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 PKC?-dependent signaling pathway. In contrast, JunB is activated by the MAP kinase ERK for the AP-1 subunits cJun and JunB to mediate VEGF regulaltion of hypoglycemia
c-jun junb hypoglycemia vegf ap-1