Functional redundancy of the Nur77 and Nor-1 orphan steroid receptors in T-cell apoptosis.
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.
Cheng
L E
LE
Department of Molecular and Cell Biology, University of California at Berkeley, 94720-3200, USA.
Chan
F K
FK
Cado
D
D
Winoto
A
A
D000818:Animals; D015703:Antigens, CD / Q000032:analysis; D017209:Apoptosis / Q000276:immunology*; D003429:Cross Reactions; D004247:DNA / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D053222:Fas Ligand Protein; D008198:Lymph Nodes / Q000276:immunology; D008213:Lymphocyte Activation; D018655:Lymphocyte Count; D008562:Membrane Glycoproteins / Q000032:analysis; D051379:Mice; D008810:Mice, Inbred C57BL; D009419:Nerve Tissue Proteins / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D057105:Nuclear Receptor Subfamily 4, Group A, Member 1; D057126:Nuclear Receptor Subfamily 4, Group A, Member 2; D011485:Protein Binding; D011948:Receptors, Antigen, T-Cell / Q000276:immunology; D018160:Receptors, Cytoplasmic and Nuclear; D011987:Receptors, Steroid / Q000235:genetics / Q000502:physiology*; D011988:Receptors, Thyroid Hormone; D013154:Spleen / Q000276:immunology; D013601:T-Lymphocytes / Q000166:cytology / Q000276:immunology*; D013950:Thymus Gland / Q000276:immunology; D014157:Transcription Factors / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D015533:Transcriptional Activation / Q000276:immunology
D015703:Antigens, CD; D004268:DNA-Binding Proteins; D053222:Fas Ligand Protein; C505658:Fasl protein, mouse; D008562:Membrane Glycoproteins; D009419:Nerve Tissue Proteins; C539818:Nr4a1 protein, mouse; C539883:Nr4a2 protein, mouse; C490411:Nr4a3 protein, mouse; D057105:Nuclear Receptor Subfamily 4, Group A, Member 1; D057126:Nuclear Receptor Subfamily 4, Group A, Member 2; D011948:Receptors, Antigen, T-Cell; D018160:Receptors, Cytoplasmic and Nuclear; D011987:Receptors, Steroid; D011988:Receptors, Thyroid Hormone; D014157:Transcription Factors; D004247:DNA