Deletion of the glucocorticoid receptor chaperone FKBP51 prevents glucocorticoid-induced skin atrophy

Gleb Baida, Pankaj Bhalla, Alexander Yemelyanov, Lance A. Stechschulte, Weinian Shou, Ben Readhead, Joel T. Dudley, Edwin R. Sánchez, Irina Budunova

Research output: Contribution to journalArticle

5 Citations (Scopus)

Abstract

FKBP51 (FK506-binding protein 51) is a known co-chaperone and regulator of theglucocorticoid receptor (GR), which usually attenuates its activity. FKBP51 is one ofthe major GR target genes in skin, but its role in clinical effects of glucocorticoids is notknown. Here, we used FKBP51 knockout (KO) mice to determine FKBP51's role in themajor adverse effect of topical glucocorticoids, skin atrophy. Unexpectedly, we foundthat 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 expressionand glucocorticoid activation of GR target genes were not increased in FKBP51 KO skinor CRISPR/Cas9-edited FKBP51 KO HaCaT human keratinocytes. FKBP51 is known tonegatively regulate Akt and mTOR. We found a significant increase in AktSer473 andmTORSer2448 phosphorylation and downstream pro-growth signaling in FKBP51-deficient keratinocytes in vivo and in vitro. As Akt/mTOR-GR crosstalk is usuallynegative in skin, our results suggest that Akt/mTOR activation could be responsiblefor the lack of increased GR function and resistance of FKBP51 KO mice to the steroidinduced skin atrophy.

Original languageEnglish (US)
Pages (from-to)34772-34783
Number of pages12
JournalOncotarget
Volume9
Issue number78
DOIs
StatePublished - Oct 1 2018

Fingerprint

Tacrolimus Binding Proteins
Glucocorticoid Receptors
Glucocorticoids
Atrophy
Skin
Keratinocytes
Knockout Mice
Clustered Regularly Interspaced Short Palindromic Repeats
Dermis
Epidermis
Genes
Stem Cells
Phosphorylation

Keywords

  • Akt
  • FKBP51
  • Glucocorticoid
  • Glucocorticoid receptor
  • Skin atrophy

ASJC Scopus subject areas

  • Oncology

Cite this

Baida, G., Bhalla, P., Yemelyanov, A., Stechschulte, L. A., Shou, W., Readhead, B., ... Budunova, I. (2018). Deletion of the glucocorticoid receptor chaperone FKBP51 prevents glucocorticoid-induced skin atrophy. Oncotarget, 9(78), 34772-34783. https://doi.org/10.18632/oncotarget.26194

Deletion of the glucocorticoid receptor chaperone FKBP51 prevents glucocorticoid-induced skin atrophy. / Baida, Gleb; Bhalla, Pankaj; Yemelyanov, Alexander; Stechschulte, Lance A.; Shou, Weinian; Readhead, Ben; Dudley, Joel T.; Sánchez, Edwin R.; Budunova, Irina.

In: Oncotarget, Vol. 9, No. 78, 01.10.2018, p. 34772-34783.

Research output: Contribution to journalArticle

Baida, G, Bhalla, P, Yemelyanov, A, Stechschulte, LA, Shou, W, Readhead, B, Dudley, JT, Sánchez, ER & Budunova, I 2018, 'Deletion of the glucocorticoid receptor chaperone FKBP51 prevents glucocorticoid-induced skin atrophy', Oncotarget, vol. 9, no. 78, pp. 34772-34783. https://doi.org/10.18632/oncotarget.26194
Baida, Gleb ; Bhalla, Pankaj ; Yemelyanov, Alexander ; Stechschulte, Lance A. ; Shou, Weinian ; Readhead, Ben ; Dudley, Joel T. ; Sánchez, Edwin R. ; Budunova, Irina. / Deletion of the glucocorticoid receptor chaperone FKBP51 prevents glucocorticoid-induced skin atrophy. In: Oncotarget. 2018 ; Vol. 9, No. 78. pp. 34772-34783.
@article{7f08ab6c608c4a16b80252c20f092036,
title = "Deletion of the glucocorticoid receptor chaperone FKBP51 prevents glucocorticoid-induced skin atrophy",
abstract = "FKBP51 (FK506-binding protein 51) is a known co-chaperone and regulator of theglucocorticoid receptor (GR), which usually attenuates its activity. FKBP51 is one ofthe major GR target genes in skin, but its role in clinical effects of glucocorticoids is notknown. Here, we used FKBP51 knockout (KO) mice to determine FKBP51's role in themajor adverse effect of topical glucocorticoids, skin atrophy. Unexpectedly, we foundthat 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 expressionand glucocorticoid activation of GR target genes were not increased in FKBP51 KO skinor CRISPR/Cas9-edited FKBP51 KO HaCaT human keratinocytes. FKBP51 is known tonegatively regulate Akt and mTOR. We found a significant increase in AktSer473 andmTORSer2448 phosphorylation and downstream pro-growth signaling in FKBP51-deficient keratinocytes in vivo and in vitro. As Akt/mTOR-GR crosstalk is usuallynegative in skin, our results suggest that Akt/mTOR activation could be responsiblefor the lack of increased GR function and resistance of FKBP51 KO mice to the steroidinduced skin atrophy.",
keywords = "Akt, FKBP51, Glucocorticoid, Glucocorticoid receptor, Skin atrophy",
author = "Gleb Baida and Pankaj Bhalla and Alexander Yemelyanov and Stechschulte, {Lance A.} and Weinian Shou and Ben Readhead and Dudley, {Joel T.} and S{\'a}nchez, {Edwin R.} and Irina Budunova",
year = "2018",
month = "10",
day = "1",
doi = "10.18632/oncotarget.26194",
language = "English (US)",
volume = "9",
pages = "34772--34783",
journal = "Oncotarget",
issn = "1949-2553",
publisher = "Impact Journals",
number = "78",

}

TY - JOUR

T1 - Deletion of the glucocorticoid receptor chaperone FKBP51 prevents glucocorticoid-induced skin atrophy

AU - Baida, Gleb

AU - Bhalla, Pankaj

AU - Yemelyanov, Alexander

AU - Stechschulte, Lance A.

AU - Shou, Weinian

AU - Readhead, Ben

AU - Dudley, Joel T.

AU - Sánchez, Edwin R.

AU - Budunova, Irina

PY - 2018/10/1

Y1 - 2018/10/1

N2 - FKBP51 (FK506-binding protein 51) is a known co-chaperone and regulator of theglucocorticoid receptor (GR), which usually attenuates its activity. FKBP51 is one ofthe major GR target genes in skin, but its role in clinical effects of glucocorticoids is notknown. Here, we used FKBP51 knockout (KO) mice to determine FKBP51's role in themajor adverse effect of topical glucocorticoids, skin atrophy. Unexpectedly, we foundthat 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 expressionand glucocorticoid activation of GR target genes were not increased in FKBP51 KO skinor CRISPR/Cas9-edited FKBP51 KO HaCaT human keratinocytes. FKBP51 is known tonegatively regulate Akt and mTOR. We found a significant increase in AktSer473 andmTORSer2448 phosphorylation and downstream pro-growth signaling in FKBP51-deficient keratinocytes in vivo and in vitro. As Akt/mTOR-GR crosstalk is usuallynegative in skin, our results suggest that Akt/mTOR activation could be responsiblefor the lack of increased GR function and resistance of FKBP51 KO mice to the steroidinduced skin atrophy.

AB - FKBP51 (FK506-binding protein 51) is a known co-chaperone and regulator of theglucocorticoid receptor (GR), which usually attenuates its activity. FKBP51 is one ofthe major GR target genes in skin, but its role in clinical effects of glucocorticoids is notknown. Here, we used FKBP51 knockout (KO) mice to determine FKBP51's role in themajor adverse effect of topical glucocorticoids, skin atrophy. Unexpectedly, we foundthat 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 expressionand glucocorticoid activation of GR target genes were not increased in FKBP51 KO skinor CRISPR/Cas9-edited FKBP51 KO HaCaT human keratinocytes. FKBP51 is known tonegatively regulate Akt and mTOR. We found a significant increase in AktSer473 andmTORSer2448 phosphorylation and downstream pro-growth signaling in FKBP51-deficient keratinocytes in vivo and in vitro. As Akt/mTOR-GR crosstalk is usuallynegative in skin, our results suggest that Akt/mTOR activation could be responsiblefor the lack of increased GR function and resistance of FKBP51 KO mice to the steroidinduced skin atrophy.

KW - Akt

KW - FKBP51

KW - Glucocorticoid

KW - Glucocorticoid receptor

KW - Skin atrophy

UR - http://www.scopus.com/inward/record.url?scp=85054501691&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85054501691&partnerID=8YFLogxK

U2 - 10.18632/oncotarget.26194

DO - 10.18632/oncotarget.26194

M3 - Article

AN - SCOPUS:85054501691

VL - 9

SP - 34772

EP - 34783

JO - Oncotarget

JF - Oncotarget

SN - 1949-2553

IS - 78

ER -