Abstract
Although the retinoblastoma-susceptibility gene RB1 is inactivated in a wide range of human tumours, in colorectal cancer, the retinoblastoma protein (Rb) function is often preserved and the RB locus even amplified. Importantly, we have previously shown that Rb interacts with the anti-apoptotic Bcl-2 associated athanogene 1 (BAG-1) protein, which is highly expressed in colorectal carcinogenesis. Here we show for the first time that Rb expression is critical for BAG-1 anti-apoptotic activity in colorectal tumour cells. We demonstrate that Rb expression not only increases the nuclear localisation of the anti-apoptotic BAG-1 protein, but that expression of Rb is required for inhibition of apoptosis by BAG-1 both in a γ-irradiated Saos-2 osteosarcoma cell line and colorectal adenoma and carcinoma cell lines. Further, consistent with the fact that nuclear BAG-1 has previously been shown to promote cell survival through increasing nuclear factor (NF)-κB activity, we demonstrate that the ability of BAG-1 to promote NF-κB activity is significantly inhibited by repression of Rb expression. Taken together, data presented suggest a novel function for Rb, promoting cell survival through regulating the function of BAG-1. As BAG-1 is highly expressed in the majority of colorectal tumours, targeting the Rb–BAG-1 complex to promote apoptosis has exciting potential for future therapeutic development.
Highlights
Retinoblastoma protein (Rb) is a well-established tumoursuppressor protein, regulating the transition of the restriction point in the cell cycle
As Rb is expressed in colorectal cancer cells, it was hypothesised that Rb expression may contribute to tumour cell survival by regulating the function of the anti-apoptotic Bcl-2 associated athanogene 1 (BAG-1) protein
These findings suggest that both BAG-1 and Rb expression are required for increased TNFainduced activation of nuclear factor (NF)-kB in colorectal epithelial cells as found in the Saos-2 cells
Summary
Retinoblastoma protein (Rb) is a well-established tumoursuppressor protein, regulating the transition of the restriction point in the cell cycle. A recent study attributed the retention of Rb function in colorectal cancer cells to its ability to repress E2F-1-dependent inactivation of b-catenin signalling.[10,12] it is well established that expression of. Studies reported that the smaller of the isoforms BAG-1S is preferentially located in the cytoplasm, the BAG-1M isoform is detected in both the nuclear and cytoplasmic compartments, and the BAG-1L isoform is located in the nucleus.[28,30,31,32] The difference in the subcellular localisation of the BAG-1 isoforms is thought to be conferred at least in part by a nuclear localisation signal present in the N-terminus of the BAG-1L isoform, but absent in the BAG-1S and truncated in the BAG-1M isoform.[28,31,32,33] Of note, contrary to the published literature, the localisation of the smaller BAG-1 isoforms in colorectal tumour cells appears distinct from other tissues, with the BAG-1M isoform being predominantly nuclear and the BAG-1S isoform exhibiting nuclear as well as cytoplasmic localisation.[34] The cumulative result is a predominant nuclear localisation of endogenous BAG-1 protein in colorectal epithelial cells (important for the transcriptional function of the protein26); previously associated with poor prognosis in colorectal cancer.[35]
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