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Critical role for NF‐κB‐induced JunB in VEGF regulation and tumor angiogenesis
Author(s) -
Schmidt Dirk,
Textor Björn,
Pein Oliver T,
Licht Alexander H,
Andrecht Sven,
SatorSchmitt Melanie,
Fusenig Norbert E,
Angel Peter,
SchorppKistner Marina
Publication year - 2007
Publication title -
the embo journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 7.484
H-Index - 392
eISSN - 1460-2075
pISSN - 0261-4189
DOI - 10.1038/sj.emboj.7601539
Subject(s) - junb , biology , angiogenesis , vegf receptors , cancer research , nf κb , nfkb1 , transcription factor , microbiology and biotechnology , signal transduction , genetics , gene
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‐κB. 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.