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Molecular and Cellular Biology, March 2006, p. 1722-1730, Vol. 26, No. 5
0270-7306/06/$08.00+0     doi:10.1128/MCB.26.5.1722-1730.2006
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

GCUNC-45 Is a Novel Regulator for the Progesterone Receptor/hsp90 Chaperoning Pathway

Ahmed Chadli,^1, J. Dinny Graham,^2,, M. Greg Abel,² Twila A. Jackson,² David F. Gordon,² William M. Wood,² Sara J. Felts,¹ Kathryn B. Horwitz,² and David Toft^1*

Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, Minnesota,¹ Division of Endocrinology, Department of Medicine, University of Colorado Health Science Center, Denver, Colorado²

Received 13 September 2005/ Returned for modification 9 October 2005/ Accepted 19 December 2005

The hsp90 chaperoning pathway is a multiprotein system that is required for the production or activation of many cell regulatory proteins, including the progesterone receptor (PR). We report here the identity of GCUNC-45 as a novel modulator of PR chaperoning by hsp90. GCUNC-45, previously implicated in the activities of myosins, can interact in vivo and in vitro with both PR-A and PR-B and with hsp90. Overexpression and knockdown experiments show GCUNC-45 to be a positive factor in promoting PR function in the cell. GCUNC-45 binds to the ATP-binding domain of hsp90 to prevent the activation of its ATPase activity by the cochaperone Aha1. This effect limits PR chaperoning by hsp90, but this can be reversed by FKBP52, a cochaperone that is thought to act later in the pathway. These findings reveal a new cochaperone binding site near the N terminus of hsp90, add insight on the role of FKBP52, and identify GCUNC-45 as a novel regulator of the PR signaling pathway.

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* Corresponding author. Mailing address: Mayo Clinic, 200 First St. Southwest, Rochester, MN 55905. Phone: (507) 284-8401. Fax: (507) 284-2053. E-mail: toft.david{at}mayo.edu.

A.C. and J.D.G. contributed equally to this study.

Present address: Westmead Institute for Cancer Research, University of Sydney Westmead Hospital, Westmead, New South Wales, Australia.

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Molecular and Cellular Biology, March 2006, p. 1722-1730, Vol. 26, No. 5
0022-538X/06/$08.00+0     doi:10.1128/MCB.26.5.1722-1730.2006
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

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