SUPPRESSION OF CELLULAR-TRANSFORMATION BY GLUCOCORTICOID RECEPTOR MUTANTS

Glucocorticoid receptor (GR) has been shown to suppress activator prot ein 1 (AP-l)-mediated transcription by several molecular mechanisms, W e previously showed that activation of endogenous AP-1 is essential fo r cellular transformation induced by oncogenes, such as v-src and c-sa -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 stim ulation via glucocorticoid response elements, we constructed two GR mu tants: CD-GR-I, lacking the COOH-terminal portion, including both the ligand and Hsp90-binding domains, and tau 1DCD-GR-1, a derivative of C D-GR-1 lacking the tau 1 transactivation domain. When these GR mutants were expressed in chicken embryonic fibroblasts by retroviral vectors , they translocated into the nucleus without addition of glucocorticoi d to the culture medium, and they suppressed cellular transformation c aused by v-src and c-aa-ras, as well as by c-fos and c-jun, Cellular t ransformation by v-myc was not suppressed by these mutants, Such suppr essive effects of these GR mutants have a very similar oncogene depend ency to that of dominant-negative mutants of AP-1, This suggests that GR can be altered to suppress cellular transformation by inhibiting en dogenous AP-1 activity without activating glucocorticoid response elem ents.