COORDINATE REGULATION OF GLUCOCORTICOID RECEPTOR AND C-JUN GENE-EXPRESSION IS CELL-TYPE-SPECIFIC AND EXHIBITS DIFFERENTIAL HORMONAL SENSITIVITY FOR DOWN-REGULATION AND UP-REGULATION

We have previously proposed a novel mechanism for the coupled regulati on of glucocorticoid receptor (GR) and c-jun transcription in triamcin olone acetonide (TA)-treated AtT-20 cells. This involved transcription al interference of AP-1 (Fos/Jun)-driven gene transcription by the for mation of inactive GR/Jun heterodimers. To further elucidate the molec ular mechanism for GR autoregulation. the expression of GR and c-jun m RNA and protein levels were examined in both mouse L929 fibroblast cel ls and human CEM-C7 acute lymphoblastic leukemia cells. A rapid down-r egulation of both GR and c-jun mRNA and protein levels occurs in TA-tr eated L929 cells. All-trans-retinoic acid (RA) treatment of Jun-defici ent, mouse F9, teratocarcinoma cells causes the induction of c-jun exp ression. The increased expression of both c-jun mRNA and protein is ac companied by the induction of GR expression. These data further sugges t that functional cJun is needed for the expression of the GR and c-ju n genes in F9 cells. CEM-C7 cells undergo apoptosis after exposure to glucocorticoids. There is a parallel up-regulation of GR and c-jun mRN A levels in TA-treated CEM-C7 cells. This is accompanied by a concomit ant increase in GR and cJun protein levels. Dose-response analyses rev eal the expected coordinate regulation of both GR and c-jun mRNA and p rotein in L929 cells (decreasing) and in CEM-C7 cells (increasing). Ho wever, similar to 20-fold less TA is required for the inhibition of GR and c-jun expression as compared to that required for the stimulation of these two genes. These data demonstrate that the coordinate regula tion of GR and c-jun gene expression is dose-dependent and cell type-s pecific. These results, along with previously reported data, suggest t hat GR complex formation with itself or with another transcription fac tor is important for the coordinate up- and down-regulation, respectiv ely, of the GR and c-jun genes.