Nuclear BAG-1 expression inhibits apoptosis in colorectal adenoma-derived epithelial cells.
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.
Barnes
J D
JD
Cancer Research UK Colorectal Tumour Biology Research Group, Department of Pathology and Microbiology, School of Medical Sciences, University of Bristol, Bristol, UK.
Arhel
N J
NJ
Lee
S S
SS
Sharp
A
A
Al-Okail
M
M
Packham
G
G
Hague
A
A
Paraskeva
C
C
Williams
A C
AC
D000236:Adenoma / Q000378:metabolism*; D000818:Animals; D017209:Apoptosis; D015153:Blotting, Western; D002117:Calcitriol / Q000031:analogs & derivatives / Q000494:pharmacology; D002352:Carrier Proteins / Q000096:biosynthesis* / Q000502:physiology*; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000378:metabolism; D015179:Colorectal Neoplasms / Q000378:metabolism*; D003593:Cytoplasm / Q000378:metabolism; D004268:DNA-Binding Proteins; D004847:Epithelial Cells / Q000166:cytology / Q000378:metabolism*; D005720:Gamma Rays; D015972:Gene Expression Regulation, Neoplastic; D017930:Genes, Reporter; D006801:Humans; D008156:Luciferases / Q000378:metabolism; D051379:Mice; D018613:Microscopy, Confocal; D041681:NIH 3T3 Cells; D011379:Prognosis; D020033:Protein Isoforms; D014157:Transcription Factors; D014162:Transfection; D014807:Vitamin D / Q000031:analogs & derivatives
C091732:BCL2-associated athanogene 1 protein; D002352:Carrier Proteins; D004268:DNA-Binding Proteins; D020033:Protein Isoforms; D014157:Transcription Factors; D014807:Vitamin D; D008156:Luciferases; D002117:Calcitriol; C078903:seocalcitol