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

Area of Science:

• Molecular Biology
• Cell Signaling
• Gene Regulation

Background:

• Vascular Endothelial Growth Factor (VEGF) is crucial for angiogenesis, and its expression is induced by physiological conditions like hypoglycemia.
• The transcription factor Activator Protein-1 (AP-1) plays a role in gene regulation, but its specific involvement in hypoglycemia-induced VEGF expression is not fully understood.

Purpose of the Study:

• To investigate the role of AP-1 transcription factor subunits, specifically c-Jun and JunB, in the regulation of VEGF expression during hypoglycemia.
• To elucidate the signaling pathways involved in the activation of c-Jun and JunB under hypoglycemic conditions.

Main Methods:

• Utilized c-jun(-/-) and junB(-/-) mouse embryonic fibroblasts to assess the necessity of these subunits.
• Employed specific inhibitors for protein kinase C (PKC) and extracellular signal-regulated kinase (ERK) signaling pathways.
• Analyzed the impact of AP-1 subunit deficiency on HIF-1 expression and stabilization.

Main Results:

• Both c-Jun and JunB are essential for hypoglycemia-mediated induction of VEGF expression.
• The observed VEGF regulation by AP-1 is independent of Hypoxia-Inducible Factor 1 (HIF-1).
• Hypoglycemia-induced c-Jun activation is dependent on PKCalpha signaling, while JunB activation is mediated by ERK signaling.

Conclusions:

• AP-1 subunits c-Jun and JunB are key mediators of VEGF expression in response to hypoglycemia.
• Distinct signaling pathways, PKCalpha for c-Jun and ERK for JunB, converge on AP-1 to regulate VEGF under low glucose conditions.
• These findings reveal a novel molecular mechanism linking metabolic stress to angiogenesis regulation.