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

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Abstract

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,1 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 γ -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 γ -radiation or exposure to EB1089. Furthermore the expression of cytoplasmic BAG-1S isoform fused with a nuclear localisation signal protected against γ -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.

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Authors and Affiliations

  1. Cancer Research UK Colorectal Tumour Biology Research Group, Department of Pathology and Microbiology, School of Medical Sciences, University of Bristol, Bristol, UK

    J. D. Barnes, N. J. Arhel, C. Paraskeva & A. C. Williams

  2. Department of Oral and Dental Science, University of Bristol, Lower Maudlin Street, Bristol, UK

    S. S. Lee & A. Hague

  3. Cancer Research UK Oncology Unit, Cancer Science Division, University of Southampton School of Medicine, Southampton General Hospital, Southampton, UK

    A. Sharp, M. Al-Okail & G. Packham

  4. Cancer Research UK Colorectal Tumour Biology Research Group, Department of Pathology and Microbiology, University of Bristol, School of Medical Sciences, Bristol, BS8 1TD, U.K.

    A. C. Williams

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  1. J. D. Barnes
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  2. N. J. Arhel
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  3. S. S. Lee
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  4. A. Sharp
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  9. A. C. Williams
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Correspondence to A. C. Williams.

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Barnes, J.D., Arhel, N.J., Lee, S.S. et al. Nuclear BAG-1 expression inhibits apoptosis in colorectal adenoma-derived epithelial cells. Apoptosis 10, 301–311 (2005). https://doi.org/10.1007/s10495-005-0804-8

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  • DOI: https://doi.org/10.1007/s10495-005-0804-8

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