Deletion of the glucocorticoid receptor chaperone FKBP51 prevents glucocorticoid-induced skin atrophy.
Deletion of the glucocorticoid receptor chaperone FKBP51 prevents glucocorticoid-induced skin atrophy.
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DOI：
10.18632/oncotarget.26194
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发表时间：
2018-10-05
期刊：
影响因子：
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通讯作者：
Budunova I
中科院分区：
文献类型：
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作者：
Baida G;Bhalla P;Yemelyanov A;Stechschulte LA;Shou W;Readhead B;Dudley JT;Sánchez ER;Budunova I
FKBP51(FK506结合蛋白51)是一种已知的糖皮质激素受体(GR)的辅助伴侣和调节剂，通常会减弱GR的活性。FKBP51是皮肤中主要的GR靶基因之一，但其在糖皮质激素临床疗效中的作用尚不清楚。在这里，我们使用FKBP51基因敲除(KO)小鼠来确定FKBP51‘S在外用糖皮质激素的主要不良反应中的作用，皮肤萎缩。出乎意料的是，我们发现FKBP51 KO动物的所有皮肤隔室(表皮、真皮、真皮脂肪和CD34+干细胞)对糖皮质激素诱导的发育不良的抵抗力要强得多。此外，尽管没有抑制FKBP51的表达，但在FKBP51 KO皮肤或CRISPR/Cas9编辑的FKBP51 KO HaCaT人角质形成细胞中，GR靶基因的基础表达水平和糖皮质激素激活水平并未增加。已知FKBP51负向调节Akt和mTOR。我们发现在体内和体外，FKBP51缺陷的角质形成细胞中AktSer473和mTORSer2448的磷酸化和下游促生长信号显著增加。由于Akt/mTOR-GR串扰在皮肤中通常是负的，我们的结果表明Akt/mTOR激活可能是FKBP51 KO小鼠缺乏增强的GR功能和对类固醇诱导的皮肤萎缩抵抗力的原因。
FKBP51 (FK506-binding protein 51) is a known co-chaperone and regulator of the glucocorticoid receptor (GR), which usually attenuates its activity. FKBP51 is one of the major GR target genes in skin, but its role in clinical effects of glucocorticoids is not known. Here, we used FKBP51 knockout (KO) mice to determine FKBP51's role in the major adverse effect of topical glucocorticoids, skin atrophy. Unexpectedly, we found that all skin compartments (epidermis, dermis, dermal adipose and CD34+ stem cells) in FKBP51 KO animals were much more resistant to glucocorticoid-induced hypoplasia. Furthermore, despite the absence of inhibitory FKBP51, the basal level of expression and glucocorticoid activation of GR target genes were not increased in FKBP51 KO skin or CRISPR/Cas9-edited FKBP51 KO HaCaT human keratinocytes. FKBP51 is known to negatively regulate Akt and mTOR. We found a significant increase in AktSer473 and mTORSer2448 phosphorylation and downstream pro-growth signaling in FKBP51-deficient keratinocytes in vivo and in vitro. As Akt/mTOR-GR crosstalk is usually negative in skin, our results suggest that Akt/mTOR activation could be responsible for the lack of increased GR function and resistance of FKBP51 KO mice to the steroid-induced skin atrophy.