High level expression of the major transactivation domain of the human glucocorticoid receptor in yeast cells inhibits endogenous gene expression and cell growth.

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 (tau 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 tau 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.