Glucocorticoid receptor (GR) activation has been shown to inhibit apoptosis in breast epithelial cells. We have identified a group of genes that is rapidly upregulated in these cells following dexamethasone (Dex) treatment. This group includes MAP kinase phosphatase-1 (MKP-1), a negative regulator of the MAPK pathway and serum and glucocorticoid-regulated kinase (SGK-1), a downstream target of PI3-Kinase signaling. Using a model of paclitaxel-induced cell death, we have recently found that induction of MKP-1 by Dex correlates with the inhibition of extracellular signal regulated kinase (ERK1/2) and c-Jun N-terminal kinase (JNK) activity, while p38 activity was minimally affected. Blocking Dex-induced MKP-1 expression by siRNA expression increased ERK1/2 and JNK phosphorylation and decreased cell survival. To explore gene expression changes that occur downstream of Dex-induced MAPK inactivation, we used a combination of temporal gene expression data and promoter element analysis. This approach yielded several previously unrecognized putative transcriptional targets of the ERK-dependent transcription factor ELK-1 that may be involved in cell survival signaling. One of these genes is tissue plasminogen activator (tPA). We verified the predicted ELK-1-tPA trascriptional regulatory relationship using a luciferase reporter assay. In parallel experiments, we are examining gene expression changes mediated by SGK-1 phosphorylation and subsequent nuclear exclusion of FOXO3a (FKHRL-1). Interestingly, we have identified several putative FKHRL-1 targets that are up-regulated or down-regulated following GR activation. Down-regulated FKHRL-1 putative target genes include several pro-apoptotic genes, while the list of putative up-regulated FKHRL-1 target genes contains several anti-apoptotic genes. Taken together, these findings are consistent with the hypothesis that GR activation signals a coordinated anti-apoptotic response in breast epithelial cells. This response appears to be executed, at least in part, by MKP-1-mediated ELK-1 dephosphorylation and SGK-1-mediated FKHRL-1 phosphorylation, both of which result in important pro- and anti-apoptotic gene expression changes.

[Proc Amer Assoc Cancer Res, Volume 46, 2005]