Transcriptional down-regulation of the retinoblastoma protein is associated with differentiation and apoptosis in human colorectal epithelial cells.
The aim of this study was to investigate the regulation of Rb protein expression in relation to increased differentiation and induction of apoptosis in colonic epithelial cells. In vivo, Rb protein expression was found to be down-regulated towards the top of the normal colonic crypt, coincident with the region of differentiation and apoptosis, but highly expressed in colonic carcinoma tissue. Using in vitro models to study the regulation of Rb expression in pre-malignant colonic epithelial cells, we have been able to show for the first time that Rb protein expression is transcriptionally down-regulated in differentiated pre-malignant cells (in post-confluent cultures) but not in malignant colorectal epithelial cells. Furthermore, suppression of rb protein function by the HPV-E7 viral oncoprotein increased both spontaneous and DNA damage-induced apoptosis. These results suggest that Rb is able to act as a survival factor in colonic epithelial cells by suppressing apoptosis, and that over-expression of pRb in colorectal tumour cells can cause a loss of sensitivity to apoptotic signalling, resulting in aberrant cell survival and resistance to therapy.
Guy
M
M
CRC Colorectal Tumour Biology Research Group, Department of Pathology and Microbiology, School of Medical Sciences, University of Bristol, University Walk, Bristol, BS8 1TD.
Moorghen
M
M
Bond
J A
JA
Collard
T J
TJ
Paraskeva
C
C
Williams
A C
AC
D000911:Antibodies, Monoclonal; D017209:Apoptosis / Q000235:genetics*; D015152:Blotting, Northern; D002277:Carcinoma / Q000235:genetics* / Q000473:pathology; D002454:Cell Differentiation / Q000235:genetics*; D015179:Colorectal Neoplasms / Q000235:genetics* / Q000473:pathology; D004249:DNA Damage; D015536:Down-Regulation; D004847:Epithelial Cells / Q000502:physiology; D006801:Humans; D009856:Oncogene Proteins, Viral; D050725:Papillomavirus E7 Proteins; D016160:Retinoblastoma Protein / Q000096:biosynthesis* / Q000235:genetics; D014158:Transcription, Genetic; D014407:Tumor Cells, Cultured
D000911:Antibodies, Monoclonal; D009856:Oncogene Proteins, Viral; D050725:Papillomavirus E7 Proteins; D016160:Retinoblastoma Protein; C059731:oncogene protein E7, Human papillomavirus type 16