c-Jun and JunB are essential for hypoglycemia-mediated VEGF induction

Ann N Y Acad Sci. 2006 Dec;1091:310-8. doi: 10.1196/annals.1378.076.

Abstract

Physiological conditions like hypoxia or hypoglycemia trigger expression of VEGF, a key regulator of angiogenesis. To elucidate the molecular mechanism underlying the VEGF regulation of hypoglycemia, we investigated the role of AP-1 transcription factor subunits c-Jun and JunB. Using c-jun(-/-) and junB(-/-) mouse embryonic fibroblasts, we demonstrate that both c-Jun and JunB are required for the hypoglycemia-mediated induction of VEGF expression. This process is independent of the master regulator of hypoxic stress HIF-1, as HIF expression and stabilization are not affected by the loss of AP-1 subunits. Analysis of signaling cascades regulating c-Jun and/or JunB activity and/or transcription upon hypoglycemia by application of specific inhibitors of protein kinase C (PKC) or extracellular signal-regulated kinase (ERK) signaling revealed that hypoglycemia-mediated induction of c-Jun is regulated via a PKCalpha-dependent signaling pathway. In contrast, JunB is activated by the MAP kinase ERK for the AP-1 subunits c-Jun and JunB to mediate VEGF regulaltion of hypoglycemia.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cells, Cultured
  • Gene Expression Regulation / physiology*
  • Hypoglycemia / genetics
  • Hypoglycemia / metabolism*
  • Mice
  • Mice, Knockout
  • Proto-Oncogene Proteins c-jun / deficiency
  • Proto-Oncogene Proteins c-jun / genetics
  • Proto-Oncogene Proteins c-jun / physiology*
  • Vascular Endothelial Growth Factor A / biosynthesis*
  • Vascular Endothelial Growth Factor A / genetics*

Substances

  • Proto-Oncogene Proteins c-jun
  • Vascular Endothelial Growth Factor A
  • vascular endothelial growth factor A, mouse