BAG-1 interacts with the p50-p50 homodimeric NF-kappa B complex: implications for colorectal carcinogenesis

作者：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; Williams A C^*

来源：Oncogene, 2012, 31(22): 2761-2772.

DOI：10.1038/onc.2011.452

• NF-kappa B
• BAG-1
• p50 homodimers
• colorectal cancer
• EGFR
• COX2

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-kappa B transcriptional activity. In this study, we identify a novel complex between BAG-1 and the p50-p50 NF-kappa B homodimers, implicating BAG-1 as a co-regulator of an atypical NF-kappa 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-kappa 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-kappa B complexes. Data presented led us to propose that BAG-1 can act as a selective regulator of p50-p50 NF-kappa 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-kappa B complexes may aid in identifying strategies for both the prevention and treatment of CRC. Oncogene (2012) 31, 2761-2772; doi: 10.1038/onc.2011.452; published online 3 October 2011

• 出版日期2012-5