Abstract
Glucocorticoids (GCs) are common components of many chemotherapeutic regimens for lymphoid malignancies. GC-induced apoptosis involves an intrinsic mitochondria-dependent pathway. BIM (BCL-2-interacting mediator of cell death), a BCL-2 homology 3-only pro-apoptotic protein, is upregulated by dexamethasone (Dex) treatment in acute lymphoblastic leukemia cells and has an essential role in Dex-induced apoptosis. It has been indicated that Dex-induced BIM is regulated mainly by transcription, however, the molecular mechanisms including responsible transcription factors are unclear. In this study, we found that Dex treatment induced transcription factor Runx2 and c-Jun in parallel with BIM induction. Dex-induced BIM and apoptosis were decreased in cells harboring dominant-negative c-Jun and were increased in cells with c-Jun overexpression. Cells harboring short hairpin RNA for Runx2 also decreased BIM induction and apoptosis. On the Bim promoter, c-Jun bound to and activated the AP-1-binding site at about -2.7 kb from the transcription start site. Treatment with RU486, a GC receptor antagonist, blocked Dex-induced Runx2, c-Jun and BIM induction, as well as apoptosis. Furthermore, pretreatment with SB203580, a p38-mitogen-activated protein kinase (MAPK) inhibitor, decreased Dex-induced Runx2, c-Jun and BIM, suggesting that p38-MAPK activation is upstream of the induction of these molecules. In conclusion, we identified the critical signaling pathway for GC-induced apoptosis, and targeting these molecules may be an alternative approach to overcome GC-resistance in leukemia treatment.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Apoptosis / drug effects*
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Apoptosis Regulatory Proteins / genetics
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Apoptosis Regulatory Proteins / metabolism*
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Bcl-2-Like Protein 11
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Binding Sites
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Cell Line, Tumor
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Core Binding Factor Alpha 1 Subunit / antagonists & inhibitors
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Core Binding Factor Alpha 1 Subunit / genetics
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Core Binding Factor Alpha 1 Subunit / metabolism*
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Dexamethasone / pharmacology*
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Glucocorticoids / pharmacology*
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HEK293 Cells
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Humans
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Imidazoles / pharmacology
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JNK Mitogen-Activated Protein Kinases / genetics
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JNK Mitogen-Activated Protein Kinases / metabolism*
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Jurkat Cells
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Membrane Proteins / genetics
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Membrane Proteins / metabolism*
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Mifepristone / pharmacology
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Precursor Cell Lymphoblastic Leukemia-Lymphoma / metabolism
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Precursor Cell Lymphoblastic Leukemia-Lymphoma / pathology
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Promoter Regions, Genetic
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Protein Kinase Inhibitors / pharmacology
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Proto-Oncogene Proteins / genetics
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Proto-Oncogene Proteins / metabolism*
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Pyridines / pharmacology
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RNA Interference
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RNA, Small Interfering / metabolism
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Receptors, Glucocorticoid / antagonists & inhibitors
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Receptors, Glucocorticoid / metabolism
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Signal Transduction / drug effects
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Transcription Factor AP-1 / metabolism
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p38 Mitogen-Activated Protein Kinases / antagonists & inhibitors
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p38 Mitogen-Activated Protein Kinases / metabolism
Substances
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Apoptosis Regulatory Proteins
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BCL2L11 protein, human
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Bcl-2-Like Protein 11
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Core Binding Factor Alpha 1 Subunit
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Glucocorticoids
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Imidazoles
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Membrane Proteins
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Protein Kinase Inhibitors
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Proto-Oncogene Proteins
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Pyridines
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RNA, Small Interfering
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Receptors, Glucocorticoid
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Transcription Factor AP-1
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Mifepristone
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Dexamethasone
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JNK Mitogen-Activated Protein Kinases
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p38 Mitogen-Activated Protein Kinases
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SB 203580