FUNCTIONAL REDUNDANCY OF THE NUR77 AND NOR-1 ORPHAN STEROID-RECEPTORSIN T-CELL APOPTOSIS

The transcription factor Nur77 (NGFI-B), a member of the steroid nucle ar receptor superfamily, is induced to a high level during T-cell rece ptor (TCR)-mediated apoptosis, A transgenic dominant-negative Nur77 pr otein can inhibit the apoptotic process accompanying negative selectio n in thymocytes, while constitutive expression of Nur77 leads to massi ve cell death, Nur77-deficient mice, however, have no phenotype, sugge sting the possible existence of a protein with redundant function to N ur77, To explore this possibility, we have characterized the role of t wo Nur77 family members, Nurr1 and Nor-1, in TCR-induced apoptosis, We found that Nor-1 and Nurr1 can transactivate through the same DNA ele ment as Nur77, and that their transactivation activities can be blocke d by a Nur77 dominant-negative protein, In thymocytes, Nor-1 protein i s induced to a very high level upon TCR stimulation and has similar ki netics to Nur77, In contrast, Nurr1 is undetectable in stimulated thym ocytes, Furthermore, constitutive expression of Nor-1 in thymocytes le ads to massive apoptosis and up-regulation of CD25, suggesting a funct ional redundancy between Nur77 and Nor-1 gene products, As in the case of our Nur77-FL mice, Fast is not detectable in the thymocytes of Nor -1 transgenic mice, Constitutive expression of Nur77 in gld/gld mice r escues the lymphoproliferative phenotype of the Fast mutant mice, Thus , Nor-1 and Nur77 demonstrate functional redundancy in an apparently F as-independent apoptosis.