The molecular chaperone Hsp90 can negatively regulate the activity of a glucocorticosteroid-dependent promoter

Kwang Il Kang, Xia Meng, Jocelyne Devin-Leclerc, Ilham Bouhouche, Ahmed Chadli, Françoise Cadepond, Etienne Emile Baulieu, Maria Grazia Catelli

Research output: Contribution to journalArticle

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Abstract

Hsp90, a molecular chaperone required for the functioning of glucocorticosteroid receptor (GR), ensures, by direct interaction, the conformational competence of the steroid-binding pocket. In addition to having this positive function, Hsp90 maintains steroid receptors in an inactive form in the absence of hormone. However, neither the participation of Hsp90 once the pathway has been activated by the ligand nor the importance of increased Hsp90 levels in determining the amplitude of the response has ever been assessed directly. Here, by increasing the Hsp90/GR ratio in the nuclear compartment, we found an attenuation of the response to glucocorticosteroids that was not due to a nonspecific or toxic effect of the Hsp90 modified by nuclear targeting. Since this negative effect was more pronounced at high levels of hormone, when receptor and Hsp90 are maximally dissociated, the possibility of an interaction between Hsp90 and GR, already activated to a DNA-binding form, was directly investigated. Indeed GR, after in vivo activation by ligand, was still able to reassociate with Hsp90, suggesting that this interaction plays a role in vivo, possibly in receptor recycling. Moreover, the GR binding to its DNA response element was inhibited by an excess of Hsp90, pointing to a function of Hsp90 in the nuclear compartment. It is thus proposed that an increased Hsp90/GR ratio influences the responsiveness to ligand at a step that is after receptor activation. This increased ratio may be of pathophysiological relevance in the different circumstances that lead to an elevated level of nuclear Hsp90.

Original languageEnglish (US)
Pages (from-to)1439-1444
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume96
Issue number4
DOIs
StatePublished - Feb 16 1999

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