Critical role for NF-[kappa]B-induced JunB in VEGF regulation and tumor angiogenesis

• Published in: The EMBO journal Vol. 26; no. 3; pp. 710 - 719
• Main Authors: Schmidt, Dirk, Textor, Björn, Pein, Oliver T, Licht, Alexander H, Andrecht, Sven, Sator-Schmitt, Melanie, Fusenig, Norbert E, Angel, Peter, Schorpp-Kistner, Marina
• Format: Journal Article
• Language: English
• Published: Heidelberg Blackwell Publishing Ltd 07-02-2007
• Subjects: Cellular biology; Embryos; Gene expression; Genotype & phenotype; Hypoxia; Molecular biology; Signal transduction
• ISSN: 0261-4189; 1460-2075
• DOI: 10.1038/sj.emboj.7601539

Regulation of vascular endothelial growth factor (VEGF) expression is a complex process involving a plethora of transcriptional regulators. The AP-1 transcription factor is considered as facilitator of hypoxia-induced VEGF expression through interaction with hypoxia-inducible factor (HIF) which plays a major role in mediating the cellular hypoxia response. As yet, both the decisive AP-1 subunit leading to VEGF induction and the molecular mechanism by which this subunit is activated have not been deciphered. Here, we demonstrate that the AP-1 subunit junB is a target gene of hypoxia-induced signaling via NF-kappaB. Loss of JunB in various cell types results in severely impaired hypoxia-induced VEGF expression, although HIF is present and becomes stabilized. Thus, we identify JunB as a critical independent regulator of VEGF transcription and provide a mechanistic explanation for the inherent vascular phenotypes seen in JunB-deficient embryos, ex vivo allantois explants and in vitro differentiated embryoid bodies. In support of these findings, tumor angiogenesis was impaired in junB(-/-) teratocarcinomas because of severely impaired paracrine-acting VEGF and the subsequent inability to efficiently recruit host-derived vessels.