Coordinate Regulation of Glucocorticoid Receptor and c-jun Gene Expression Is Cell Type-Specific and Exhibits Differential Hormonal Sensitivity for Down- and Up-Regulation

Abstract

We have previously proposed a novel mechanism for the coupled regulation of glucocorticoid receptor (GR) and c-jun transcription in triamcinolone acetonide (TA)-treated AtT-20 cells. This involved transcriptional interference of AP-1 (Fos/Jun)-driven gene transcription by the formation of inactive GR/Jun heterodimers. To further elucidate the molecular mechanism for GR autoregulation, the expression of GR and c-jun mRNA and protein levels were examined in both mouse L929 fibroblast cells and human CEM-C7 acute lymphoblastic leukemia cells. A rapid down-regulation of both GR and c-jun mRNA and protein levels occurs in TA-treated L929 cells. All-trans-retinoic acid (RA) treatment of Jun-deficient, mouse F9, teratocarcinoma cells causes the induction of c-jun expression. The increased expression of both c-jun mRNA and protein is accompanied by the induction of GR expression. These data further suggest that functional cJun is needed for the expression of the GR and c-jun genes in F9 cells. CEM-C7 cells undergo apoptosis after exposure to glucocorticoids. There is a parallel up-regulation of GR and c-jun mRNA levels in TA-treated CEM-C7 cells. This is accompanied by a concomitant increase in GR and cJun protein levels. Dose-response analyses reveal the expected coordinate regulation of both GR and c-jun mRNA and protein in L929 cells (decreasing) and in CEM-C7 cells (increasing). However, approximately 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 regulation of GR and c-jun gene expression is dose-dependent and cell type-specific. These results, along with previously reported data, suggest that GR complex formation with itself or with another transcription factor is important for the coordinate up- and down-regulation, respectively, of the GR and c-jun genes.

The delayed induction of c-jun in apoptotic human leukemic lymphoblasts is primarily transcriptional

“…The regulation can be purely transcriptional, post-transcriptional, or both [26][27][28][29][30]. Glucocorticoid induces c-jun expression in some cells, but suppresses it in others [25,[31][32][33]. In both AtT-20 pituitary tumor cells and U-937 monocytic leukemia cells, Dex represses the transcription of c-jun [25,34].…”

Expression of the Glucocorticoid Receptor from the 1A Promoter Correlates with T Lymphocyte Sensitivity to Glucocorticoid-Induced Cell Death

“…It is therefore interesting that most cell types, mainly of nonlymphoid origin, appear to survive GC treatment by decreasing transcription of GR mRNA to reduce GR protein levels (9,10), and that sequences in the GR promoter seem to regulate this process (11). This down-regulation is tissue specific, because GR mRNA and protein levels were increased in the GC-sensitive human CEM-7 and mouse S49 T lymphocyte cell lines upon GC treatment (12,13), and increased GR expression was suggested to be essential for subsequent GICD in T lymphoblasts (14).…”

Structure of the glucocorticoid receptor (NR3C1) gene 5′ untranslated region: identification, and tissue distribution of multiple new human exon 1

“…Only three alternative (heterogenous) non-coding exon 1s, and two of the corresponding promoter regions have been described for the hGR (Breslin & Vedeckis 1998, Breslin et al 2001. Careful examination of the gene sequence and the known hGR transcription initiation sites have shown that each previously reported initiation site has its own promoter region (Barrett et al 1996, Wei & Vedeckis 1997, Breslin & Vedeckis 1998, Breslin et al 2001, Nunez & Vedeckis 2002. Multiple independent promoter regions producing the same protein by splicing upstream of the translation initiation site, partially explain tissue-specific GR expression (Nunez & Vedeckis 2002, Pedersen & Vedeckis 2003, Pedersen et al 2004.…”