Abstract
Promyelocytic Leukemia (PML) is a nuclear protein that forms sub-nuclear structures termed nuclear bodies associated with transcriptionally active genomic regions. PML is a tumour suppressor and regulator of cell differentiation. We demonstrate that PML promotes TNFα-induced transcriptional responses by promoting NF-κB activity. TNFα-treated PML-/- cells show normal IκBα degradation and NF-κB nuclear translocation but significantly reduced NF-κB DNA binding and phosphorylation of NF-κB p65. We also demonstrate that the PML retinoic acid receptor-α (PML-RARα) oncofusion protein, which causes acute promyelocytic leukemia, inhibits TNFα induced gene expression and phosphorylation of NF-κB. This study establishes PML as an important regulator of NF-κB and demonstrates that PML-RARα dysregulates NF-κB.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Embryo, Mammalian
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Fibroblasts / cytology
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Fibroblasts / metabolism
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Gene Expression Regulation*
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Gene Ontology
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Genes, Reporter
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HEK293 Cells
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Humans
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Luciferases / genetics
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Luciferases / metabolism
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Mice
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Molecular Sequence Annotation
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NF-KappaB Inhibitor alpha / genetics
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NF-KappaB Inhibitor alpha / metabolism
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Neoplasm Proteins / genetics*
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Neoplasm Proteins / metabolism
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Oncogene Proteins, Fusion / genetics*
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Oncogene Proteins, Fusion / metabolism
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Plasmids / chemistry
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Plasmids / metabolism
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Promyelocytic Leukemia Protein / genetics*
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Promyelocytic Leukemia Protein / metabolism
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Signal Transduction
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Transcription Factor RelA / genetics*
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Transcription Factor RelA / metabolism
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Transfection
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Tumor Necrosis Factor-alpha / genetics
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Tumor Necrosis Factor-alpha / metabolism
Substances
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Neoplasm Proteins
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Oncogene Proteins, Fusion
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Promyelocytic Leukemia Protein
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Transcription Factor RelA
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Tumor Necrosis Factor-alpha
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promyelocytic leukemia-retinoic acid receptor alpha fusion oncoprotein
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NF-KappaB Inhibitor alpha
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PML protein, human
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Luciferases