C‐Jun regulates MMP‐2 and MT1‐MMP mRNA expression in endothelium.

Abstract

Angiogenesis is the formation of new capillaries from pre-existing ones. Proteolysis of the basement membrane and the interstitial matrix is mediated by the matrix metalloproteinases (MMPs) and is critical to the angiogenic process. We showed previously that reorganization of the actin cytoskeleton induces the expression of MMP-2 and membrane type (MT)1-MMP through the activation of JNK. Here we examined the involvement of the transcription factor c-Jun, a downstream effector of JNK. We hypothesized that c-Jun regulates the transcription of both MMP-2 and MT1-MMP. Treatment of skeletal muscle endothelial cells (SMEC) with small interference (si)RNA targeting c-Jun decreased basal levels of c-Jun protein by 40% and resulted in decreased basal MMP-2 and MT1-MMP mRNA expression. Activation of JNK by anisomycin increased MMP-2 and MT1-MMP mRNA expression and this induction was attenuated by c-Jun siRNA treatment. Depolymerization of the actin cytoskeleton, which increases MMP-2 protein production and activation, and both were attenuated with siRNA treatment. Vascular endothelial growth factor (VEGF) induction of MMP-2 mRNA expression was repressed by c-Jun siRNA. Our results point to c-Jun as the transcription factor regulating MMP-2 and MT1-MMP mRNA expression downstream of JNK. Funded by NSERC and CIHR.