EMBO J 2007,
PMID: 17255940
Schmidt, Dirk; Textor, Björn; Pein, Oliver T; Licht, Alexander H; Andrecht, Sven; Sator-Schmitt, Melanie; Fusenig, Norbert E; Angel, Peter; Schorpp-Kistner, Marina
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.
Diseases/Pathways annotated by Medline MESH: Neoplasms, Neovascularization, Pathologic
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Text Mining Data
JunB → NF-kappaB: "
Critical role for
NF-kappaB induced
JunB in VEGF regulation and tumor angiogenesis
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VEGF ⊣ JunB: "
Loss of JunB in various cell types results in severely impaired hypoxia induced VEGF expression, although HIF is present and becomes stabilized
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