Abstract
Jun is essential for fetal development, as fetuses lacking Jun die at mid-gestation with multiple cellular defects in liver and heart. Embryos expressing JunD in place of Jun (Jun(d/d)) can develop to term with normal fetal livers, but display cardiac defects as observed in fetuses lacking Jun. Jun(d/d) mouse embryonic fibroblasts (MEFs) exhibit early senescence, which can be rescued by EGF and HB-EGF stimulation, probably through activation of Akt signaling. Thus, JunD cannot functionally replace Jun in regulating fibroblast proliferation. In Jun(-/-) fetal livers, increased hydrogen peroxide levels are detected and expression of Nrf1 and Nrf2 (nuclear erythroid 2-related transcription factors) is downregulated. Importantly, increased oxidative stress as well as expression of Nrf1 and Nrf2 is rescued by JunD in Jun(d/d) fetal livers. These data show that Jun is of critical importance for cellular protection against oxidative stress in fetal livers and fibroblasts, and Jun-dependent cellular senescence can be restored by activation of the epidermal growth factor receptor pathway.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animal Structures / abnormalities
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Animal Structures / metabolism
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Animal Structures / pathology
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Animals
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Antioxidants / pharmacology
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Cell Proliferation* / drug effects
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Cellular Senescence / drug effects
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Cellular Senescence / genetics
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Cyclin D1 / genetics
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Cyclin D1 / metabolism
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Cyclin-Dependent Kinase Inhibitor p21 / metabolism
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Embryo, Mammalian / abnormalities
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Embryo, Mammalian / metabolism
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Embryo, Mammalian / pathology
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Epidermal Growth Factor / pharmacology
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ErbB Receptors / genetics
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Fibroblasts / metabolism
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Fibroblasts / pathology
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Gene Expression / drug effects
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Gene Expression / genetics
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Heart Defects, Congenital / genetics
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Heart Defects, Congenital / pathology
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Hepatocytes / cytology
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Hepatocytes / metabolism
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Hydrogen Peroxide / metabolism
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Liver / metabolism
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Liver / pathology
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Mice
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Mice, 129 Strain
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Mice, Inbred C57BL
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Mice, Knockout
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Mice, Transgenic
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NF-E2-Related Factor 2 / genetics
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Nuclear Respiratory Factor 1 / genetics
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Oxidative Stress* / genetics
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Proto-Oncogene Proteins / genetics
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Proto-Oncogene Proteins / metabolism*
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Proto-Oncogene Proteins c-akt / metabolism
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Proto-Oncogene Proteins c-jun / genetics
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Proto-Oncogene Proteins c-jun / metabolism*
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Signal Transduction / drug effects
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Signal Transduction / physiology*
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Tumor Suppressor Protein p53 / genetics
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Tumor Suppressor Protein p53 / metabolism
Substances
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Antioxidants
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Ccnd1 protein, mouse
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Cyclin-Dependent Kinase Inhibitor p21
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NF-E2-Related Factor 2
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Nfe2l2 protein, mouse
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Nrf1 protein, mouse
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Nuclear Respiratory Factor 1
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Proto-Oncogene Proteins
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Proto-Oncogene Proteins c-jun
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Tumor Suppressor Protein p53
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junD protein, mouse
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Cyclin D1
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Epidermal Growth Factor
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Hydrogen Peroxide
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EGFR protein, mouse
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ErbB Receptors
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Proto-Oncogene Proteins c-akt