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T. Yorio, X. Zhang, A. F. Clark; Immunophilins-FK506 Binding Proteins 51 and 52: Role in Nuclear Transport of the Glucocorticoid Receptor and Gluocorticoid Responsiveness. Invest. Ophthalmol. Vis. Sci. 2007;48(13):1552. doi: https://doi.org/.
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© ARVO (1962-2015); The Authors (2016-present)
FK506 binding protein FKBP51 and FKBP52 are family members of immunophilins which may control protein folding and their ability to interact with heat shock protein 90 (Hsp90) or the motor protein dynein. FKBP52 regulates the activation of the glucocorticoid receptor α (GRα) and subsequently glucocorticoid (GC) action, while FKBP51 overexpression is associated with glucocorticoid resistance. Previously, we showed that the expression of glucocorticoid receptor ß (GRß) participates in GC responsiveness in trabecular meshwork (TM) cells. Presently, we investigated the effect of FKBP52 and FKBP51 on the nuclear transport of GRα and GRß and GC responsiveness in human TM cell lines and in HeLa cells.
Protein-protein interactions were investigated by co-immunoprecipitation and western immunoblotting. FKBP51 affects on the nuclear transport of GRß was studied by overexpression of FKBP51 and treatment with FK506. FKBP51 overexpression on the cellular responsiveness to dexamethasone (DEX) was also studied using a GRE-luciferase reporter assay.
FKBP51 and FKBP52 were complexed with GRα. DEX treatment caused the nuclear translocation of the GRα-FKBP52 complex. In contrast, only FKBP51 complexed with GRß and this was not affected by DEX. Immunoprecipitation with anti-FKBP51 antibody also pulled down Hsp90 and dynein. Overexpression of FKBP51 increased the association of GRß with FKBP51. FK506 treatment did not change DEX-induced nuclear translocation of FKBP52-GRα, while increasing nuclear accumulation of FKBP51-GRß in normal HTM-5 cells, but not in glaucomatous GTM-3 cells. Western blot analysis showed a differential expression pattern of FKBP51 between HTM-5 and GTM-3 cells. These data are consistent with the reporter gene assay in that FK506 decreased DEX- induced luciferase in HTM-5 cells, but not in GTM-3 cells.
FKBP51, but not FKBP52, is involved in constitutive nuclear transport of GRα and GRß without hormone binding. This represents a novel mechanism through which FKBP51 produces GC resistance. The differential expression of FKBP51 in glaucomatous TM cells could affect its interaction with GRß, hsp90 and dynein complex and disrupt the constitutive nuclear import of GRß and contribute to the low nuclear expression of GRß and the hyper-responsiveness to GC that is often seen in glaucoma patients.
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