Potentiation of glucocorticoid receptor-mediated gene expression by the immunophilin ligands FK506 and rapamycin.
Potentiation of glucocorticoid receptor-mediated gene expression by the immunophilin ligands FK506 and rapamycin.
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DOI：
10.1016/s0021-9258(18)53220-8
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发表时间：
1993-03
期刊：
影响因子：
--
通讯作者：
Y. Ning;E. R. Sánchez
中科院分区：
文献类型：
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作者：
Y. Ning;E. R. Sánchez
最近发现类固醇受体相关的热休克蛋白hsp56属于免疫亲和素FK506家族。HSP56结合免疫抑制大环内酯类FK506的能力使得人们推测类固醇受体和免疫亲和素信号转导通路在功能上是相互关联的。我们通过评估FK506对糖皮质激素受体(GR)介导的小鼠乳腺肿瘤病毒氯霉素乙酰转移酶(MMTV-CAT)报告质粒表达的影响来验证这一想法。我们报告了联合使用FK506和低浓度的地塞米松(10(-8)或10(-7)M)可以显著增强MMTV-CAT基因的表达，而不是单独使用地塞米松(Dex)。10(-6)M地塞米松或完全无激素时，FK506对MMTV-CAT的表达没有增强作用。我们还表明，地塞米松介导的MMTV-CAT表达的增强发生在雷帕霉素的反应中，糖皮质激素调节的增强子序列足以发挥FK506介导的增强作用，这种作用可以被RU486拮抗剂阻断。最后，我们提供的证据表明，FK506对GR介导的基因表达的增强是GR核转位增加的结果。
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.