Skip to main content
PMC home page
Molecular and Cellular Biology logoLink to Molecular and Cellular Biology
. 1994 Dec;14(12):7731–7743. doi: 10.1128/mcb.14.12.7731

Involvement of JunD in transcriptional activation of the orphan receptor gene nur77 by nerve growth factor and membrane depolarization in PC12 cells.

J K Yoon 1, L F Lau 1
PMCID: PMC359314  PMID: 7969116

Abstract

nur77, an immediate-early gene that encodes an orphan nuclear receptor, is rapidly and transiently induced by nerve growth factor (NGF) stimulation or membrane depolarization in the rat pheochromocytoma-derived cell line PC12. The Nur77 protein can act as a potent transcription activator and may function to regulate the expression of downstream genes in response to extracellular stimuli. We show here that activation of nur77 by NGF treatment and membrane depolarization is signalled through distinct pathways. These distinct signals appear to converge on the same transcription factors acting on the same promoter elements. We show that nur77 activation by both processes requires two cis-acting AP1-like elements, NAP1 and NAP2, which contain the core sequence TGCGTCA centered at 67 and 38 nucleotides upstream of the transcription start site. The NAP elements can confer inducibility by NGF and membrane depolarization on an otherwise unresponsive heterologous promoter. We identified JunD as a key mediator of nur77 activation by reason of the following observations. (i) JunD, but not CREB or other members of the Fos/Jun family, is a component of NAP binding activity in PC12 cell nuclear extracts. (ii) JunD, but not other Fos/Jun family members, specifically transactivates the nur77 promoter through the NAP elements (iii) A dominant-negative mutant of JunD effectively abolishes the activation of nur77 by either NGF treatment or membrane depolarization. These data draw a contrast between the regulation of nur77 with that of c-fos, in which the sequence requirements for activation by NGF treatment and membrane depolarization appear separable, and CREB appears to play a role in activation by both NGF and membrane depolarization.

Full text

PDF
7731

Images in this article

7733Image
on p.7733
7734Image
on p.7734
7735Image
on p.7735
7736Image
on p.7736
7737Image
on p.7737
7737Image
on p.7737
7738Image
on p.7738
7740Image
on p.7740
7740Image
on p.7740

Selected References

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

  1. Aszódi A., Müller U., Friedrich P., Spatz H. C. Signal convergence on protein kinase A as a molecular correlate of learning. Proc Natl Acad Sci U S A. 1991 Jul 1;88(13):5832–5836. doi: 10.1073/pnas.88.13.5832. [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. Bartel D. P., Sheng M., Lau L. F., Greenberg M. E. Growth factors and membrane depolarization activate distinct programs of early response gene expression: dissociation of fos and jun induction. Genes Dev. 1989 Mar;3(3):304–313. doi: 10.1101/gad.3.3.304. [DOI] [PubMed] [Google Scholar]
  4. Christy B., Nathans D. DNA binding site of the growth factor-inducible protein Zif268. Proc Natl Acad Sci U S A. 1989 Nov;86(22):8737–8741. doi: 10.1073/pnas.86.22.8737. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Cowan N. J., Dobner P. R., Fuchs E. V., Cleveland D. W. Expression of human alpha-tubulin genes: interspecies conservation of 3' untranslated regions. Mol Cell Biol. 1983 Oct;3(10):1738–1745. doi: 10.1128/mcb.3.10.1738. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Dalton S., Treisman R. Characterization of SAP-1, a protein recruited by serum response factor to the c-fos serum response element. Cell. 1992 Feb 7;68(3):597–612. doi: 10.1016/0092-8674(92)90194-h. [DOI] [PubMed] [Google Scholar]
  7. Dash P. K., Karl K. A., Colicos M. A., Prywes R., Kandel E. R. cAMP response element-binding protein is activated by Ca2+/calmodulin- as well as cAMP-dependent protein kinase. Proc Natl Acad Sci U S A. 1991 Jun 1;88(11):5061–5065. doi: 10.1073/pnas.88.11.5061. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Davis I. J., Hazel T. G., Chen R. H., Blenis J., Lau L. F. Functional domains and phosphorylation of the orphan receptor Nur77. Mol Endocrinol. 1993 Aug;7(8):953–964. doi: 10.1210/mend.7.8.8232315. [DOI] [PubMed] [Google Scholar]
  9. Davis I. J., Hazel T. G., Lau L. F. Transcriptional activation by Nur77, a growth factor-inducible member of the steroid hormone receptor superfamily. Mol Endocrinol. 1991 Jun;5(6):854–859. doi: 10.1210/mend-5-6-854. [DOI] [PubMed] [Google Scholar]
  10. Davis I. J., Lau L. F. Endocrine and neurogenic regulation of the orphan nuclear receptors Nur77 and Nurr-1 in the adrenal glands. Mol Cell Biol. 1994 May;14(5):3469–3483. doi: 10.1128/mcb.14.5.3469. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. DeFranco C., Damon D. H., Endoh M., Wagner J. A. Nerve growth factor induces transcription of NGFIA through complex regulatory elements that are also sensitive to serum and phorbol 12-myristate 13-acetate. Mol Endocrinol. 1993 Mar;7(3):365–379. doi: 10.1210/mend.7.3.8483478. [DOI] [PubMed] [Google Scholar]
  12. Dichter M. A., Tischler A. S., Greene L. A. Nerve growth factor-induced increase in electrical excitability and acetylcholine sensitivity of a rat pheochromocytoma cell line. Nature. 1977 Aug 11;268(5620):501–504. doi: 10.1038/268501a0. [DOI] [PubMed] [Google Scholar]
  13. Fisch T. M., Prywes R., Simon M. C., Roeder R. G. Multiple sequence elements in the c-fos promoter mediate induction by cAMP. Genes Dev. 1989 Feb;3(2):198–211. doi: 10.1101/gad.3.2.198. [DOI] [PubMed] [Google Scholar]
  14. Fujita K., Lazarovici P., Guroff G. Regulation of the differentiation of PC12 pheochromocytoma cells. Environ Health Perspect. 1989 Mar;80:127–142. doi: 10.1289/ehp.8980127. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Gabellini N., Minozzi M. C., Leon A., Dal Toso R. Nerve growth factor transcriptional control of c-fos promoter transfected in cultured spinal sensory neurons. J Cell Biol. 1992 Jul;118(1):131–138. doi: 10.1083/jcb.118.1.131. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Ginty D. D., Bonni A., Greenberg M. E. Nerve growth factor activates a Ras-dependent protein kinase that stimulates c-fos transcription via phosphorylation of CREB. Cell. 1994 Jun 3;77(5):713–725. doi: 10.1016/0092-8674(94)90055-8. [DOI] [PubMed] [Google Scholar]
  17. Ginty D. D., Glowacka D., Bader D. S., Hidaka H., Wagner J. A. Induction of immediate early genes by Ca2+ influx requires cAMP-dependent protein kinase in PC12 cells. J Biol Chem. 1991 Sep 15;266(26):17454–17458. [PubMed] [Google Scholar]
  18. 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]
  19. Greenberg M. E., Ziff E. B., Greene L. A. Stimulation of neuronal acetylcholine receptors induces rapid gene transcription. Science. 1986 Oct 3;234(4772):80–83. doi: 10.1126/science.3749894. [DOI] [PubMed] [Google Scholar]
  20. Greene L. A., Tischler A. S. Establishment of a noradrenergic clonal line of rat adrenal pheochromocytoma cells which respond to nerve growth factor. Proc Natl Acad Sci U S A. 1976 Jul;73(7):2424–2428. doi: 10.1073/pnas.73.7.2424. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Hai T., Curran T. Cross-family dimerization of transcription factors Fos/Jun and ATF/CREB alters DNA binding specificity. Proc Natl Acad Sci U S A. 1991 May 1;88(9):3720–3724. doi: 10.1073/pnas.88.9.3720. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Halegoua S., Armstrong R. C., Kremer N. E. Dissecting the mode of action of a neuronal growth factor. Curr Top Microbiol Immunol. 1991;165:119–170. doi: 10.1007/978-3-642-75747-1_7. [DOI] [PubMed] [Google Scholar]
  23. Hazel T. G., Misra R., Davis I. J., Greenberg M. E., Lau L. F. Nur77 is differentially modified in PC12 cells upon membrane depolarization and growth factor treatment. Mol Cell Biol. 1991 Jun;11(6):3239–3246. doi: 10.1128/mcb.11.6.3239. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Hazel T. G., Nathans D., Lau L. F. A gene inducible by serum growth factors encodes a member of the steroid and thyroid hormone receptor superfamily. Proc Natl Acad Sci U S A. 1988 Nov;85(22):8444–8448. doi: 10.1073/pnas.85.22.8444. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Hempstead B. L., Martin-Zanca D., Kaplan D. R., Parada L. F., Chao M. V. High-affinity NGF binding requires coexpression of the trk proto-oncogene and the low-affinity NGF receptor. Nature. 1991 Apr 25;350(6320):678–683. doi: 10.1038/350678a0. [DOI] [PubMed] [Google Scholar]
  26. Herschman H. R. Primary response genes induced by growth factors and tumor promoters. Annu Rev Biochem. 1991;60:281–319. doi: 10.1146/annurev.bi.60.070191.001433. [DOI] [PubMed] [Google Scholar]
  27. Hipskind R. A., Rao V. N., Mueller C. G., Reddy E. S., Nordheim A. Ets-related protein Elk-1 is homologous to the c-fos regulatory factor p62TCF. Nature. 1991 Dec 19;354(6354):531–534. doi: 10.1038/354531a0. [DOI] [PubMed] [Google Scholar]
  28. Kaplan D. R., Hempstead B. L., Martin-Zanca D., Chao M. V., Parada L. F. The trk proto-oncogene product: a signal transducing receptor for nerve growth factor. Science. 1991 Apr 26;252(5005):554–558. doi: 10.1126/science.1850549. [DOI] [PubMed] [Google Scholar]
  29. Kaplan D. R., Martin-Zanca D., Parada L. F. Tyrosine phosphorylation and tyrosine kinase activity of the trk proto-oncogene product induced by NGF. Nature. 1991 Mar 14;350(6314):158–160. doi: 10.1038/350158a0. [DOI] [PubMed] [Google Scholar]
  30. Kobierski L. A., Chu H. M., Tan Y., Comb M. J. cAMP-dependent regulation of proenkephalin by JunD and JunB: positive and negative effects of AP-1 proteins. Proc Natl Acad Sci U S A. 1991 Nov 15;88(22):10222–10226. doi: 10.1073/pnas.88.22.10222. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. Kovary K., Bravo R. Existence of different Fos/Jun complexes during the G0-to-G1 transition and during exponential growth in mouse fibroblasts: differential role of Fos proteins. Mol Cell Biol. 1992 Nov;12(11):5015–5023. doi: 10.1128/mcb.12.11.5015. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. Kovary K., Bravo R. Expression of different Jun and Fos proteins during the G0-to-G1 transition in mouse fibroblasts: in vitro and in vivo associations. Mol Cell Biol. 1991 May;11(5):2451–2459. doi: 10.1128/mcb.11.5.2451. [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. Kunkel T. A., Roberts J. D., Zakour R. A. Rapid and efficient site-specific mutagenesis without phenotypic selection. Methods Enzymol. 1987;154:367–382. doi: 10.1016/0076-6879(87)54085-x. [DOI] [PubMed] [Google Scholar]
  34. Liu Z. G., Smith S. W., McLaughlin K. A., Schwartz L. M., Osborne B. A. Apoptotic signals delivered through the T-cell receptor of a T-cell hybrid require the immediate-early gene nur77. Nature. 1994 Jan 20;367(6460):281–284. doi: 10.1038/367281a0. [DOI] [PubMed] [Google Scholar]
  35. Marais R., Wynne J., Treisman R. The SRF accessory protein Elk-1 contains a growth factor-regulated transcriptional activation domain. Cell. 1993 Apr 23;73(2):381–393. doi: 10.1016/0092-8674(93)90237-k. [DOI] [PubMed] [Google Scholar]
  36. Masquilier D., Sassone-Corsi P. Transcriptional cross-talk: nuclear factors CREM and CREB bind to AP-1 sites and inhibit activation by Jun. J Biol Chem. 1992 Nov 5;267(31):22460–22466. [PubMed] [Google Scholar]
  37. Milbrandt J. Nerve growth factor induces a gene homologous to the glucocorticoid receptor gene. Neuron. 1988 May;1(3):183–188. doi: 10.1016/0896-6273(88)90138-9. [DOI] [PubMed] [Google Scholar]
  38. Minty A., Kedes L. Upstream regions of the human cardiac actin gene that modulate its transcription in muscle cells: presence of an evolutionarily conserved repeated motif. Mol Cell Biol. 1986 Jun;6(6):2125–2136. doi: 10.1128/mcb.6.6.2125. [DOI] [PMC free article] [PubMed] [Google Scholar]
  39. Nakabeppu Y., Ryder K., Nathans D. DNA binding activities of three murine Jun proteins: stimulation by Fos. Cell. 1988 Dec 2;55(5):907–915. doi: 10.1016/0092-8674(88)90146-8. [DOI] [PubMed] [Google Scholar]
  40. Okuno H., Suzuki T., Yoshida T., Hashimoto Y., Curran T., Iba H. Inhibition of jun transformation by a mutated fos gene: design of an anti-oncogene. Oncogene. 1991 Sep;6(9):1491–1497. [PubMed] [Google Scholar]
  41. Parkes D., Rivest S., Lee S., Rivier C., Vale W. Corticotropin-releasing factor activates c-fos, NGFI-B, and corticotropin-releasing factor gene expression within the paraventricular nucleus of the rat hypothalamus. Mol Endocrinol. 1993 Oct;7(10):1357–1367. doi: 10.1210/mend.7.10.8264665. [DOI] [PubMed] [Google Scholar]
  42. Ransone L. J., Visvader J., Wamsley P., Verma I. M. Trans-dominant negative mutants of Fos and Jun. Proc Natl Acad Sci U S A. 1990 May;87(10):3806–3810. doi: 10.1073/pnas.87.10.3806. [DOI] [PMC free article] [PubMed] [Google Scholar]
  43. Risse G., Jooss K., Neuberg M., Brüller H. J., Müller R. Asymmetrical recognition of the palindromic AP1 binding site (TRE) by Fos protein complexes. EMBO J. 1989 Dec 1;8(12):3825–3832. doi: 10.1002/j.1460-2075.1989.tb08560.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  44. Rivera V. M., Greenberg M. E. Growth factor-induced gene expression: the ups and downs of c-fos regulation. New Biol. 1990 Sep;2(9):751–758. [PubMed] [Google Scholar]
  45. Rodriguez-Pena A., Rozengurt E. Disappearance of Ca2+-sensitive, phospholipid-dependent protein kinase activity in phorbol ester-treated 3T3 cells. Biochem Biophys Res Commun. 1984 May 16;120(3):1053–1059. doi: 10.1016/s0006-291x(84)80213-2. [DOI] [PubMed] [Google Scholar]
  46. Ryder K., Lanahan A., Perez-Albuerne E., Nathans D. jun-D: a third member of the jun gene family. Proc Natl Acad Sci U S A. 1989 Mar;86(5):1500–1503. doi: 10.1073/pnas.86.5.1500. [DOI] [PMC free article] [PubMed] [Google Scholar]
  47. Ryseck R. P., Bravo R. c-JUN, JUN B, and JUN D differ in their binding affinities to AP-1 and CRE consensus sequences: effect of FOS proteins. Oncogene. 1991 Apr;6(4):533–542. [PubMed] [Google Scholar]
  48. Ryseck R. P., Macdonald-Bravo H., Mattéi M. G., Ruppert S., Bravo R. Structure, mapping and expression of a growth factor inducible gene encoding a putative nuclear hormonal binding receptor. EMBO J. 1989 Nov;8(11):3327–3335. doi: 10.1002/j.1460-2075.1989.tb08494.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  49. Sheng M., Dougan S. T., McFadden G., Greenberg M. E. Calcium and growth factor pathways of c-fos transcriptional activation require distinct upstream regulatory sequences. Mol Cell Biol. 1988 Jul;8(7):2787–2796. doi: 10.1128/mcb.8.7.2787. [DOI] [PMC free article] [PubMed] [Google Scholar]
  50. 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]
  51. Sheng M., McFadden G., Greenberg M. E. Membrane depolarization and calcium induce c-fos transcription via phosphorylation of transcription factor CREB. Neuron. 1990 Apr;4(4):571–582. doi: 10.1016/0896-6273(90)90115-v. [DOI] [PubMed] [Google Scholar]
  52. 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]
  53. Thomas S. M., DeMarco M., D'Arcangelo G., Halegoua S., Brugge J. S. Ras is essential for nerve growth factor- and phorbol ester-induced tyrosine phosphorylation of MAP kinases. Cell. 1992 Mar 20;68(6):1031–1040. doi: 10.1016/0092-8674(92)90075-n. [DOI] [PubMed] [Google Scholar]
  54. Tokumitsu H., Chijiwa T., Hagiwara M., Mizutani A., Terasawa M., Hidaka H. KN-62, 1-[N,O-bis(5-isoquinolinesulfonyl)-N-methyl-L-tyrosyl]-4-phenylpiperazi ne, a specific inhibitor of Ca2+/calmodulin-dependent protein kinase II. J Biol Chem. 1990 Mar 15;265(8):4315–4320. [PubMed] [Google Scholar]
  55. Treisman R. Identification and purification of a polypeptide that binds to the c-fos serum response element. EMBO J. 1987 Sep;6(9):2711–2717. doi: 10.1002/j.1460-2075.1987.tb02564.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  56. Treisman R. The SRE: a growth factor responsive transcriptional regulator. Semin Cancer Biol. 1990 Feb;1(1):47–58. [PubMed] [Google Scholar]
  57. Velcich A., Ziff E. B. Functional analysis of an isolated fos promoter element with AP-1 site homology reveals cell type-specific transcriptional properties. Mol Cell Biol. 1990 Dec;10(12):6273–6282. doi: 10.1128/mcb.10.12.6273. [DOI] [PMC free article] [PubMed] [Google Scholar]
  58. Vetter M. L., Martin-Zanca D., Parada L. F., Bishop J. M., Kaplan D. R. Nerve growth factor rapidly stimulates tyrosine phosphorylation of phospholipase C-gamma 1 by a kinase activity associated with the product of the trk protooncogene. Proc Natl Acad Sci U S A. 1991 Jul 1;88(13):5650–5654. doi: 10.1073/pnas.88.13.5650. [DOI] [PMC free article] [PubMed] [Google Scholar]
  59. Visvader J., Sassone-Corsi P., Verma I. M. Two adjacent promoter elements mediate nerve growth factor activation of the c-fos gene and bind distinct nuclear complexes. Proc Natl Acad Sci U S A. 1988 Dec;85(24):9474–9478. doi: 10.1073/pnas.85.24.9474. [DOI] [PMC free article] [PubMed] [Google Scholar]
  60. Watson M. A., Milbrandt J. Expression of the nerve growth factor-regulated NGFI-A and NGFI-B genes in the developing rat. Development. 1990 Sep;110(1):173–183. doi: 10.1242/dev.110.1.173. [DOI] [PubMed] [Google Scholar]
  61. Watson M. A., Milbrandt J. The NGFI-B gene, a transcriptionally inducible member of the steroid receptor gene superfamily: genomic structure and expression in rat brain after seizure induction. Mol Cell Biol. 1989 Oct;9(10):4213–4219. doi: 10.1128/mcb.9.10.4213. [DOI] [PMC free article] [PubMed] [Google Scholar]
  62. Williams G. T., Lau L. F. Activation of the inducible orphan receptor gene nur77 by serum growth factors: dissociation of immediate-early and delayed-early responses. Mol Cell Biol. 1993 Oct;13(10):6124–6136. doi: 10.1128/mcb.13.10.6124. [DOI] [PMC free article] [PubMed] [Google Scholar]
  63. Wilson T. E., Fahrner T. J., Johnston M., Milbrandt J. Identification of the DNA binding site for NGFI-B by genetic selection in yeast. Science. 1991 May 31;252(5010):1296–1300. doi: 10.1126/science.1925541. [DOI] [PubMed] [Google Scholar]
  64. Wilson T. E., Mouw A. R., Weaver C. A., Milbrandt J., Parker K. L. The orphan nuclear receptor NGFI-B regulates expression of the gene encoding steroid 21-hydroxylase. Mol Cell Biol. 1993 Feb;13(2):861–868. doi: 10.1128/mcb.13.2.861. [DOI] [PMC free article] [PubMed] [Google Scholar]
  65. Wood K. W., Sarnecki C., Roberts T. M., Blenis J. ras mediates nerve growth factor receptor modulation of three signal-transducing protein kinases: MAP kinase, Raf-1, and RSK. Cell. 1992 Mar 20;68(6):1041–1050. doi: 10.1016/0092-8674(92)90076-o. [DOI] [PubMed] [Google Scholar]
  66. Woronicz J. D., Calnan B., Ngo V., Winoto A. Requirement for the orphan steroid receptor Nur77 in apoptosis of T-cell hybridomas. Nature. 1994 Jan 20;367(6460):277–281. doi: 10.1038/367277a0. [DOI] [PubMed] [Google Scholar]
  67. 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]
  68. Yoon J. K., Lau L. F. Transcriptional activation of the inducible nuclear receptor gene nur77 by nerve growth factor and membrane depolarization in PC12 cells. J Biol Chem. 1993 Apr 25;268(12):9148–9155. [PubMed] [Google Scholar]

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

RESOURCES