The retinoblastoma protein (Rb) as an anti-apoptotic factor: expression of Rb is required for the anti-apoptotic function of BAG-1 protein in colorectal tumour cells.
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.
Cancer Research UK Colorectal Tumour Biology Research Group, School of Cellular and Molecular Medicine, University of Bristol, Bristol, UK.
T J
TJ
Collard
B C
BC
Urban
H A
HA
Patsos
A
A
Hague
P A
PA
Townsend
C
C
Paraskeva
A C
AC
Williams
D017209:Apoptosis; D002467:Cell Nucleus / Q000378:metabolism; D015179:Colorectal Neoplasms / Q000378:metabolism / Q000473:pathology; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D016328:NF-kappa B / Q000378:metabolism; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D016160:Retinoblastoma Protein / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D014157:Transcription Factors / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D014407:Tumor Cells, Cultured
C091732:BCL2-associated athanogene 1 protein; D004268:DNA-Binding Proteins; D016328:NF-kappa B; D034741:RNA, Small Interfering; D016160:Retinoblastoma Protein; D014157:Transcription Factors