Glucocorticoid-specific gene activation by the intact human glucocorticoid receptor expressed in yeast. Glucocorticoid specificity depends on low level receptor expression.

In the presence of appropriate reporter genes mammalian nuclear receptors are competent to transactivate gene expression when expressed in yeast cells. Thus yeast genetics could be used to identify determinants of steroid specificity for these mammalian proteins. However, unlike the estrogen, progesterone, vitamin D3, and thyroid hormone receptors, the glucocorticoid receptor shows an apparently abnormal steroid specificity in yeast (Schena, M., and Yamamoto, K. (1988) Science 241, 965-967), suggesting that the expressed protein might be incorrectly folded. We show here that the glucocorticoid receptor does exhibit a normal steroid specificity in yeast cells, but only at low levels of expressed receptor protein. Thus, at least under these conditions, genetic studies on steroid specificity are possible. At least part of the abnormal specificity that is sometimes observed for the glucocorticoid receptor in yeast appears to result from an artifact of the assay system and is not due to an abnormal receptor structure. This mechanism could account for all our data and so could provide the sole explanation of the abnormal specificity observed. However, it is also possible that part of the abnormal specificity could result from structural or other changes in receptor function, which occur when the receptor expression level is increased.