Regulation of the transcriptional coactivator PGC-1 via MAPK-sensitive interaction with a repressor.
Mechanisms and signals that regulate transcriptional coactivators are still largely unknown. Here we provide genetic evidence for a repressor that interacts with and regulates the nuclear receptor coactivator PGC-1. Association with the repressor requires a PGC-1 protein interface that is similar to the one used by nuclear receptors. Removal of the repressor enhances PGC-1 coactivation of steroid hormone responses. We also provide evidence that interaction of the repressor with PGC-1 is regulated by mitogen-activated protein kinase (MAPK) signaling. Activation of the MAPK p38 enhances the activity of wild-type PGC-1 but not of a PGC-1 variant that no longer interacts with the repressor. Finally, p38 activation enhances steroid hormone response in a PGC-1-dependent manner. Our data suggest a model where the repressor and nuclear receptors compete for recruiting PGC-1 to an inactive and active state, respectively. Extracellular signals such as nuclear receptor ligands or activators of the MAPK p38 can shift the equilibrium between the two states.
Knutti
D
D
Division of Biochemistry, Biozentrum of the University of Basel, Switzerland.
Kressler
D
D
Kralli
A
A
D020816:Amino Acid Motifs; D000818:Animals; D001667:Binding, Competitive; D019556:COS Cells; D002522:Chlorocebus aethiops; D004789:Enzyme Activation; D005786:Gene Expression Regulation / Q000502:physiology*; D005938:Glucocorticoids / Q000494:pharmacology; D006367:HeLa Cells; D006801:Humans; D020935:MAP Kinase Signaling System / Q000502:physiology*; D046911:Macromolecular Substances; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D008954:Models, Biological; D020239:Receptor Cross-Talk; D011965:Receptors, Glucocorticoid / Q000187:drug effects / Q000502:physiology; D011993:Recombinant Fusion Proteins / Q000096:biosynthesis; D012097:Repressor Proteins / Q000378:metabolism*; D012441:Saccharomyces cerevisiae / Q000235:genetics; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic; D014162:Transfection; D020798:Two-Hybrid System Techniques; D048051:p38 Mitogen-Activated Protein Kinases
D005938:Glucocorticoids; D046911:Macromolecular Substances; D011965:Receptors, Glucocorticoid; D011993:Recombinant Fusion Proteins; D012097:Repressor Proteins; D014157:Transcription Factors; C111264:peroxisome-proliferator-activated receptor-gamma coactivator-1; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases