Abstract
The nucleosomal response refers to the rapid phosphorylation of histone H3 on serine 10 and HMG-14 on serine 6 that occurs concomitantly with immediate-early (IE) gene induction in response to a wide variety of stimuli. Using antibodies against the phosphorylated residues, we show that H3 and HMG-14 phosphorylation is mediated via different MAP kinase (MAPK) cascades, depending on the stimulus. The nucleosomal response elicited by TPA is ERK-dependent, whereas that elicited by anisomycin is p38 MAPK-dependent. In intact cells, the nucleosomal response can be selectively inhibited using the protein kinase inhibitor H89. MAPK activation and phosphorylation of transcription factors are largely unaffected by H89, whereas induction of IE genes is inhibited and its characteristics markedly altered. MSK1 is considered the most likely kinase to mediate this response because (i) it is activated by both ERK and p38 MAPKs; (ii) it is an extremely efficient kinase for HMG-14 and H3, utilizing the physiologically relevant sites; and (iii) its activity towards H3/HMG-14 is uniquely sensitive to H89 inhibition. Thus, the nucleosomal response is an invariable consequence of ERK and p38 but not JNK/SAPK activation, and MSK1 potentially provides a link to complete the circuit between cell surface and nucleosome.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Anisomycin / pharmacology
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Blotting, Western
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Calcium-Calmodulin-Dependent Protein Kinases / metabolism*
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Cells, Cultured
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Enzyme Inhibitors / pharmacology
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Fibroblasts / metabolism
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Gene Expression Regulation, Enzymologic*
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Genes, Immediate-Early / drug effects
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Genes, Immediate-Early / genetics*
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High Mobility Group Proteins / metabolism
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Histones / metabolism*
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Isoquinolines / pharmacology
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Mice
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Mice, Inbred C3H
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Mitogen-Activated Protein Kinases / metabolism*
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Models, Biological
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Nucleosomes / metabolism*
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Phosphorylation
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Protein Synthesis Inhibitors / pharmacology
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Proto-Oncogene Proteins c-fos / metabolism
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Proto-Oncogene Proteins c-jun / metabolism
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Ribosomal Protein S6 Kinases, 90-kDa*
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Signal Transduction
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Sulfonamides*
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Tetradecanoylphorbol Acetate / pharmacology
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Time Factors
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Transcriptional Activation
Substances
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Enzyme Inhibitors
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High Mobility Group Proteins
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Histones
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Isoquinolines
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Nucleosomes
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Protein Synthesis Inhibitors
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Proto-Oncogene Proteins c-fos
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Proto-Oncogene Proteins c-jun
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Sulfonamides
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Anisomycin
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Ribosomal Protein S6 Kinases, 90-kDa
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mitogen and stress-activated protein kinase 1
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Calcium-Calmodulin-Dependent Protein Kinases
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Mitogen-Activated Protein Kinases
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N-(2-(4-bromocinnamylamino)ethyl)-5-isoquinolinesulfonamide
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Tetradecanoylphorbol Acetate