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NUCLEAR RECEPTOR CO-REPRESSOR (N-COR) REGULATES THE TRANSCRIPTION OF PIGMENT EPITHELIUM DERIVED FACTOR (PEDF) IN EPITHELIAL INTESTINAL CELLS
G Doyon, C Asselin, F Boudreau
Département d’Anatomie et Biologie Cellulaire, Faculté de Médecine et des Sciences de la Santé, Université de Sherbrooke, CIHR Team on Digestive Epithelium, Sherbrooke, Québec
INTRODUCTION: The intestinal epithelium is organized in crypts mostly populated by proliferative cells as well as villi composed of differentiated cells. Stem cells constantly produce precursor cells that progressively undergo a succession of molecular changes that lead to an arrest of proliferation and a commitment into specific differentiation programs. We have previously identified NCoR as being crucial to maintain cell proliferation in intestinal epithelial cells. Our aim was to identify molecular targets that were responsible for NCoR action on cell proliferation.
METHODS AND RESULTS: A gene profiling analysis was performed on intestinal epithelial cells that were silenced for NCoR expression by RNA interference. PEDF, a potent inhibitor of angiogenesis as well as epithelial growth in pancreas and prostate, was predicted to be induced in cells silenced for NCoR expression. PEDF mRNA was significantly upregulated more than 3 fold in the NCoR shRNA cell line as confirmed by real time PCR. Chromatin Immunoprecipitation experiments demonstrated that NCoR occupied PEDF gene promoter in proliferating epithelial cells. Finally, forced expression of PEDF in intestinal epithelial cells in culture resulted in a slower growth rate as compared to control cells.
CONCLUSION: Our findings identify PEDF as a novel transcriptional target of NCoR repressive action during intestinal epithelial cell proliferation. Based on the previously reported role of PEDF in other tissues, these observations suggest that PEDF could potentially play a tumor suppressor role in the intestinal epithelium.
Supported by NSERC.