REGULATION OF THE NUR77 ORPHAN STEROID-RECEPTOR IN ACTIVATION-INDUCEDAPOPTOSIS

T-cell receptor (TCR)-mediated apoptosis in immature thymocytes and T- cell hybridomas is calcium dependent and can be inhibited by cyclospor in A (CsA). Induction of the orphan steroid receptor Nur77 (NGFI-B) is required for activation-induced apoptosis. Here, we examined the regu lation of Nur77 expression, in response to apoptotic TCR signals, whic h consists of kinase C and calcium pathways. We show that the major co ntrol of Nur77 induction is mediated by the calcium signaling pathway. In contrast, protein kinase C signals induce only a low level of Nur7 7 activity. Nur77 promoter activity parallels its protein levels. CsA decreases both Nur77 protein levels and promoter activity, and the kin etics of CsA inhibition of apoptosis correlates with a decrease in Nur 77 protein levels. TCR signals and kinase C signals result in a simila r level of Nur77 protein phosphorylation but mediate differential tran sactivation activity of Nur77. In addition, Nur77 promoter deletion an alysis revealed two RSRF (related to serum-responsive factor) binding sites, which can confer calcium and CsA sensitivity on a heterologous promoter. Taken together, our data suggest that the levels of transcri ptional induction of Nur77 play an important role during activation-in duced apoptosis and that calcium signals regulate a novel CsA-sensitiv e nuclear factor required for Nur77 transcription in T cells.