Functional interaction of the immunosuppressant mizoribine with the 14-3-3protein

Mizoribine (MIZ) is a novel imidazole nucleoside with immunosuppressive act ivity. MIZ has been approved in japan and combination therapy with MIZ and glucocorticoids has been used after renal transplantation and for lupus nep hritis and rheumatoid arthritis. In this study, we identify 14-3-3 proteins as MIZ-binding proteins. 14-3-3 proteins interact with many proteins invol ved in cellular signaling, including the glucocorticoid receptor (GR). The 14-3-3/GR interaction enhances the transcriptional activity of the receptor . We show that MIZ affects the conformation of 14-3-3 proteins and enhances the interaction of GR and 14-3-3 eta dose dependently in vitro. MIZ also h as a stimulatory effect on transcriptional activation by the GR. Our result s point to the possibility that one mechanism for the therapeutic effect of MIZ could he to regulate the GB function via 14-3-3 proteins. (C) 2000 Aca demic Press.