Abstract
The cJun NH(2)-terminal kinase (JNK) signal transduction pathway is established to be an important mechanism of regulation of the cJun transcription factor. Studies of Jnk1(-/-) and Jnk2(-/-) mice suggest that the JNK1 and JNK2 isoforms have opposite effects on cJun expression and proliferation. Here, we demonstrate, using a chemical genetic approach, that both JNK1 and JNK2 are positive regulators of these processes. We show that competition between JNK1 and JNK2 contributes to the opposite phenotypes caused by JNK1 and JNK2 deficiency. Our analysis illustrates the power of a chemical genetics approach for the analysis of signal transduction pathways and also highlights the limitations of single gene knockout strategies for the analysis of signaling pathways that are formed by a network of interacting proteins.
Publication types
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Comparative Study
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Research Support, N.I.H., Extramural
MeSH terms
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Animals
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Cell Movement / drug effects
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Cell Proliferation / drug effects
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Gene Expression Regulation* / drug effects
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Germ-Line Mutation
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MAP Kinase Signaling System / drug effects
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MAP Kinase Signaling System / physiology*
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Mice
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Mitogen-Activated Protein Kinase 9 / chemistry
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Mitogen-Activated Protein Kinase 9 / genetics
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Mitogen-Activated Protein Kinase 9 / physiology*
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Mutagenesis, Site-Directed
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Phosphorylation
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Point Mutation
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Protein Kinase Inhibitors / pharmacology
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Protein Structure, Tertiary
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Proto-Oncogene Proteins c-jun / genetics*
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Proto-Oncogene Proteins c-jun / metabolism
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Pyrazoles / pharmacology
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Pyrimidines / pharmacology
Substances
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1-tert-butyl-3-naphthalen-1-ylmethyl-1H-pyrazolo(3,4-d)pyrimidin-4-ylemine
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Protein Kinase Inhibitors
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Proto-Oncogene Proteins c-jun
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Pyrazoles
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Pyrimidines
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Mitogen-Activated Protein Kinase 9