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.
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- Transcriptional Activation
- Transcription Factors
- Thymus Gland
- T-Lymphocytes
- Spleen
- Receptors, Thyroid Hormone
- Receptors, Steroid
- Receptors, Cytoplasmic and Nuclear
- Receptors, Antigen, T-Cell
- Protein Binding
Citation
Published In
DOI
ISSN
Publication Date
Volume
Issue
Start / End Page
Location
Related Subject Headings
- Transcriptional Activation
- Transcription Factors
- Thymus Gland
- T-Lymphocytes
- Spleen
- Receptors, Thyroid Hormone
- Receptors, Steroid
- Receptors, Cytoplasmic and Nuclear
- Receptors, Antigen, T-Cell
- Protein Binding