Jun and JunD-dependent functions in cell proliferation and stress response

Cell Death Differ. 2010 Sep;17(9):1409-19. doi: 10.1038/cdd.2010.22. Epub 2010 Mar 19.

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

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animal Structures / abnormalities
  • Animal Structures / metabolism
  • Animal Structures / pathology
  • Animals
  • Antioxidants / pharmacology
  • Cell Proliferation* / drug effects
  • Cellular Senescence / drug effects
  • Cellular Senescence / genetics
  • Cyclin D1 / genetics
  • Cyclin D1 / metabolism
  • Cyclin-Dependent Kinase Inhibitor p21 / metabolism
  • Embryo, Mammalian / abnormalities
  • Embryo, Mammalian / metabolism
  • Embryo, Mammalian / pathology
  • Epidermal Growth Factor / pharmacology
  • ErbB Receptors / genetics
  • Fibroblasts / metabolism
  • Fibroblasts / pathology
  • Gene Expression / drug effects
  • Gene Expression / genetics
  • Heart Defects, Congenital / genetics
  • Heart Defects, Congenital / pathology
  • Hepatocytes / cytology
  • Hepatocytes / metabolism
  • Hydrogen Peroxide / metabolism
  • Liver / metabolism
  • Liver / pathology
  • Mice
  • Mice, 129 Strain
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mice, Transgenic
  • NF-E2-Related Factor 2 / genetics
  • Nuclear Respiratory Factor 1 / genetics
  • Oxidative Stress* / genetics
  • Proto-Oncogene Proteins / genetics
  • Proto-Oncogene Proteins / metabolism*
  • Proto-Oncogene Proteins c-akt / metabolism
  • Proto-Oncogene Proteins c-jun / genetics
  • Proto-Oncogene Proteins c-jun / metabolism*
  • Signal Transduction / drug effects
  • Signal Transduction / physiology*
  • Tumor Suppressor Protein p53 / genetics
  • Tumor Suppressor Protein p53 / metabolism

Substances

  • Antioxidants
  • Ccnd1 protein, mouse
  • Cyclin-Dependent Kinase Inhibitor p21
  • NF-E2-Related Factor 2
  • Nfe2l2 protein, mouse
  • Nrf1 protein, mouse
  • Nuclear Respiratory Factor 1
  • Proto-Oncogene Proteins
  • Proto-Oncogene Proteins c-jun
  • Tumor Suppressor Protein p53
  • junD protein, mouse
  • Cyclin D1
  • Epidermal Growth Factor
  • Hydrogen Peroxide
  • EGFR protein, mouse
  • ErbB Receptors
  • Proto-Oncogene Proteins c-akt