Abstract
During the development of multicellular organisms, concerted actions of molecular signalling networks determine whether cells undergo proliferation, differentiation, death or ageing. Here we show that genetic inactivation of the stress signalling kinase, MKK7, a direct activator of JNKs in mice, results in embryonic lethality and impaired proliferation of hepatocytes. Beginning at passage 4-5, mkk7(-/-) mouse embryonic fibroblasts (MEFs) display impaired proliferation, premature senescence and G2/M cell cycle arrest. Similarly, loss of c-Jun or expression of a c-JunAA mutant in which the JNK phosphorylation sites were replaced with alanine results in a G2/M cell-cycle block. The G2/M cell-cycle kinase CDC2 was identified as a target for the MKK7-JNK-c-Jun pathway. These data show that the MKK7-JNK-c-Jun signalling pathway couples developmental and environmental cues to CDC2 expression, G2/M cell cycle progression and cellular senescence in fibroblasts.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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CDC2 Protein Kinase / metabolism
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Cell Cycle Proteins / genetics
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Cell Cycle Proteins / metabolism
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Cells, Cultured
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Cellular Senescence / genetics*
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Fetus
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Fibroblasts / cytology
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Fibroblasts / enzymology
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G2 Phase / genetics*
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Genes, Lethal / genetics
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Hepatocytes / cytology
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Hepatocytes / enzymology*
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JNK Mitogen-Activated Protein Kinases
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Liver / abnormalities
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Liver / pathology
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MAP Kinase Kinase 7
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MAP Kinase Signaling System / genetics
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Mice
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Mitogen-Activated Protein Kinase Kinases / deficiency*
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Mitogen-Activated Protein Kinase Kinases / genetics
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Mitogen-Activated Protein Kinases / metabolism
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Mitosis / genetics*
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Mutation / genetics
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Phosphorylation
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Proto-Oncogene Proteins c-jun / deficiency
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Proto-Oncogene Proteins c-jun / genetics
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Stress, Physiological / enzymology*
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Stress, Physiological / genetics
Substances
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Cell Cycle Proteins
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Proto-Oncogene Proteins c-jun
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CDC2 Protein Kinase
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JNK Mitogen-Activated Protein Kinases
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Mitogen-Activated Protein Kinases
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MAP Kinase Kinase 7
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Map2k7 protein, mouse
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Mitogen-Activated Protein Kinase Kinases