Article
- The EMBO Journal (2007) 26, 710 - 719
- doi:10.1038/sj.emboj.7601539
Published online: 25 January 2007
Subject Categories:
Critical role for NF-
B-induced JunB in VEGF regulation and tumor angiogenesis
Dirk Schmidt1,a, Björn Textor1, Oliver T Pein1, Alexander H Licht1, Sven Andrecht1,b, Melanie Sator-Schmitt1, Norbert E Fusenig2, Peter Angel1 and Marina Schorpp-Kistner1
- Division of Signal Transduction and Growth Control, DKFZ (German Cancer Research Center), Heidelberg, Germany
- Division of Carcinogenesis and Differentiation, DKFZ (German Cancer Research Center), Heidelberg, Germany
Correspondence to:
Marina Schorpp-Kistner, Division of Signal Transduction and Growth Control, DKFZ (German Cancer Research Center), A100, Im Neuenheimer Feld 280, Heidelberg 69120, Germany. Tel.: +49 6221 42 4575; Fax: +49 6221 42 4554; E-mail: marina.schorpp@dkfz.de
aThese authors contributed equally to this work
bPresent address: Merck KGaA, Life Science Products, R&D MDA Proteomics, Frankfurter Str. 250, Darmstadt 64293, Germany
Received 14 June 2006; Accepted 8 December 2006
Abstract
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-
B. 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.
Keywords:
- AP-1,
- hypoxia,
- JunB,
- NF-B,
- VEGF
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