| First Author | Balamurugan K | Year | 2010 |
| Journal | EMBO J | Volume | 29 |
| Issue | 24 | Pages | 4106-17 |
| PubMed ID | 21076392 | Mgi Jnum | J:167167 |
| Mgi Id | MGI:4867360 | Doi | 10.1038/emboj.2010.280 |
| Citation | Balamurugan K, et al. (2010) The tumour suppressor C/EBPdelta inhibits FBXW7 expression and promotes mammary tumour metastasis. EMBO J 29(24):4106-17 |
| abstractText | Inflammation and hypoxia are known to promote the metastatic progression of tumours. The CCAAT/enhancer-binding protein-delta (C/EBPdelta, 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/EBPdelta using transgenic mice overexpressing the Neu/Her2/ERBB2 proto-oncogene in the mammary gland. Unexpectedly, this study also revealed that C/EBPdelta is necessary for efficient tumour metastasis. We show that C/EBPdelta is induced by hypoxia in tumours in vivo and in breast tumour cells in vitro, and that C/EBPdelta-deficient cells exhibit reduced glycolytic metabolism and cell viability under hypoxia. C/EBPdelta supports CXCR4 expression. On the other hand, C/EBPdelta 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/EBPdelta enhances mTOR/AKT/S6K1 signalling and augments translation and activity of hypoxia-inducible factor-1alpha (HIF-1alpha), which is necessary for hypoxia adaptation. This work provides new insight into the mechanisms by which metastasis-promoting signals are induced specifically under hypoxia. |
