Abstract
The tumor suppressor protein promyelocytic leukemia (PML) is a key regulator of inflammatory responses and tumorigenesis and functions through the assembly of subnuclear structures known as PML nuclear bodies (NBs). The inflammation-related cytokine tumor necrosis factor-α (TNFα) is known to induce PML protein accumulation and PML NB formation that mediate TNFα-induced cell death in cancer cells and inhibition of migration and capillary tube formation in endothelial cells (ECs). In this study, we uncover a novel mechanism of PML gene regulation in which the p38 MAPK and its downstream kinase MAP kinase-activated protein kinase 1 (MNK1) mediate TNFα-induced PML protein accumulation and PML NB formation. The mechanism includes the presence of an internal ribosome entry site (IRES) found within the well-conserved 100 nucleotides upstream of the PML initiation codon. The activity of the PML IRES is induced by TNFα in a manner that involves MNK1 activation. It is proposed that the p38-MNK1-PML network regulates TNFα-induced apoptosis in breast cancer cells and TNFα-mediated inhibition of migration and capillary tube formation in ECs.
Publication types
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Research Support, N.I.H., Extramural
MeSH terms
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5' Untranslated Regions
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Apoptosis*
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Breast Neoplasms
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Cell Movement
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Cell Proliferation
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Chemokine CCL2 / genetics
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Chemokine CCL2 / metabolism
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Gene Expression Regulation, Neoplastic
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HL-60 Cells
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Human Umbilical Vein Endothelial Cells / physiology*
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Humans
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Internal Ribosome Entry Sites
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Intracellular Signaling Peptides and Proteins / metabolism
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MCF-7 Cells
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Matrix Metalloproteinase 10 / genetics
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Matrix Metalloproteinase 10 / metabolism
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Neovascularization, Physiologic
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Nuclear Proteins / genetics*
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Nuclear Proteins / metabolism
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Promyelocytic Leukemia Protein
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Protein Biosynthesis*
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Protein Serine-Threonine Kinases / metabolism
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Transcription Factors / genetics*
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Transcription Factors / metabolism
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Tumor Necrosis Factor-alpha / physiology*
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Tumor Suppressor Proteins / genetics*
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Tumor Suppressor Proteins / metabolism
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p38 Mitogen-Activated Protein Kinases / metabolism
Substances
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5' Untranslated Regions
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CCL2 protein, human
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Chemokine CCL2
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Internal Ribosome Entry Sites
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Intracellular Signaling Peptides and Proteins
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Nuclear Proteins
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Promyelocytic Leukemia Protein
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TNF protein, human
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Transcription Factors
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Tumor Necrosis Factor-alpha
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Tumor Suppressor Proteins
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PML protein, human
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MKNK1 protein, human
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Protein Serine-Threonine Kinases
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p38 Mitogen-Activated Protein Kinases
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MMP10 protein, human
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Matrix Metalloproteinase 10