
  4. Baeuerle P. A., Baltimore D. Activation of DNA-binding activity in an apparently cytoplasmic precursor of the NF-kappa B transcription factor. Cell. 1988 Apr 22;53(2):211–217. doi: 10.1016/0092-8674(88)90382-0. [DOI] [PubMed] [Google Scholar]
  5. Bohmann D., Bos T. J., Admon A., Nishimura T., Vogt P. K., Tjian R. Human proto-oncogene c-jun encodes a DNA binding protein with structural and functional properties of transcription factor AP-1. Science. 1987 Dec 4;238(4832):1386–1392. doi: 10.1126/science.2825349. [DOI] [PubMed] [Google Scholar]
  6. Boyle W. J., Smeal T., Defize L. H., Angel P., Woodgett J. R., Karin M., Hunter T. Activation of protein kinase C decreases phosphorylation of c-Jun at sites that negatively regulate its DNA-binding activity. Cell. 1991 Feb 8;64(3):573–584. doi: 10.1016/0092-8674(91)90241-p. [DOI] [PubMed] [Google Scholar]
  7. Chiu R., Boyle W. J., Meek J., Smeal T., Hunter T., Karin M. The c-Fos protein interacts with c-Jun/AP-1 to stimulate transcription of AP-1 responsive genes. Cell. 1988 Aug 12;54(4):541–552. doi: 10.1016/0092-8674(88)90076-1. [DOI] [PubMed] [Google Scholar]
  8. Currie M. G., Newman W. H. Evidence for alpha-1 adrenergic receptor regulation of atriopeptin release from the isolated rat heart. Biochem Biophys Res Commun. 1986 May 29;137(1):94–100. doi: 10.1016/0006-291x(86)91180-0. [DOI] [PubMed] [Google Scholar]
  9. Day M. L., Schwartz D., Wiegand R. C., Stockman P. T., Brunnert S. R., Tolunay H. E., Currie M. G., Standaert D. G., Needleman P. Ventricular atriopeptin. Unmasking of messenger RNA and peptide synthesis by hypertrophy or dexamethasone. Hypertension. 1987 May;9(5):485–491. doi: 10.1161/01.hyp.9.5.485. [DOI] [PubMed] [Google Scholar]
  10. Distel R. J., Ro H. S., Rosen B. S., Groves D. L., Spiegelman B. M. Nucleoprotein complexes that regulate gene expression in adipocyte differentiation: direct participation of c-fos. Cell. 1987 Jun 19;49(6):835–844. doi: 10.1016/0092-8674(87)90621-0. [DOI] [PubMed] [Google Scholar]
  11. 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]
  12. Gardner D. G., Gertz B. J., Deschepper C. F., Kim D. Y. Gene for the rat atrial natriuretic peptide is regulated by glucocorticoids in vitro. J Clin Invest. 1988 Oct;82(4):1275–1281. doi: 10.1172/JCI113726. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Gardner D. G., Gertz B. J., Hane S. Thyroid hormone increases rat atrial natriuretic peptide messenger ribonucleic acid accumulation in vivo and in vitro. Mol Endocrinol. 1987 Mar;1(3):260–265. doi: 10.1210/mend-1-3-260. [DOI] [PubMed] [Google Scholar]
  14. Gardner D. G., Hane S., Trachewsky D., Schenk D., Baxter J. D. Atrial natriuretic peptide mRNA is regulated by glucocorticoids in vivo. Biochem Biophys Res Commun. 1986 Sep 30;139(3):1047–1054. doi: 10.1016/s0006-291x(86)80283-2. [DOI] [PubMed] [Google Scholar]
  15. Gardner D. G., Wu J. P., LaPointe M. C., Hedges B. K., Deschepper C. F. Expression of the gene for the atrial natriuretic peptide in cardiac myocytes in vitro. Cardiovasc Drugs Ther. 1988 Nov;2(4):479–486. doi: 10.1007/BF00051186. [DOI] [PubMed] [Google Scholar]
  16. Gius D., Cao X. M., Rauscher F. J., 3rd, Cohen D. R., Curran T., Sukhatme V. P. Transcriptional activation and repression by Fos are independent functions: the C terminus represses immediate-early gene expression via CArG elements. Mol Cell Biol. 1990 Aug;10(8):4243–4255. doi: 10.1128/mcb.10.8.4243. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. 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]
  18. Iwaki K., Sukhatme V. P., Shubeita H. E., Chien K. R. Alpha- and beta-adrenergic stimulation induces distinct patterns of immediate early gene expression in neonatal rat myocardial cells. fos/jun expression is associated with sarcomere assembly; Egr-1 induction is primarily an alpha 1-mediated response. J Biol Chem. 1990 Aug 15;265(23):13809–13817. [PubMed] [Google Scholar]
  19. Izumo S., Nadal-Ginard B., Mahdavi V. Protooncogene induction and reprogramming of cardiac gene expression produced by pressure overload. Proc Natl Acad Sci U S A. 1988 Jan;85(2):339–343. doi: 10.1073/pnas.85.2.339. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Knowlton K. U., Baracchini E., Ross R. S., Harris A. N., Henderson S. A., Evans S. M., Glembotski C. C., Chien K. R. Co-regulation of the atrial natriuretic factor and cardiac myosin light chain-2 genes during alpha-adrenergic stimulation of neonatal rat ventricular cells. Identification of cis sequences within an embryonic and a constitutive contractile protein gene which mediate inducible expression. J Biol Chem. 1991 Apr 25;266(12):7759–7768. [PubMed] [Google Scholar]
  21. Komuro I., Kaida T., Shibazaki Y., Kurabayashi M., Katoh Y., Hoh E., Takaku F., Yazaki Y. Stretching cardiac myocytes stimulates protooncogene expression. J Biol Chem. 1990 Mar 5;265(7):3595–3598. [PubMed] [Google Scholar]
  22. LaPointe M. C., Deschepper C. F., Wu J. P., Gardner D. G. Extracellular calcium regulates expression of the gene for atrial natriuretic factor. Hypertension. 1990 Jan;15(1):20–28. doi: 10.1161/01.hyp.15.1.20. [DOI] [PubMed] [Google Scholar]
  23. LaPointe M. C., Wu J. P., Greenberg B., Gardner D. G. Upstream sequences confer atrial-specific expression on the human atrial natriuretic factor gene. J Biol Chem. 1988 Jul 5;263(19):9075–9078. [PubMed] [Google Scholar]
  24. Lamph W. W., Wamsley P., Sassone-Corsi P., Verma I. M. Induction of proto-oncogene JUN/AP-1 by serum and TPA. Nature. 1988 Aug 18;334(6183):629–631. doi: 10.1038/334629a0. [DOI] [PubMed] [Google Scholar]
  25. Lassar A. B., Thayer M. J., Overell R. W., Weintraub H. Transformation by activated ras or fos prevents myogenesis by inhibiting expression of MyoD1. Cell. 1989 Aug 25;58(4):659–667. doi: 10.1016/0092-8674(89)90101-3. [DOI] [PubMed] [Google Scholar]
  26. Lattion A. L., Michel J. B., Arnauld E., Corvol P., Soubrier F. Myocardial recruitment during ANF mRNA increase with volume overload in the rat. Am J Physiol. 1986 Nov;251(5 Pt 2):H890–H896. doi: 10.1152/ajpheart.1986.251.5.H890. [DOI] [PubMed] [Google Scholar]
  27. Leitman D. C., Ribeiro R. C., Mackow E. R., Baxter J. D., West B. L. Identification of a tumor necrosis factor-responsive element in the tumor necrosis factor alpha gene. J Biol Chem. 1991 May 25;266(15):9343–9346. [PubMed] [Google Scholar]
  28. Majerus P. W., Ross T. S., Cunningham T. W., Caldwell K. K., Jefferson A. B., Bansal V. S. Recent insights in phosphatidylinositol signaling. Cell. 1990 Nov 2;63(3):459–465. doi: 10.1016/0092-8674(90)90442-h. [DOI] [PubMed] [Google Scholar]
  29. Nadal-Ginard B., Mahdavi V. Molecular basis of cardiac performance. Plasticity of the myocardium generated through protein isoform switches. J Clin Invest. 1989 Dec;84(6):1693–1700. doi: 10.1172/JCI114351. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Nielsen D. A., Chou J., MacKrell A. J., Casadaban M. J., Steiner D. F. Expression of a preproinsulin-beta-galactosidase gene fusion in mammalian cells. Proc Natl Acad Sci U S A. 1983 Sep;80(17):5198–5202. doi: 10.1073/pnas.80.17.5198. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. Nishizuka Y. Studies and perspectives of protein kinase C. Science. 1986 Jul 18;233(4761):305–312. doi: 10.1126/science.3014651. [DOI] [PubMed] [Google Scholar]
  32. O'Shea E. K., Rutkowski R., Stafford W. F., 3rd, Kim P. S. Preferential heterodimer formation by isolated leucine zippers from fos and jun. Science. 1989 Aug 11;245(4918):646–648. doi: 10.1126/science.2503872. [DOI] [PubMed] [Google Scholar]
  33. Ofir R., Dwarki V. J., Rashid D., Verma I. M. Phosphorylation of the C terminus of Fos protein is required for transcriptional transrepression of the c-fos promoter. Nature. 1990 Nov 1;348(6296):80–82. doi: 10.1038/348080a0. [DOI] [PubMed] [Google Scholar]
  34. Parker T. G., Chow K. L., Schwartz R. J., Schneider M. D. Differential regulation of skeletal alpha-actin transcription in cardiac muscle by two fibroblast growth factors. Proc Natl Acad Sci U S A. 1990 Sep;87(18):7066–7070. doi: 10.1073/pnas.87.18.7066. [DOI] [PMC free article] [PubMed] [Google Scholar]
  35. Parker T. G., Packer S. E., Schneider M. D. Peptide growth factors can provoke "fetal" contractile protein gene expression in rat cardiac myocytes. J Clin Invest. 1990 Feb;85(2):507–514. doi: 10.1172/JCI114466. [DOI] [PMC free article] [PubMed] [Google Scholar]
  36. Rauscher F. J., 3rd, Voulalas P. J., Franza B. R., Jr, Curran T. Fos and Jun bind cooperatively to the AP-1 site: reconstitution in vitro. Genes Dev. 1988 Dec;2(12B):1687–1699. doi: 10.1101/gad.2.12b.1687. [DOI] [PubMed] [Google Scholar]
  37. Rivera V. M., Sheng M., Greenberg M. E. The inner core of the serum response element mediates both the rapid induction and subsequent repression of c-fos transcription following serum stimulation. Genes Dev. 1990 Feb;4(2):255–268. doi: 10.1101/gad.4.2.255. [DOI] [PubMed] [Google Scholar]
  38. Ruskoaho H., Toth M., Lang R. E. Atrial natriuretic peptide secretion: synergistic effect of phorbol ester and A23187. Biochem Biophys Res Commun. 1985 Dec 17;133(2):581–588. doi: 10.1016/0006-291x(85)90945-3. [DOI] [PubMed] [Google Scholar]
  39. Sassone-Corsi P., Lamph W. W., Kamps M., Verma I. M. fos-associated cellular p39 is related to nuclear transcription factor AP-1. Cell. 1988 Aug 12;54(4):553–560. doi: 10.1016/0092-8674(88)90077-3. [DOI] [PubMed] [Google Scholar]
  40. Sassone-Corsi P., Sisson J. C., Verma I. M. Transcriptional autoregulation of the proto-oncogene fos. Nature. 1988 Jul 28;334(6180):314–319. doi: 10.1038/334314a0. [DOI] [PubMed] [Google Scholar]
  41. Schönthal A., Büscher M., Angel P., Rahmsdorf H. J., Ponta H., Hattori K., Chiu R., Karin M., Herrlich P. The Fos and Jun/AP-1 proteins are involved in the downregulation of Fos transcription. Oncogene. 1989 May;4(5):629–636. [PubMed] [Google Scholar]
  42. Sharp J. W., Sagar S. M., Hisanaga K., Jasper P., Sharp F. R. The NMDA receptor mediates cortical induction of fos and fos-related antigens following cortical injury. Exp Neurol. 1990 Sep;109(3):323–332. doi: 10.1016/s0014-4886(05)80023-8. [DOI] [PubMed] [Google Scholar]
  43. Shubeita H. E., McDonough P. M., Harris A. N., Knowlton K. U., Glembotski C. C., Brown J. H., Chien K. R. Endothelin induction of inositol phospholipid hydrolysis, sarcomere assembly, and cardiac gene expression in ventricular myocytes. A paracrine mechanism for myocardial cell hypertrophy. J Biol Chem. 1990 Nov 25;265(33):20555–20562. [PubMed] [Google Scholar]
  44. Starksen N. F., Simpson P. C., Bishopric N., Coughlin S. R., Lee W. M., Escobedo J. A., Williams L. T. Cardiac myocyte hypertrophy is associated with c-myc protooncogene expression. Proc Natl Acad Sci U S A. 1986 Nov;83(21):8348–8350. doi: 10.1073/pnas.83.21.8348. [DOI] [PMC free article] [PubMed] [Google Scholar]
  45. Turner R., Tjian R. Leucine repeats and an adjacent DNA binding domain mediate the formation of functional cFos-cJun heterodimers. Science. 1989 Mar 31;243(4899):1689–1694. doi: 10.1126/science.2494701. [DOI] [PubMed] [Google Scholar]
  46. Wu J. P., Deschepper C. F., Gardner D. G. Perinatal expression of the atrial natriuretic factor gene in rat cardiac tissue. Am J Physiol. 1988 Sep;255(3 Pt 1):E388–E396. doi: 10.1152/ajpendo.1988.255.3.E388. [DOI] [PubMed] [Google Scholar]
  47. Wu J. P., Kovacic-Milivojević B., Lapointe M. C., Nakamura K., Gardner D. G. Cis-active determinants of cardiac-specific expression in the human atrial natriuretic peptide gene. Mol Endocrinol. 1991 Sep;5(9):1311–1322. doi: 10.1210/mend-5-9-1311. [DOI] [PubMed] [Google Scholar]
  48. de Bold A. J., Borenstein H. B., Veress A. T., Sonnenberg H. A rapid and potent natriuretic response to intravenous injection of atrial myocardial extract in rats. Life Sci. 1981 Jan 5;28(1):89–94. doi: 10.1016/0024-3205(81)90370-2. [DOI] [PubMed] [Google Scholar]

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