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Molecular and Cellular Biology, November 2004, p. 9371-9382, Vol. 24, No. 21
0270-7306/04/$08.00+0     DOI: 10.1128/MCB.24.21.9371-9382.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

Cofilin 1 Is Revealed as an Inhibitor of Glucocorticoid Receptor by Analysis of Hormone-Resistant Cells

Joëlle Rüegg, Florian Holsboer, Christoph Turck, and Theo Rein^*

Max Planck Institute of Psychiatry, Munich, Germany

Received 7 April 2004/ Returned for modification 12 May 2004/ Accepted 26 July 2004

Significant knowledge about glucocorticoid signaling has accumulated, yet many aspects remain unknown. We aimed to discover novel factors involved in glucocorticoid receptor regulation that do not necessarily require direct receptor interaction. We achieved this by using a functional genetic screen: a stable cell line which cannot survive hormone treatment was engineered, randomly mutated, and selected in the presence of glucocorticoid. A hormone-resistant clone was analyzed by two-dimensional gel electrophoresis. Differentially expressed proteins were identified and tested as candidates for regulation of the glucocorticoid receptor. An unexpected candidate, cofilin 1, inhibited receptor activity. Cofilin is known to promote actin depolymerization and filament severing. Several experiments suggest that this feature of cofilin is involved in its inhibitory action. Both its actin depolymerization activity and its inhibitory action on the receptor are dependent on its phosphorylation state. Treatment of cells with a cytoskeleton-disrupting agent decreased receptor activity, as did overexpression of actin, particularly a mutant actin that does not polymerize. In addition, overexpression of cofilin and actin as well as chemical cytoskeleton disruption changed the subcellular receptor distribution and upregulated c-Jun, which could constitute the inhibitory mechanism of cofilin. In summary, cofilin represents a novel factor that can cause glucocorticoid resistance.

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* Corresponding author. Mailing address: Max Planck Institute of Psychiatry, Kraepelinstr. 10, D-80804 Munich, Germany. Phone: 49-89-30622-531. Fax: 49-89-30622-610. E-mail: theorein{at}mpipsykl.mpg.de.

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Molecular and Cellular Biology, November 2004, p. 9371-9382, Vol. 24, No. 21
0022-538X/04/$08.00+0     DOI: 10.1128/MCB.24.21.9371-9382.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

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