| First Author | Burgermeister E | Year | 2011 |
| Journal | Mol Cell Biol | Volume | 31 |
| Issue | 16 | Pages | 3497-510 |
| PubMed ID | 21690289 | Mgi Jnum | J:175088 |
| Mgi Id | MGI:5142354 | Doi | 10.1128/MCB.01421-10 |
| Citation | Burgermeister E, et al. (2011) The Ras Inhibitors Caveolin-1 and Docking Protein 1 Activate Peroxisome Proliferator-Activated Receptor {gamma} through Spatial Relocalization at Helix 7 of Its Ligand-Binding Domain. Mol Cell Biol 31(16):3497-510 |
| abstractText | Peroxisome proliferator-activated receptor gamma (PPARgamma) is a transcription factor that promotes differentiation and cell survival in the stomach. PPARgamma upregulates and interacts with caveolin-1 (Cav1), a scaffold protein of Ras/mitogen-activated protein kinases (MAPKs). The cytoplasmic-to-nuclear localization of PPARgamma is altered in gastric cancer (GC) patients, suggesting a so-far-unknown role for Cav1 in spatial regulation of PPARgamma signaling. We show here that loss of Cav1 accelerated proliferation of normal stomach and GC cells in vitro and in vivo. Downregulation of Cav1 increased Ras/MAPK-dependent phosphorylation of serine 84 in PPARgamma and enhanced nuclear translocation and ligand-independent transcription of PPARgamma target genes. In contrast, Cav1 overexpression sequestered PPARgamma in the cytosol through interaction of the Cav1 scaffolding domain (CSD) with a conserved hydrophobic motif in helix 7 of PPARgamma's ligand-binding domain. Cav1 cooperated with the endogenous Ras/MAPK inhibitor docking protein 1 (Dok1) to promote the ligand-dependent transcriptional activity of PPARgamma and to inhibit cell proliferation. Ligand-activated PPARgamma also reduced tumor growth and upregulated the Ras/MAPK inhibitors Cav1 and Dok1 in a murine model of GC. These results suggest a novel mechanism of PPARgamma regulation by which Ras/MAPK inhibitors act as scaffold proteins that sequester and sensitize PPARgamma to ligands, limiting proliferation of gastric epithelial cells. |
