| First Author | Guo C | Year | 2015 |
| Journal | J Biol Chem | Volume | 290 |
| Issue | 6 | Pages | 3666-79 |
| PubMed ID | 25519902 | Mgi Jnum | J:219351 |
| Mgi Id | MGI:5620549 | Doi | 10.1074/jbc.M114.598797 |
| Citation | Guo C, et al. (2015) The optimal corepressor function of nuclear receptor corepressor (NCoR) for peroxisome proliferator-activated receptor gamma requires G protein pathway suppressor 2. J Biol Chem 290(6):3666-79 |
| abstractText | Repression of peroxisome proliferator-activated receptor gamma (PPARgamma)-dependent transcription by the nuclear receptor corepressor (NCoR) is important for homeostatic expression of PPARgamma target genes in vivo. The current model states that NCoR-mediated repression requires its direct interaction with PPARgamma in the repressive conformation. Previous studies, however, have shown that DNA-bound PPARgamma is incompatible with a direct, high-affinity association with NCoR because of the inherent ability of PPARgamma to adopt the active conformation. Here we show that NCoR acquires the ability to repress active PPARgamma-mediated transcription via G protein pathway suppressor 2 (GPS2), a component of the NCoR corepressor complex. Unlike NCoR, GPS2 can recognize and bind the active state of PPARgamma. In GPS2-deficient mouse embryonic fibroblast cells, loss of GPS2 markedly reduces the corepressor function of NCoR for PPARgamma, leading to constitutive activation of PPARgamma target genes and spontaneous adipogenesis of the cells. GPS2, however, is dispensable for repression mediated by unliganded thyroid hormone receptor alpha or a PPARgamma mutant unable to adopt the active conformation. This study shows that GPS2, although dispensable for the intrinsic repression function of NCoR, can mediate a novel corepressor repression pathway that allows NCoR to directly repress active PPARgamma-mediated transcription, which is important for the optimal corepressor function of NCoR for PPARgamma. Interestingly, GPS2-dependent repression specifically targets PPARgamma but not PPARalpha or PPARdelta. Therefore, GPS2 may serve as a unique target to manipulate PPARgamma signaling in diseases. |
