c-Jun and JunB are essential for hypoglycemia-mediated VEGF induction.
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.
Textor
Björn
B
Division of Signal Transduction and Growth Control, Deutsches Krebsforschungszentrum (DKFZ), Im Neuenheimer Feld 280, D-69120 Heidelberg, Germany.
Sator-Schmitt
Melanie
M
Richter
Karl Hartmut
KH
Angel
Peter
P
Schorpp-Kistner
Marina
M
D000818:Animals; D002478:Cells, Cultured; D005786:Gene Expression Regulation / Q000502:physiology*; D007003:Hypoglycemia / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D016755:Proto-Oncogene Proteins c-jun / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D042461:Vascular Endothelial Growth Factor A / Q000096:biosynthesis* / Q000235:genetics*
D016755:Proto-Oncogene Proteins c-jun; D042461:Vascular Endothelial Growth Factor A; C467480:vascular endothelial growth factor A, mouse