Nuclear BAG-1 expression inhibits apoptosis in colorectal adenoma-derived epithelial cells

• Published in: Apoptosis (London) 2005-03, Vol.10 (2), p.301-311
• Main Authors: Barnes, J D, Arhel, N J, Lee, S S, Sharp, A, Al-Okail, M, Packham, G, Hague, A, Paraskeva, C, Williams, A C
• Format: Article
• Language: English
• Subjects: Adenoma - metabolism; Animals; Apoptosis; Blotting, Western; Calcitriol - analogs & derivatives; Calcitriol - pharmacology; Cancer; Carcinogenesis; Carrier Proteins - biosynthesis; Carrier Proteins - physiology; Cell Line, Tumor; Cell Nucleus - metabolism; Cells; Colorectal cancer; Colorectal carcinoma; Colorectal Neoplasms - metabolism; Cytoplasm - metabolism; DNA-Binding Proteins; Epithelial Cells - cytology; Epithelial Cells - metabolism; Gamma Rays; Gene Expression Regulation, Neoplastic; Genes, Reporter; Humans; Life Sciences; Luciferases - metabolism; Mice; Microscopy, Confocal; NIH 3T3 Cells; Prognosis; Protein Isoforms; Transcription Factors; Transfection; Vitamin D; Vitamin D - analogs & derivatives
• ISSN: 1360-8185; 1573-675X
• DOI: 10.1007/s10495-005-0804-8

BAG-1 is an anti-apoptotic protein that is frequently deregulated in a variety of malignancies including colorectal cancer. There are three isoforms: BAG-1L is located in the nucleus, BAG-1M and BAG-1S are located both in the nucleus and the cytoplasm. In colon cancer, the expression of nuclear BAG-1 is associated with poorer prognosis and is potentially a useful predictive factor for distant metastasis. However, the function of BAG-1 in colonic epithelial cells has not been studied. Having previously shown a predominant nuclear localisation of BAG-1 in adenoma-derived cell lines, we wanted to determine the function of nuclear BAG-1 in these non-tumourigenic cells, to identify whether nuclear BAG-1 was implicated in tumour progression in the colon. In the current report we established that nuclear BAG-1 inhibits apoptosis in a colorectal adenoma-derived cell line. We demonstrate that apoptosis induced by gamma-radiation or the vitamin D analogue EB1089 in the non-tumourigenic human colorectal adenoma-derived S/RG/C2 cell line, was preceded by a decrease in nuclear and an increase in cytoplasmic BAG-1 expression. This change in subcellular localisation of BAG-1 was due to the redistribution of the BAG-1M isoform. In addition, we have shown that the maintenance of high nuclear BAG-1 through enforced expression of the nuclear localised BAG-1L isoform enhanced cellular survival after gamma-radiation or exposure to EB1089. Furthermore the expression of cytoplasmic BAG-1S isoform fused with a nuclear localisation signal protected against gamma-radiation induced apoptosis. This demonstrates that nuclear localisation of the BAG-1 protein confers a survival advantage in colorectal adenoma-derived cells and that nuclear BAG-1 could potentially be an important survival factor in colorectal carcinogenesis.