Abstract
Although PGC-1 (peroxisome proliferator-activated receptor-gamma coactivator-1) has been previously shown to enhance thyroid hormone receptor (TR)/retinoid X receptor-mediated ucp-1 gene expression in a ligand-induced manner in rat fibroblast cells, the precise mechanism of PGC-1 modulation of TR function has yet to be determined. In this study, we show that PGC-1 can potentiate TR-mediated transactivation of reporter genes driven by natural thyroid hormone response elements both in a ligand-dependent and ligand-independent manner and that the extent of coactivation is a function of the thyroid hormone response element examined. Our data also show that PGC-1 stimulation of TR activity in terms of Gal4 DNA-binding domain fusion is strictly ligand-dependent. In addition, an E457A AF-2 mutation had no effect on the ligand-induced PGC-1 enhancement of TR activity, indicating that the conserved charged residue in AF-2 is not essential for this PGC-1 function. Furthermore, GST pull-down and mammalian two-hybrid assays demonstrated that the PGC-1 LXXLL motif is required for ligand-induced PGC-1/TR interaction. This agonist-dependent PGC-1/TR interaction also requires both helix 1 and the AF-2 region of the TR ligand-binding domain. Taken together, these results support the notion that PGC-1 is a bona fide TR coactivator and that PGC-1 modulates TR activity via a mechanism different from that utilized with peroxisome proliferator activator receptor-gamma.
Highlights
Thyroid hormone (T3)1 plays profound roles in development, homeostasis, and metabolism
Because nuclear receptors control a wide array of physiological processes in response to a variety of stimuli, selective regulation of target gene expression appears to be critical for diverse nuclear receptor actions
PGC-1 exhibits a regulated expression pattern both in terms of a tissue-selective pattern of expression and in various physiological states and modulates a variety of nuclear receptor activities that are important for energy metabolism and adaptive thermogenesis
Summary
T3, thyroid hormone; TR, thyroid hormone receptor; DBD, DNA-binding domain; LBD, ligand-binding domain; TRE, thyroid hormone response element; PPAR, peroxisome proliferator-activated receptor; GR, glucocorticoid receptor; GST, glutathione S-transferase. The binding of unliganded TRs to “positive” TREs results in repression of basal transcription, and this silencing is mediated by interaction of TR with a corepressor complex that contains histone deacetylase activity [15, 16]. A coactivator complex is usually associated with histone acetyltransferase activity, through which the chromatin structure may be modified, leading to transcriptional activation [20, 21] It appears that ligand-dependent recruitment of coactivators is critical for TR and other nuclear receptor-mediated transcriptional activation. Most of the characterized coactivators interact with the LBDs of ligand-bound nuclear receptors, including TRs, through helical LXXLL motifs (where X is any amino acid) present within p160 family members and other coactivators [32]. Functional studies demonstrate that the effect of PGC-1 on TR transcriptional activation can be ligand-dependent and ligandindependent, depending on the structure of the response element with which TR interacts
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