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

Y.M Ning,E.R Sánchez

doi:10.1016/s0021-9258(18)53220-8

Abstract

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.

Highlights

Ohio,Toledo, Ohio 43699 immobilized FK506 and that this protein contains an NH2terminal sequence identical to that previously published for hsp56 [10]
We show that potentiation of Dexmediated MMTV-CAT expression occurs in response to rapamycin, that glucocorticoid-regulated enhancer sequences are sufficient for the FK506-mediated potentiation effect, and that this effectcan be blocked by
In supportof these observations was a report by Tai et al [13], in which the authors showed that a -60-kDa FK506-binding protein from human thymus was identical to hsp56 when their respective NHn-terminalsequences were compared, and that untransformed glucocorticoid hormone receptors (GR) complexes from humanIM-9 cell cytosols werespecifically retained by an FK506 affinity matrix

Summary

Introduction

Ohio,Toledo, Ohio 43699 immobilized FK506 and that this protein contains an NH2terminal sequence identical to that previously published for hsp56 [10]. We show that potentiation of Dexmediated MMTV-CAT expression occurs in response to rapamycin, that glucocorticoid-regulated enhancer sequences are sufficient for the FK506-mediated potentiation effect, and that this effectcan be blocked by

Results

Conclusion