Glucocorticoid Receptor-induced MAPK Phosphatase-1 (MPK-1) Expression Inhibits Paclitaxel-associated MAPK Activation and Contributes to Breast Cancer Cell Survival

• Published in: The Journal of biological chemistry Vol. 280; no. 6; pp. 4117 - 4124
• Main Authors: Wu, Wei, Pew, Travis, Zou, Min, Pang, Diana, Conzen, Suzanne D.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 11.02.2005; American Society for Biochemistry and Molecular Biology
• Subjects: Amino Acid Motifs; Antineoplastic Agents, Phytogenic - pharmacology; Apoptosis; Blotting, Northern; Blotting, Western; Breast - metabolism; Cell Cycle Proteins - metabolism; Cell Cycle Proteins - physiology; Cell Line, Tumor; Cell Survival; DNA-Binding Proteins - biosynthesis; Down-Regulation; Dual Specificity Phosphatase 1; Enzyme Activation; ets-Domain Protein Elk-1; Gene Expression Regulation, Neoplastic; Genes, Reporter; Humans; Immediate-Early Proteins - metabolism; Immediate-Early Proteins - physiology; JNK Mitogen-Activated Protein Kinases - biosynthesis; JNK Mitogen-Activated Protein Kinases - metabolism; Luciferases - metabolism; MAP Kinase Kinase 4; MAP Kinase Signaling System; Mitogen-Activated Protein Kinase 1 - biosynthesis; Mitogen-Activated Protein Kinase 3 - biosynthesis; Mitogen-Activated Protein Kinase Kinases - metabolism; Mitogen-Activated Protein Kinases - metabolism; Models, Biological; Oligonucleotide Array Sequence Analysis; p38 Mitogen-Activated Protein Kinases - metabolism; Paclitaxel - pharmacology; Phosphoprotein Phosphatases - metabolism; Phosphoprotein Phosphatases - physiology; Phosphorylation; Protein Binding; Protein Phosphatase 1; Protein Tyrosine Phosphatases - metabolism; Protein Tyrosine Phosphatases - physiology; Proto-Oncogene Proteins - biosynthesis; Receptors, Glucocorticoid - metabolism; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger - metabolism; RNA, Small Interfering - metabolism; Time Factors; Tissue Plasminogen Activator - metabolism; Transcription Factors - biosynthesis; Transcription, Genetic; Transfection
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M411200200

Glucocorticoid receptor (GR) activation has recently been shown to inhibit apoptosis in breast epithelial cells. We have previously described a group of genes that is rapidly up-regulated in these cells following dexamethasone (Dex) treatment. In an effort to dissect the mechanisms of GR-mediated breast epithelial cell survival, we now examine the molecular events downstream of GR activation. Here we show that GR activation leads to both the rapid induction of MAPK phosphatase-1 (MKP-1) mRNA and its sustained expression. Induction of the MKP-1 protein in the MCF10A-Myc and MDA-MB-231 breast epithelial cell lines was also seen. Paclitaxel treatment resulted in MAPK activation and apoptosis of MDA-MB-231 breast cancer cells, and both processes were inhibited by Dex pretreatment. Furthermore, induction of MKP-1 correlated with the inhibition of extracellular signal-regulated kinase (ERK1/2) and c-Jun N-terminal kinase (JNK) activity, whereas p38 activity was minimally affected. Blocking Dex-induced MKP-1 induction using small interfering RNA increased ERK1/2 and JNK phosphorylation and decreased cell survival. ERK1/2 and JNK inactivation was associated with Ets-like transcription factor-1 (ELK-1) dephosphorylation. To explore the gene expression changes that occur downstream of ELK-1 dephosphorylation, we used a combination of temporal gene expression data and promoter element analyses. This approach revealed a previously unrecognized transcriptional target of ELK-1, the human tissue plasminogen activator (tPA). We verified the predicted ELK-1 → tPA transcriptional regulatory relationship using a luciferase reporter assay. We conclude that GR-mediated MAPK inactivation contributes to cell survival and that the potential transcriptional targets of this inhibition can be identified from large scale gene array analysis.