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Molecular and Cellular Biology, June 2003, p. 4319-4330, Vol. 23, No. 12
0270-7306/03/$08.00+0     DOI: 10.1128/MCB.23.12.4319-4330.2003

Molecular Origins for the Dominant Negative Function of Human Glucocorticoid Receptor Beta

Matthew R. Yudt,1,{dagger} Christine M. Jewell,1 Rachelle J. Bienstock,2 and John A. Cidlowski1*

Laboratory of Signal Transduction,1 Laboratory of Structural Biology, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, North Carolina 277092

Received 12 November 2002/ Returned for modification 2 January 2003/ Accepted 31 March 2003

This study molecularly elucidates the basis for the dominant negative mechanism of the glucocorticoid receptor (GR) isoform hGRß, whose overexpression is associated with human glucocorticoid resistance. Using a series of truncated hGR{alpha} mutants and sequential mutagenesis to generate a series of hGR{alpha}/ß hybrids, we find that the absence of helix 12 is neither necessary nor sufficient for the GR dominant negative phenotype. Moreover, we have localized the dominant negative activity of hGRß to two residues and found that nuclear localization, in addition to heterodimerization, is a critical feature of the dominant negative activity. Molecular modeling of wild-type and mutant hGR{alpha} and hGRß provides structural insight and a potential physical explanation for the lack of hormone binding and the dominant negative actions of hGRß.

* Corresponding author. Mailing address: Laboratory of Signal Transduction, National Institute of Environmental Health Sciences, National Institutes of Health, 111 Alexander Dr., Research Triangle Park, NC 27709. Phone (919) 541-1564. Fax (919) 541-1367. E-mail: cidlowski{at}niehs.nih.gov.

{dagger} Present address: Wyeth Research, Philadelphia, PA 19101.

Molecular and Cellular Biology, June 2003, p. 4319-4330, Vol. 23, No. 12
0022-538X/03/$08.00+0     DOI: 10.1128/MCB.23.12.4319-4330.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.



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