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J. Biol. Chem., Vol. 279, Issue 38, 39279-39288, September 17, 2004

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A Single Amino Acid Change in the First Zinc Finger of the DNA Binding Domain of the Glucocorticoid Receptor Regulates Differential Promoter Selectivity^*

Brian M. Necela and John A. Cidlowski

From the Laboratory of Signal Transduction, NIEHS, and Department of Health and Human Services, National Institutes of Health, Research Triangle Park, North Carolina 27709

Mammalian species are well known to differ in their sensitivity to glucocorticoids, but the molecular basis for this difference remains largely uncharacterized. To address this issue, the transcriptional activity of the mouse and human glucocorticoid receptor (GR) was analyzed on two model glucocorticoid-responsive promoters. Mouse GR (mGR) displayed unique promoter discrimination in response to a range of glucocorticoids, with enhanced activity on a simple glucocorticoid response element (GRE)-based promoter and diminished activity on the complex mouse mammary tumor virus promoter compared with human GR (hGR). Promoter discrimination between mGR and hGR was mapped to a single amino acid change at residue 437 (glycine to valine) of mGR and to sequence differences within individual GREs of the different promoters. Mouse GR displayed higher activation on GREs with a guanine rather than a thymine at the –6 position. Binding studies indicated mGR (mGR437V) displayed a weaker affinity for GREs containing a thymine at the –6 position than a mGR mutant containing a glycine at residue 437 (mGR437G). Despite distinct transcriptional activities, both receptors had similar affinities for response elements that contain a guanine at the –6 position. Our findings support a model by which the presence of a valine residue at position 437 of mGR induces a conformational change that leads to alterations in affinity and/or transcriptional activation in a promoter-dependent context.

Received for publication, May 17, 2004 , and in revised form, June 23, 2004.

^* The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

To whom correspondence should be addressed: Laboratory of Signal Transduction, NIEHS, National Institutes of Health, 111 Alexander Dr., Bldg. 101, MD F3-07, Research Triangle Park, NC 27709. Tel.: 919-541-0793; Fax: 919-541-1367; E-mail: cidlowski{at}niehs.nih.gov.

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