Differential Effects of Fkbp4 and Fkbp5 on Regulation of the Proopiomelanocortin Gene in Murine AtT-20 Corticotroph Cells.

Kazunori Kageyama,Kanako Niioka,Makoto Daimon,Yutaka Watanuki,Yasumasa Iwasaki

doi:10.3390/ijms22115724

Kazunori Kageyama, Kanako Niioka + Show 3 more

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https://doi.org/10.3390/ijms22115724

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Abstract

The hypothalamic-pituitary-adrenal axis is stimulated in response to stress. When activated, it is suppressed by the negative feedback effect of glucocorticoids. Glucocorticoids directly inhibit proopiomelanocortin (Pomc) gene expression in the pituitary. Glucocorticoid signaling is mediated via glucocorticoid receptors, 11β-hydroxysteroid dehydrogenases, and the FK506-binding immunophilins, Fkbp4 and Fkbp5. Fkbp4 and Fkbp5 differentially regulate dynein interaction and nuclear translocation of the glucocorticoid receptor, resulting in modulation of the glucocorticoid action. Here, we explored the regulation of Fkbp4 and Fkbp5 genes and their proteins with dexamethasone, a major synthetic glucocorticoid drug, in murine AtT-20 corticotroph cells. To elucidate further roles of Fkbp4 and Fkbp5, we examined their effects on Pomc mRNA levels in corticotroph cells. Dexamethasone decreased Pomc mRNA levels as well as Fkpb4 mRNA levels in mouse corticotroph cells. Dexamethasone tended to decrease Fkbp4 protein levels, while it increased Fkpb5 mRNA and its protein levels. The dexamethasone-induced decreases in Pomc mRNA levels were partially canceled by Fkbp4 knockdown. Alternatively, Pomc mRNA levels were further decreased by Fkbp5 knockdown. Thus, Fkbp4 contributes to the negative feedback of glucocorticoids, and Fkbp5 reduces the efficiency of the glucocorticoid effect on Pomc gene expression in pituitary corticotroph cells.

Highlights

Fkbp5 mRNA levels were increased as dexamethasone concentrations increased (p < 0.0001), with significant effects initially occurring at 1 nM dexamethasone (Figure 3B)
Glucocorticoid suppression of the Pomc gene is specific for the pituitary, while Pomc gene expression is upregulated by glucocorticoids in the hypothalamus [16]
Suppression of Nur77 or NeuroD1 by glucocorticoids is involved in the glucocorticoid-mediated negative regulation of Pomc in the pituitary [16,20]

Summary

Introduction

The activated HPA axis is suppressed by the negative feedback effect of glucocorticoids. Corticotropinreleasing factor (CRF), produced in the hypothalamic paraventricular nucleus in response to stress, stimulates the release of the adrenocorticotropic hormone (ACTH) from the anterior pituitary [1,2,3]. ACTH, cleaved from the proopiomelanocortin (Pomc) gene, stimulates the secretion of corticosterone and cortisol, the principal glucocorticoid in rodents and human, respectively, from the adrenal glands [3]. Glucocorticoids bind to the glucocorticoid receptor (GR), and subsequently inhibit CRF production in the hypothalamus and the ACTH in the pituitary as an inhibitory feedback loop [4,5,6].

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