title: Critical role for NF-kappaB-induced JunB in VEGF regulation and tumor angiogenesis.
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-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.
authors.affiliation: Division of Signal Transduction and Growth Control, DKFZ (German Cancer Research Center), Heidelberg, Germany.
authors.forename: Dirk
authors.initials: D
authors.lastname: Schmidt
authors.forename: Björn
authors.initials: B
authors.lastname: Textor
authors.forename: Oliver T
authors.initials: OT
authors.lastname: Pein
authors.forename: Alexander H
authors.initials: AH
authors.lastname: Licht
authors.forename: Sven
authors.initials: S
authors.lastname: Andrecht
authors.forename: Melanie
authors.initials: M
authors.lastname: Sator-Schmitt
authors.forename: Norbert E
authors.initials: NE
authors.lastname: Fusenig
authors.forename: Peter
authors.initials: P
authors.lastname: Angel
authors.forename: Marina
authors.initials: M
authors.lastname: Schorpp-Kistner
mesh_terms: D000482:Allantois / Q000166:cytology / Q000378:metabolism; D000818:Animals; D015687:Cell Hypoxia / Q000502:physiology; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D047369:Chromatin Immunoprecipitation; D024202:Electrophoretic Mobility Shift Assay; D005455:Fluorescent Antibody Technique; D005786:Gene Expression Regulation / Q000502:physiology*; D015151:Immunoblotting; D051379:Mice; D008822:Mice, Transgenic; D016328:NF-kappa B / Q000378:metabolism*; D009369:Neoplasms / Q000098:blood supply*; D009389:Neovascularization, Pathologic / Q000378:metabolism / Q000503:physiopathology*; D016755:Proto-Oncogene Proteins c-jun / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism*
chemical_list: D016328:NF-kappa B; D016755:Proto-Oncogene Proteins c-jun; D042461:Vascular Endothelial Growth Factor A; C467480:vascular endothelial growth factor A, mouse