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PGC-1 RELATED COACTIVATOR (PRC) IS A CO-ACTIVATOR OF ESTROGEN-RELATED RECEPTOR ALPHA
J Carrier, L Thomas, G Bernatchez, M TheriaultUniversité de Sherbrooke, Sherbrooke, Quebec
Aims: Estrogen receptor-related receptor alpha (ERRalpha) is an orphan member of the nuclear receptor superfamily. ERRalpha activity is not controlled by physiological ligands, but by interacting cofactors that act as protein ligands. Its function in many metabolically active tissues is intimately linked to its coactivation by PGC-1alpha or PGC-1beta. In addition, growing evidence suggests that ERRalpha promotes the progression of various cancers. PRC, a third member of the PGC family is induced during cellular proliferative growth and is though to coordinate cell growth with mitochondrial energy production. Our aim is to determine if PRC acts as a coactivator of ERRalpha in colon-cancer cells.
Methods: PRC transcript levels have been measured in human colon cancer samples and matched adjacent normal colon. Co-immunoprecipitation and GST pull-down assays has been used to investigate the physical interaction between PRC and ERRalpha. The transcriptional activation of ERRalpha by PRC has been investigated by luciferase assays and measurement of ERRalpha's target gene induction.
Results: We first observed higher PRC gene expression in colon cancer samples compared with paired adjacent tumor-free colon. Second, we determined using co-immunoprecipitation experiments that ERRalpha exists in complexes with PRC in cell extracts. Furthermore, we also observed that ERRalpha association with PRC requires an intact ligand-binding domain as a dominant negative variant lacking part of the ligand-binding domain was not detected in co-immunoprecipitation assays. Third, GST pull-down assays also revealed that PRC interacts directly with ERRalpha. Forth, through luciferase reporter gene assays, PRC was found to enhance the transcriptional activity of ERRalpha. This is further supported by the higher expression in colon cancer cells of the well-known ERRalpha target gene cytochrome c in the presence of PRC.
Conclusions: These findings reveal a new function for PRC as a co-activator of ERRalpha, possibly relevant to the proliferation of colon cancer cells.