Differences in nuclear retention characteristics of agonist-activated glucocorticoid receptor may determine specific responses
We studied the glucocorticoid response to the synthetic steroid pregna-1,4-diene-11β-ol-3,20-dione (ΔHOP) in several cell types and correlated its biological effect with the ability of the glucocorticoid receptor (GR) to be retained in the nuclear compartment. We observed that the ΔHOP-transformed G...
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| Autores principales: | , , |
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2002
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| Acceso en línea: | https://bibliotecadigital.exactas.uba.ar/collection/paper/document/paper_00144827_v276_n2_p142_Vicent http://hdl.handle.net/20.500.12110/paper_00144827_v276_n2_p142_Vicent |
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| Sumario: | We studied the glucocorticoid response to the synthetic steroid pregna-1,4-diene-11β-ol-3,20-dione (ΔHOP) in several cell types and correlated its biological effect with the ability of the glucocorticoid receptor (GR) to be retained in the nuclear compartment. We observed that the ΔHOP-transformed GR was diffusely distributed in the nucleus compared to the discrete structures observed for the dexamethasone (DEX)-transformed GR. Despite the fact that the receptor was entirely nuclear upon binding of each steroid and exhibited identical nuclear export rates, a greater amount of ΔHOP-transformed GR was recovered in the cytoplasmic fraction after hypotonic cell lysis. Furthermore, accelerated nuclear export of GR was evidenced in digitonin-permeabilized cells treated with ATP and molybdate. Inasmuch as limited trypsinization of DEX-GR and ΔHOP-GR complexes yielded different proteolytic products, we conclude that GR undergoes a differential conformational change upon binding of each ligand. We propose that these conformational differences may consequently lead to changes of stability in the interaction of the GR with chromatin. Therefore, the dynamic exchange of liganded GR with chromatin is likely to have significant consequences for the observed pleiotropic physiological responses triggered by glucocorticoid ligands, not only in different tissues but also in the same cell type. © 2002 Elsevier Science (USA). |
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