Abstract
The AP-1 transcription factor complex has been implicated in a variety of biological processes including cell differentiation, proliferation, apoptosis and oncogenic transformation. We previously established that activation of the AP-1 family member JunD contributes to deregulated expression of the anti-apoptotic IL-6 gene in prostate cancer cells. We now show that inhibition of JunD in prostate cancer cells results in GADD45α- and γ-dependent induction of cell death and inhibition of tumor growth that is mediated at least partially via c-Jun N-terminal kinase (JNK) and p38 kinase activation. Apoptosis induction by dominant negative JunD and JNK and p38 kinase activation are impeded upon knock down of GADD45α and γ expression by small interfering RNA, most vividly demonstrating the central role of GADD45α and γ in JunD-mediated escape of prostate cancer cells from programmed cell death.
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*
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Cell Cycle Proteins / antagonists & inhibitors
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Cell Cycle Proteins / genetics
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Cell Cycle Proteins / metabolism*
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Cell Line, Tumor
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Humans
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Interleukin-6 / genetics
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Interleukin-6 / metabolism
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Intracellular Signaling Peptides and Proteins / antagonists & inhibitors
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Intracellular Signaling Peptides and Proteins / genetics
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Intracellular Signaling Peptides and Proteins / metabolism*
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Male
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Mitogen-Activated Protein Kinase 8 / metabolism
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Nuclear Proteins / antagonists & inhibitors
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Nuclear Proteins / genetics
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Nuclear Proteins / metabolism*
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Prostatic Neoplasms / metabolism*
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Prostatic Neoplasms / pathology
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Proto-Oncogene Proteins c-jun / antagonists & inhibitors
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Proto-Oncogene Proteins c-jun / metabolism*
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RNA Interference
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RNA, Small Interfering / metabolism
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p38 Mitogen-Activated Protein Kinases / metabolism
Substances
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Cell Cycle Proteins
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GADD45A protein, human
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GADD45G protein, human
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Interleukin-6
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Intracellular Signaling Peptides and Proteins
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JunD protein, human
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Nuclear Proteins
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Proto-Oncogene Proteins c-jun
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RNA, Small Interfering
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Mitogen-Activated Protein Kinase 8
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p38 Mitogen-Activated Protein Kinases