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Tumor Biology |
Department of Pharmacology, Uniformed Services University of the Health Sciences, Bethesda, Maryland 20814-4799
ABSTRACT
In contrast to the negative autoregulation of glucocorticoid receptor (GR) expression seen in most cells and tissues, GR expression is positively autoregulated in human leukemic T cells and in other cells sensitive to glucocorticoid-induced cell death. To determine whether positive autoregulation is a necessary component of glucocorticoid-induced cell death, a wild-type GR gene under the control of a tetracycline-regulated promoter was stably transfected into glucocorticoid-resistant cells lacking endogenous functional receptor. Transfectants grown in the presence of tetracycline contained about 15,000 receptors/cell, a value approximately equal to basal level GR expression in glucocorticoid-sensitive 6TG1.1 cells before steroid treatment. Under these conditions, dexamethasone had a minimal effect on cell growth, elicited little internucleosomal DNA fragmentation, and induced no cell cycle perturbation. In the absence of tetracycline, GR mRNA and protein expression increased 2–3-fold, and cells expressed 48,000 receptors, a level nearly equivalent to that present in 6TG1.1 cells after 18 h of autoinduction. Under these conditions, dexamethasone markedly inhibited cell growth, caused G1 arrest, and induced significant internucleosomal DNA fragmentation. These studies therefore suggest that basal level GR expression is inadequate to mediate glucocorticoid-induced apoptosis in glucocorticoid-sensitive T cells and that positive autoregulation is a necessary component of this process.
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