Critical role for NF-kappaB-induced JunB in VEGF regulation and tumor angiogenesis.
EMBO J
; 26(3): 710-9, 2007 Feb 07.
Article
em En
| MEDLINE
| ID: mdl-17255940
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.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Regulação da Expressão Gênica
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NF-kappa B
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Proteínas Proto-Oncogênicas c-jun
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Fator A de Crescimento do Endotélio Vascular
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Neoplasias
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Neovascularização Patológica
Limite:
Animals
Idioma:
En
Revista:
EMBO J
Ano de publicação:
2007
Tipo de documento:
Article
País de afiliação:
Alemanha