| First Author | Shalom-Barak T | Year | 2018 |
| Journal | Mol Cell Biol | Volume | 38 |
| Issue | 9 | PubMed ID | 29463649 |
| Mgi Jnum | J:261633 | Mgi Id | MGI:6155967 |
| Doi | 10.1128/MCB.00107-17 | Citation | Shalom-Barak T, et al. (2018) Ligand-Dependent Corepressor (LCoR) Is a Rexinoid-Inhibited Peroxisome Proliferator-Activated Receptor gamma-Retinoid X Receptor alpha Coactivator. Mol Cell Biol 38(9) |
| abstractText | The nuclear receptor peroxisome proliferator-activated receptor gamma (PPARgamma) is an essential regulator of placental development. To gain deeper insights into placental PPARgamma signaling, we dissected its regulation of the Muc1 promoter. We find that, unlike prototypic target activation by heterodimeric receptors, which is either stimulated by or refractory to retinoid X receptor (RXR) ligands (rexinoids), the induction of Muc1 by liganded PPARgamma requires RXRalpha but is inhibited by rexinoids. We demonstrate that this inhibition is mediated by the activation function 2 (AF2) domain of RXRalpha and that Muc1 activation entails altered AF2 structures of both PPARgamma and RXRalpha. This unique regulation of Muc1 reflects specific coactivation of PPARgamma-RXRalpha heterodimers by the transcription cofactor ligand-dependent corepressor (LCoR), corroborated by significant downregulation of Muc1 in Lcor-null placentas. LCoR interacts with PPARgamma and RXRalpha in a synergistic fashion via adjacent noncanonical protein motifs, and the AF2 domain of ligand-bound RXRalpha inhibits this interaction. We further identify the transcription factor Kruppel-like factor 6 (KLF6) as a critical regulator of placental development and a component of Muc1 regulation in cooperation with PPARgamma, RXRalpha, and LCoR. Combined, these studies reveal new principles and players in nuclear receptor function in general and placental PPARgamma signaling in particular. |
