THU042 FOXO1 Stimulates Hsp90b1 Expression To Promote Efficient Glucocorticoid Signaling And Facilitate Maturation Of Somatotropes

Disclosure: P. Das: None. D.M. Abou-Jabal: None. B.S. Ellsworth: None. Glucocorticoids promote differentiation and maturation of many tissues. There is significant evidence that glucocorticoids are also important for maturation of pituitary somatotropes. We find that treating pregnant mice with the synthetic glucocorticoid, dexamethasone, leads to premature appearance of GH-positive cells, suggesting premature somatotrope maturation. Expression of Gh1 and Foxo1 are significantly increased in mice treated with dexamethasone compared to control mice. We have previously shown that deletion of the forkhead transcription factor, FOXO1, causes a delay in somatotrope maturation. Thus, both FOXO1 and glucocorticoid signaling affect the timing of somatotrope maturation. Interestingly, we find that the ability of glucocorticoids to promote somatotrope maturation is impaired in mice lacking FOXO1. Similar to what we find in vivo, deletion of Foxo1 from the somatotrope-derived MtT/S cells (MtT/S(ΔFoxo1)) impairs glucocorticoid-induced expression of Gh1 suggesting FOXO1 may be required for glucocorticoid-induced somatotrope maturation. Glucocorticoid signaling depends on a number of chaperone proteins. Heat-shock protein 90 (HSP90) is essential for protecting the glucocorticoid receptor (NR3C1) from degradation and preparing it for ligand binding. Hsp90aa1, Hsp90ab1, and Hsp90b1 are all expressed in MtT/S cells. Chromatin immunoprecipitation sequencing (ChIPseq) for FOXO1 reveals FOXO1 binding at the promoter of Hsp90b1. Consistent with this, we find a reduction in Hsp90b1 expression in MtT/S(ΔFoxo1) cells. Thus, Hsp90b1 may be a direct transcriptional target of FOXO1. Expression of Hsp90ab1 is also reduced in the absence of FOXO1, however FOXO1 binding is not detected at its promoter suggesting Hsp90ab1 may be an indirect target of FOXO1. Together these data suggest that FOXO1 promotes somatotrope maturation by fostering efficient glucocorticoid signaling. Presentation: Thursday, June 15, 2023