Skip to main content
PMC home page
The EMBO Journal logoLink to The EMBO Journal
. 1997 Apr 15;16(8):1865–1875. doi: 10.1093/emboj/16.8.1865

Functional redundancy of the Nur77 and Nor-1 orphan steroid receptors in T-cell apoptosis.

L E Cheng 1, F K Chan 1, D Cado 1, A Winoto 1
PMCID: PMC1169790  PMID: 9155013

Abstract

The transcription factor Nur77 (NGFI-B), a member of the steroid nuclear receptor superfamily, is induced to a high level during T-cell receptor (TCR)-mediated apoptosis. A transgenic dominant-negative Nur77 protein can inhibit the apoptotic process accompanying negative selection in thymocytes, while constitutive expression of Nur77 leads to massive cell death. Nur77-deficient mice, however, have no phenotype, suggesting the possible existence of a protein with redundant function to Nur77. To explore this possibility, we have characterized the role of two Nur77 family members, Nurr1 and Nor-1, in TCR-induced apoptosis. We found that Nor-1 and Nurr1 can transactivate through the same DNA element as Nur77, and that their transactivation activities can be blocked by a Nur77 dominant-negative protein. In thymocytes, Nor-1 protein is induced to a very high level upon TCR stimulation and has similar kinetics to Nur77. In contrast, Nurr1 is undetectable in stimulated thymocytes. Furthermore, constitutive expression of Nor-1 in thymocytes leads to massive apoptosis and up-regulation of CD25, suggesting a functional redundancy between Nur77 and Nor-1 gene products. As in the case of our Nur77-FL mice, FasL is not detectable in the thymocytes of Nor-1 transgenic mice. Constitutive expression of Nur77 in gld/gld mice rescues the lymphoproliferative phenotype of the FasL mutant mice. Thus, Nor-1 and Nur77 demonstrate functional redundancy in an apparently Fas-independent apoptosis.

Full Text

The Full Text of this article is available as a PDF (600.9 KB).

Selected References

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

  1. Abbas A. K. Die and let live: eliminating dangerous lymphocytes. Cell. 1996 Mar 8;84(5):655–657. doi: 10.1016/s0092-8674(00)81042-9. [DOI] [PubMed] [Google Scholar]
  2. Allen P. M. Peptides in positive and negative selection: a delicate balance. Cell. 1994 Feb 25;76(4):593–596. doi: 10.1016/0092-8674(94)90497-9. [DOI] [PubMed] [Google Scholar]
  3. Caamaño J. H., Perez P., Lira S. A., Bravo R. Constitutive expression of Bc1-3 in thymocytes increases the DNA binding of NF-kappaB1 (p50) homodimers in vivo. Mol Cell Biol. 1996 Apr;16(4):1342–1348. doi: 10.1128/mcb.16.4.1342. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Calnan B. J., Szychowski S., Chan F. K., Cado D., Winoto A. A role for the orphan steroid receptor Nur77 in apoptosis accompanying antigen-induced negative selection. Immunity. 1995 Sep;3(3):273–282. doi: 10.1016/1074-7613(95)90113-2. [DOI] [PubMed] [Google Scholar]
  5. Carson-Jurica M. A., Schrader W. T., O'Malley B. W. Steroid receptor family: structure and functions. Endocr Rev. 1990 May;11(2):201–220. doi: 10.1210/edrv-11-2-201. [DOI] [PubMed] [Google Scholar]
  6. Chaffin K. E., Beals C. R., Wilkie T. M., Forbush K. A., Simon M. I., Perlmutter R. M. Dissection of thymocyte signaling pathways by in vivo expression of pertussis toxin ADP-ribosyltransferase. EMBO J. 1990 Dec;9(12):3821–3829. doi: 10.1002/j.1460-2075.1990.tb07600.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Chan F. K., Zhang J., Cheng L., Shapiro D. N., Winoto A. Identification of human and mouse p19, a novel CDK4 and CDK6 inhibitor with homology to p16ink4. Mol Cell Biol. 1995 May;15(5):2682–2688. doi: 10.1128/mcb.15.5.2682. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Cohen P. L., Eisenberg R. A. Lpr and gld: single gene models of systemic autoimmunity and lymphoproliferative disease. Annu Rev Immunol. 1991;9:243–269. doi: 10.1146/annurev.iy.09.040191.001331. [DOI] [PubMed] [Google Scholar]
  9. Crawford P. A., Sadovsky Y., Woodson K., Lee S. L., Milbrandt J. Adrenocortical function and regulation of the steroid 21-hydroxylase gene in NGFI-B-deficient mice. Mol Cell Biol. 1995 Aug;15(8):4331–4316. doi: 10.1128/mcb.15.8.4331. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. 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]
  11. Forman B. M., Umesono K., Chen J., Evans R. M. Unique response pathways are established by allosteric interactions among nuclear hormone receptors. Cell. 1995 May 19;81(4):541–550. doi: 10.1016/0092-8674(95)90075-6. [DOI] [PubMed] [Google Scholar]
  12. Gavrieli Y., Sherman Y., Ben-Sasson S. A. Identification of programmed cell death in situ via specific labeling of nuclear DNA fragmentation. J Cell Biol. 1992 Nov;119(3):493–501. doi: 10.1083/jcb.119.3.493. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Giese T., Davidson W. F. Chronic treatment of C3H-lpr/lpr and C3H-gld/gld mice with anti-CD8 monoclonal antibody prevents the accumulation of double negative T cells but not autoantibody production. J Immunol. 1994 Feb 15;152(4):2000–2010. [PubMed] [Google Scholar]
  14. 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]
  15. Hedvat C. V., Irving S. G. The isolation and characterization of MINOR, a novel mitogen-inducible nuclear orphan receptor. Mol Endocrinol. 1995 Dec;9(12):1692–1700. doi: 10.1210/mend.9.12.8614405. [DOI] [PubMed] [Google Scholar]
  16. Krammer P. H., Dhein J., Walczak H., Behrmann I., Mariani S., Matiba B., Fath M., Daniel P. T., Knipping E., Westendorp M. O. The role of APO-1-mediated apoptosis in the immune system. Immunol Rev. 1994 Dec;142:175–191. doi: 10.1111/j.1600-065x.1994.tb00889.x. [DOI] [PubMed] [Google Scholar]
  17. Law S. W., Conneely O. M., DeMayo F. J., O'Malley B. W. Identification of a new brain-specific transcription factor, NURR1. Mol Endocrinol. 1992 Dec;6(12):2129–2135. doi: 10.1210/mend.6.12.1491694. [DOI] [PubMed] [Google Scholar]
  18. Lee S. L., Wesselschmidt R. L., Linette G. P., Kanagawa O., Russell J. H., Milbrandt J. Unimpaired thymic and peripheral T cell death in mice lacking the nuclear receptor NGFI-B (Nur77). Science. 1995 Jul 28;269(5223):532–535. doi: 10.1126/science.7624775. [DOI] [PubMed] [Google Scholar]
  19. Lenardo M. J., Boehme S., Chen L., Combadiere B., Fisher G., Freedman M., McFarland H., Pelfrey C., Zheng L. Autocrine feedback death and the regulation of mature T lymphocyte antigen responses. Int Rev Immunol. 1995;13(2):115–134. doi: 10.3109/08830189509061742. [DOI] [PubMed] [Google Scholar]
  20. 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]
  21. Mages H. W., Rilke O., Bravo R., Senger G., Kroczek R. A. NOT, a human immediate-early response gene closely related to the steroid/thyroid hormone receptor NAK1/TR3. Mol Endocrinol. 1994 Nov;8(11):1583–1591. doi: 10.1210/mend.8.11.7877627. [DOI] [PubMed] [Google Scholar]
  22. 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]
  23. Nagata S., Golstein P. The Fas death factor. Science. 1995 Mar 10;267(5203):1449–1456. doi: 10.1126/science.7533326. [DOI] [PubMed] [Google Scholar]
  24. Nakai A., Kartha S., Sakurai A., Toback F. G., DeGroot L. J. A human early response gene homologous to murine nur77 and rat NGFI-B, and related to the nuclear receptor superfamily. Mol Endocrinol. 1990 Oct;4(10):1438–1443. doi: 10.1210/mend-4-10-1438. [DOI] [PubMed] [Google Scholar]
  25. Nossal G. J. Negative selection of lymphocytes. Cell. 1994 Jan 28;76(2):229–239. doi: 10.1016/0092-8674(94)90331-x. [DOI] [PubMed] [Google Scholar]
  26. Ohkura N., Hijikuro M., Yamamoto A., Miki K. Molecular cloning of a novel thyroid/steroid receptor superfamily gene from cultured rat neuronal cells. Biochem Biophys Res Commun. 1994 Dec 30;205(3):1959–1965. doi: 10.1006/bbrc.1994.2900. [DOI] [PubMed] [Google Scholar]
  27. Pagano M., Tam S. W., Theodoras A. M., Beer-Romero P., Del Sal G., Chau V., Yew P. R., Draetta G. F., Rolfe M. Role of the ubiquitin-proteasome pathway in regulating abundance of the cyclin-dependent kinase inhibitor p27. Science. 1995 Aug 4;269(5224):682–685. doi: 10.1126/science.7624798. [DOI] [PubMed] [Google Scholar]
  28. Paulsen R. E., Weaver C. A., Fahrner T. J., Milbrandt J. Domains regulating transcriptional activity of the inducible orphan receptor NGFI-B. J Biol Chem. 1992 Aug 15;267(23):16491–16496. [PubMed] [Google Scholar]
  29. Perez P., Lira S. A., Bravo R. Overexpression of RelA in transgenic mouse thymocytes: specific increase in levels of the inhibitor protein I kappa B alpha. Mol Cell Biol. 1995 Jul;15(7):3523–3530. doi: 10.1128/mcb.15.7.3523. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Perlmann T., Jansson L. A novel pathway for vitamin A signaling mediated by RXR heterodimerization with NGFI-B and NURR1. Genes Dev. 1995 Apr 1;9(7):769–782. doi: 10.1101/gad.9.7.769. [DOI] [PubMed] [Google Scholar]
  31. Robey E., Fowlkes B. J. Selective events in T cell development. Annu Rev Immunol. 1994;12:675–705. doi: 10.1146/annurev.iy.12.040194.003331. [DOI] [PubMed] [Google Scholar]
  32. 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]
  33. 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]
  34. Surh C. D., Sprent J. T-cell apoptosis detected in situ during positive and negative selection in the thymus. Nature. 1994 Nov 3;372(6501):100–103. doi: 10.1038/372100a0. [DOI] [PubMed] [Google Scholar]
  35. Takahashi T., Tanaka M., Brannan C. I., Jenkins N. A., Copeland N. G., Suda T., Nagata S. Generalized lymphoproliferative disease in mice, caused by a point mutation in the Fas ligand. Cell. 1994 Mar 25;76(6):969–976. doi: 10.1016/0092-8674(94)90375-1. [DOI] [PubMed] [Google Scholar]
  36. Veis D. J., Sorenson C. M., Shutter J. R., Korsmeyer S. J. Bcl-2-deficient mice demonstrate fulminant lymphoid apoptosis, polycystic kidneys, and hypopigmented hair. Cell. 1993 Oct 22;75(2):229–240. doi: 10.1016/0092-8674(93)80065-m. [DOI] [PubMed] [Google Scholar]
  37. Weih F., Ryseck R. P., Chen L., Bravo R. Apoptosis of nur77/N10-transgenic thymocytes involves the Fas/Fas ligand pathway. Proc Natl Acad Sci U S A. 1996 May 28;93(11):5533–5538. doi: 10.1073/pnas.93.11.5533. [DOI] [PMC free article] [PubMed] [Google Scholar]
  38. 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]
  39. Wilson T. E., Fahrner T. J., Milbrandt J. The orphan receptors NGFI-B and steroidogenic factor 1 establish monomer binding as a third paradigm of nuclear receptor-DNA interaction. Mol Cell Biol. 1993 Sep;13(9):5794–5804. doi: 10.1128/mcb.13.9.5794. [DOI] [PMC free article] [PubMed] [Google Scholar]
  40. 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]
  41. Woronicz J. D., Lina A., Calnan B. J., Szychowski S., Cheng L., Winoto A. Regulation of the Nur77 orphan steroid receptor in activation-induced apoptosis. Mol Cell Biol. 1995 Nov;15(11):6364–6376. doi: 10.1128/mcb.15.11.6364. [DOI] [PMC free article] [PubMed] [Google Scholar]
  42. Zheng L., Fisher G., Miller R. E., Peschon J., Lynch D. H., Lenardo M. J. Induction of apoptosis in mature T cells by tumour necrosis factor. Nature. 1995 Sep 28;377(6547):348–351. doi: 10.1038/377348a0. [DOI] [PubMed] [Google Scholar]
  43. Zhou T., Cheng J., Yang P., Wang Z., Liu C., Su X., Bluethmann H., Mountz J. D. Inhibition of Nur77/Nurr1 leads to inefficient clonal deletion of self-reactive T cells. J Exp Med. 1996 Apr 1;183(4):1879–1892. doi: 10.1084/jem.183.4.1879. [DOI] [PMC free article] [PubMed] [Google Scholar]
  44. von Boehmer H. Positive selection of lymphocytes. Cell. 1994 Jan 28;76(2):219–228. doi: 10.1016/0092-8674(94)90330-1. [DOI] [PubMed] [Google Scholar]

Articles from The EMBO Journal are provided here courtesy of Nature Publishing Group

RESOURCES