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Molecular and Cellular Biology, July 2001, p. 4379-4390, Vol. 21, No. 13
0270-7306/01/$04.00+0   DOI: 10.1128/MCB.21.13.4379-4390.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.

Use of Suppressor Mutants To Probe the Function of Estrogen Receptor-p160 Coactivator Interactions

Ho Yi Makdagger and Malcolm G. Parker*

Molecular Endocrinology Laboratory, Imperial Cancer Research Fund, London WC2A 3PX, United Kingdom

Received 21 December 2000/Returned for modification 20 February 2001/Accepted 9 April 2001

Estrogen-dependent recruitment of coactivators by estrogen receptor alpha (ERalpha ) represents a crucial step in the transcriptional activation of target genes. However, studies of the function of individual coactivators has been hindered by the presence of endogenous coactivators, many of which are potentially recruited in the presence of agonist via a common mechanism. To circumvent this problem, we have generated second-site suppressor mutations in the nuclear receptor interaction domain of p160 coactivators which rescue their binding to a transcriptionally defective ERalpha that is refractory to wild-type coactivators. Analysis of these altered-specificity receptor-coactivator combinations, in the absence of interference from endogenous coregulators, indicated that estrogen-dependent transcription from reporter genes is critically dependent on direct recruitment of a p160 coactivator in mammalian cells and that the three p160 family members serve functionally redundant roles. Furthermore, our results suggest that such a change-of-specificity mutation may act as a transposable protein-protein interaction module which provides a novel tool with which to dissect the functional roles of other nuclear receptor coregulators at the cellular level.

* Corresponding author. Mailing address: Institute of Reproductive and Developmental Biology, Hammersmith Hospital, Du Cane Road, London W12 ONN, United Kingdom. Phone: 44 20 7594 2177. Fax: 44 20 7594 2184. E-mail: m.parker{at}ic.ac.uk.

dagger Present address: Department of Molecular Biology, Massachusetts General Hospital, Boston, MA 02114.

Molecular and Cellular Biology, July 2001, p. 4379-4390, Vol. 21, No. 13
0270-7306/01/$04.00+0   DOI: 10.1128/MCB.21.13.4379-4390.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.


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