The role of the retinoblastoma protein (Rb) in the nuclear localization of BAG-1: implications for colorectal tumour cell survival.
Although the retinoblastoma susceptibility gene RB1 is inactivated in a wide variety of human cancers, the retinoblastoma protein (Rb) has been shown to be overexpressed in colon cancers, which is linked to the anti-apoptotic function of the protein. However, the mechanisms by which Rb regulates apoptosis are yet to be fully elucidated. We have established that Rb interacts with the anti-apoptotic BAG-1 (Bcl-2 associated athanogene-1) protein, and that a decrease in nuclear localization of BAG-1 is detectable when the interaction between Rb and BAG-1 is disrupted by expression of the E7 viral oncoprotein. Interestingly, although reported as deregulated in colorectal cancers, we have found that BAG-1 expression is also altered in small adenomas, where its localization was found to be predominantly nuclear. In addition, we have established that maintenance of high nuclear BAG-1 in vitro increases the resistance of adenoma-derived cells to gamma-radiation-induced apoptosis. Our work suggests a novel function for Rb, involving modulation of the subcellular localization of BAG-1. We have found predominant nuclear BAG-1 localization in small adenomas, and suggest that BAG-1 may promote colorectal tumour cell survival by making colonic epithelial cells less sensitive to DNA damage.
Clemo
N K
NK
Department of Pathology and Microbiology, Bristol University, Bristol B58 1TD, UK.
Arhel
N J
NJ
Barnes
J D
JD
Baker
J
J
Moorghen
M
M
Packham
G K
GK
Paraskeva
C
C
Williams
A C
AC
D000236:Adenoma / Q000235:genetics / Q000473:pathology; D017209:Apoptosis; D002352:Carrier Proteins / Q000378:metabolism*; D002467:Cell Nucleus / Q000473:pathology; D002470:Cell Survival / Q000235:genetics; D015179:Colorectal Neoplasms / Q000235:genetics* / Q000473:pathology; D004249:DNA Damage; D004268:DNA-Binding Proteins; D006801:Humans; D007413:Intestinal Mucosa; D016160:Retinoblastoma Protein / Q000378:metabolism / Q000502:physiology*; D014157:Transcription Factors
C091732:BCL2-associated athanogene 1 protein; D002352:Carrier Proteins; D004268:DNA-Binding Proteins; D016160:Retinoblastoma Protein; D014157:Transcription Factors