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High Level Expression of the Major Transactivation Domain of the Human Glucocorticoid Receptor in Yeast Cells Inhibits Endogenous Gene Expression and Cell Growth

Centre for Biotechnology and Department of Medical Nutrition, Karolinska Institute, NOVUM, Huddinge University Hospital Huddinge S-141 57, Sweden

Address requests for reprints to: Dr. Anthony P. H. Wright, Centre for Biotechnology, Karolinska Institute, NOVUM, HuddingeS-141 57, Sweden.

Abstract

A number of alternative mechanisms by which the DNA-bound glucocorticoid receptor transactivates gene expression have been suggested. The fact that the glucocorticoid and other steroid hormone receptors function in yeast suggests that at least one of these mechanisms has been conserved throughout evolution. Here we show that overexpression of one of the glucocorticoid receptor transactivation domains (₁) in yeast causes a reduction in expression of a yeast reporter gene, followed by a severe reduction in the growth rate of the yeast cells. This is analogous to the phenomenon of squelching, first described for the GAL4 protein, and suggests that the ₁, domain of the glucocorticoid receptor functions by contacting limiting transcription factors needed for efficient gene activity. A similar level of squelching was seen after removal of the up-stream activation sequences from the yeast reporter gene, suggesting that the squelching interactions were with transcription factors needed for the activity of a basal promoter.

FOOTNOTES

This work was supported by Grant 13X-2819 and salary support (to K.D.-W.) from the Swedish Medical Research Council and Grant 89–00521P from the Swedish National Board for Technical Development.

Received for publication April 18, 1991. Revision received June 18, 1991. Accepted for publication July 5, 1991.

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