Suppression of cellular transformation by glucocorticoid receptor mutants.

Abstract

Glucocorticoid receptor (GR) has been shown to suppress activator protein 1 (AP-1)-mediated transcription by several molecular mechanisms. We previously showed that activation of endogenous AP-1 is essential for cellular transformation induced by oncogenes, such as v-src and c-Ha-ras. In the present study, we have analyzed whether high levels of GR expression suppress cellular transformation caused by these oncogenes. To eliminate the ligand effects that induce the transcriptional stimulation via glucocorticoid response elements, we constructed two GR mutants: CD-GR-1, lacking the COOH-terminal portion, including both the ligand and Hsp90-binding domains, and tau1TDCD-GR-1, a derivative of CD-GR-1 lacking the tau1 transactivation domain. When these GR mutants were expressed in chicken embryonic fibroblasts by retroviral vectors, they translocated into the nucleus without addition of glucocorticoid to the culture medium, and they suppressed cellular transformation caused by v-src and c-Ha-ras, as well as by c-fos and c-jun. Cellular transformation by v-myc was not suppressed by these mutants. Such suppressive effects of these GR mutants have a very similar oncogene dependency to that of dominant-negative mutants of AP-1. This suggests that GR can be altered to suppress cellular transformation by inhibiting endogenous AP-1 activity without activating glucocorticoid response elements.