The tumour suppressor C/EBPδ inhibits FBXW7 expression and promotes mammary tumour metastasis.
EMBO J
; 29(24): 4106-17, 2010 Dec 15.
Article
em En
| MEDLINE
| ID: mdl-21076392
ABSTRACT
Inflammation and hypoxia are known to promote the metastatic progression of tumours. The CCAAT/enhancer-binding protein-δ (C/EBPδ, CEBPD) is an inflammatory response gene and candidate tumour suppressor, but its physiological role in tumourigenesis in vivo is unknown. Here, we demonstrate a tumour suppressor function of C/EBPδ using transgenic mice overexpressing the Neu/Her2/ERBB2 proto-oncogene in the mammary gland. Unexpectedly, this study also revealed that C/EBPδ is necessary for efficient tumour metastasis. We show that C/EBPδ is induced by hypoxia in tumours in vivo and in breast tumour cells in vitro, and that C/EBPδ-deficient cells exhibit reduced glycolytic metabolism and cell viability under hypoxia. C/EBPδ supports CXCR4 expression. On the other hand, C/EBPδ directly inhibits expression of the tumour suppressor F-box and WD repeat-domain containing 7 gene (FBXW7, FBW7, AGO, Cdc4), encoding an F-box protein that promotes degradation of the mammalian target of rapamycin (mTOR). Consequently, C/EBPδ enhances mTOR/AKT/S6K1 signalling and augments translation and activity of hypoxia-inducible factor-1α (HIF-1α), which is necessary for hypoxia adaptation. This work provides new insight into the mechanisms by which metastasis-promoting signals are induced specifically under hypoxia.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Neoplasias Mamárias Animais
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Regulação da Expressão Gênica
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Ubiquitina-Proteína Ligases
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Proteínas F-Box
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Proteína delta de Ligação ao Facilitador CCAAT
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Hipóxia
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Metástase Neoplásica
Limite:
Animals
Idioma:
En
Revista:
EMBO J
Ano de publicação:
2010
Tipo de documento:
Article
País de afiliação:
Estados Unidos