Identification of a Specific Molecular Repressor of the Peroxisome Proliferator-activated Receptor γ Coactivator-1 α (PGC-1α)*
By M. Ichida, S. Nemoto, Toren Finkel. Journal of Biological Chemistry, 2002
129 citations recorded by the source corpus.
The nuclear co-activator PGC-1α is a pivotal regulator of numerous pathways controlling both metabolism and overall energy homeostasis. Inappropriate increases in PGC-1α activity have been linked to a number of pathological conditions including heart failure and diabetes mellitus. Previous studies (Puigserver, P., Adelmant, G., Wu, Z., Fan, M., Xu, J., O'Malley, B., and Spiegelman, B. M. (1999) Science 286, 1368–1371) have demonstrated an inhibitory domain within PGC-1α that limits transcriptional activity. Using this inhibitory domain in a yeast two-hybrid screen, we demonstrate that PGC-1α directly associates with the orphan nuclear receptor estrogen-related receptor-α (ERR-α). The binding of ERR-α to PGC-1α requires the C-terminal AF2 domain of ERR-α. PGC-1α and ERR-α have a similar pattern of expression in human tissues, with both being present predominantly in organs with high metabolic needs such as skeletal muscle and kidney. Similarly, we show that in mice physiological stimuli such as fasting coordinately induces PGC-1α and ERR-α transcription. We also demonstrate that under normal conditions PGC-1α is located within discrete nuclear speckles, whereas the expression of ERR-α results in PGC-1α redistributing uniformly throughout the nucleoplasm. Finally, we show that the expression of ERR-α can dramatically and specifically repress PGC-1α transcriptional activity. These results suggest a novel mechanism of transcriptional control wherein ERR-α can function as a specific molecular repressor of PGC-1α activity. In addition, our results suggest that other co-activators might also have specific repressors, thereby identifying another layer of combinatorial complexity in transcriptional regulation.
Subfields: Molecular Biology, Physiology
View Paper: https://www.semanticscholar.org/paper/0a5a9ccf5522767d2088ff47ba2dfc83fabfe303
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Citations in the corpus
- Transcriptional control of mitochondrial biogenesis and function. (2009, background): “Moreover, ERRα, which is induced by PGC-1α via a positive autoregulatory loop (30, 69, 76), responds to signals central to the regulation of mitochondrial biogenesis or function, such as upon exposure to cold (in BAT and muscle), fasting (in liver), and exercise (in skeletal muscle) (25, 69, 77).”