Deletion of the glucocorticoid receptor chaperone FKBP51 prevents glucocorticoid-induced skin atrophy
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Gleb Baida1, Pankaj Bhalla1, Alexander Yemelyanov2, Lance A. Stechschulte3, Weinian Shou4, Ben Readhead5,6, Joel T. Dudley5,6, Edwin R. Sánchez3 and Irina Budunova1
1Department of Dermatology, Northwestern University, Chicago, IL, USA
2Department of Medicine, Pulmonary Division, Northwestern University, Chicago, IL, USA
3Department of Physiology & Pharmacology, The Center for Diabetes and Endocrine Research, University of Toledo College of Medicine, Toledo, OH, USA
4Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN, USA
5Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA
6Institute for Next Generation Healthcare, Mount Sinai Health System, New York, NY, USA
Irina Budunova, email: email@example.com
Keywords: glucocorticoid; glucocorticoid receptor; skin atrophy; FKBP51; Akt
Received: July 27, 2018 Accepted: September 15, 2018 Published: October 05, 2018
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.
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