Abstract
The protein arginine methyltransferases (PRMTs) include a family of proteins with related putative methyltransferase domains that modify chromatin and regulate cellular transcription. Although some family members, PRMT1 and PRMT4, have been implicated in transcriptional modulation or intracellular signaling, the roles of other PRMTs in diverse cellular processes have not been fully established. Here, we report that PRMT2 inhibits NF-kappaB-dependent transcription and promotes apoptosis. PRMT2 exerted this effect by blocking nuclear export of IkappaB-alpha through a leptomycin-sensitive pathway, increasing nuclear IkappaB-alpha and decreasing NF-kappaB DNA binding. The highly conserved S-adenosylmethionine-binding domain of PRMT2 mediated this effect. PRMT2 also rendered cells susceptible to apoptosis by cytokines or cytotoxic drugs, likely due to its effects on NF-kappaB. Mouse embryo fibroblasts from PRMT2 genetic knockouts showed elevated NF-kappaB activity and decreased susceptibility to apoptosis compared to wild-type or complemented cells. Taken together, these data suggest that PRMT2 inhibits cell activation and promotes programmed cell death through this NF-kappaB-dependent mechanism.
Publication types
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Comparative Study
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Research Support, N.I.H., Intramural
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Research Support, U.S. Gov't, Non-P.H.S.
MeSH terms
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Alanine / metabolism
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Amino Acid Sequence
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Amino Acid Substitution
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Animals
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Apoptosis / drug effects
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Apoptosis / physiology*
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Blotting, Western
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Cell Line
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Cell Survival / drug effects
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Cells, Cultured
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DNA-Binding Proteins / metabolism*
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DNA-Binding Proteins / pharmacology
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Dose-Response Relationship, Drug
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Electrophoretic Mobility Shift Assay
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Fibroblasts / drug effects
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Fibroblasts / metabolism
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Fluorescein-5-isothiocyanate
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Fluorescent Antibody Technique
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Fluorescent Dyes
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Gene Deletion
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Genes, Reporter
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Glutathione Transferase / metabolism
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Humans
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Immunohistochemistry
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Luciferases / metabolism
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Mice
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Microscopy, Confocal
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NF-kappa B / antagonists & inhibitors*
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NIH 3T3 Cells
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Plasmids / genetics
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Precipitin Tests
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Protein O-Methyltransferase / chemistry
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Protein O-Methyltransferase / genetics
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Protein O-Methyltransferase / metabolism*
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Protein O-Methyltransferase / pharmacology
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Protein Structure, Tertiary
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Recombinant Fusion Proteins / metabolism
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Transcription, Genetic / drug effects*
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Tumor Necrosis Factor-alpha / pharmacology
Substances
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DNA-Binding Proteins
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Fluorescent Dyes
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NF-kappa B
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Recombinant Fusion Proteins
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Tumor Necrosis Factor-alpha
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Luciferases
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Protein O-Methyltransferase
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Glutathione Transferase
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Fluorescein-5-isothiocyanate
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Alanine