Potentiation of glucocorticoid receptor-mediated gene expression by the immunophilin ligands FK506 and rapamycin.

It has recently been discovered that the steroid receptor-associated heat shock protein, hsp56, belongs to the FK506 family of immunophilin proteins. The ability of hsp56 to bind the immunosuppressive macrolide FK506 has led to the speculation that the steroid receptor and immunophilin signal transduction pathways are functionally interrelated. We have tested this idea by assessing the effects of FK506 on glucocorticoid receptor (GR)-mediated expression of the murine mammary tumor virus-chloramphenicol acetyltransferase (MMTV-CAT) reporter plasmid. We report that combined treatment with FK506 and low concentrations of dexamethasone (10(-8) or 10(-7) M) results in a large enhancement of MMTV-CAT gene expression over that seen in response to dexamethasone (Dex) alone. FK506 potentiation of MMTV-CAT expression did not occur at 10(-6) M Dex or in the complete absence of hormone. We also show that potentiation of Dex-mediated MMTV-CAT expression occurs in response to rapamycin, that glucocorticoid-regulated enhancer sequences are sufficient for the FK506-mediated potentiation effect, and that this effect can be blocked by RU486 antagonist. Finally, we provide evidence that FK506 potentiation of GR-mediated gene expression is the result of increased translocation to the nucleus of the GR.