Southern, S.L., Collard, T. J., Urban, B. C., Skeen, V. R., Smartt, H. J., Hague, A., Oakley, F., Townsend, P. A., Perkins, N. D., Paraskeva, C. and Williams, A. C.
BAG-1 interacts with the p50–p50 homodimeric NF-?B complex: implications for colorectal carcinogenesis
Oncogene, 31, (22), . (doi:10.1038/onc.2011.452).
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Understanding the mechanisms that promote aberrant tumour cell survival is critical for the determination of novel strategies to combat colorectal cancer (CRC). We have recently shown that the anti-apoptotic protein BAG-1, highly expressed in pre-malignant and CRC tissue, can potentiate cell survival through regulating NF-?B transcriptional activity. In this study, we identify a novel complex between BAG-1 and the p50–p50 NF-?B homodimers, implicating BAG-1 as a co-regulator of an atypical NF-?B pathway. Importantly, the BAG-1-p50 complex was detected at gene regulatory sequences including the epidermal growth factor receptor (EGFR) and COX-2 (PTGS2) genes. Suppression of BAG-1 expression using small interfering RNA was shown to increase EGFR and suppress COX-2 expression in CRC cells. Furthermore, mouse embryonic fibroblasts derived from the NF-?B1 (p105/p50) knock-out mouse were used to demonstrate that p50 expression was required for BAG-1 to suppress EGFR expression. This was shown to be functionally relevant as attenuation of BAG-1 expression increased ligand activated phosphorylation of EGFR in CRC cells. In summary, this paper identifies a novel role for BAG-1 in modulating gene expression through interaction with the p50–p50 NF-?B complexes. Data presented led us to propose that BAG-1 can act as a selective regulator of p50–p50 NF-?B responsive genes in colorectal tumour cells, potentially important for the promotion of cell survival in the context of the fluctuating tumour microenvironment. As BAG-1 expression is increased in the developing adenoma through to metastatic lesions, understanding the function of the BAG-1-p50 NF-?B complexes may aid in identifying strategies for both the prevention and treatment of CRC.
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