The Ras inhibitors caveolin-1 and docking protein 1 activate peroxisome proliferator-activated receptor ? through spatial relocalization at helix 7 of its ligand-binding domain

Burgermeister, Elke; Friedrich, Teresa; Hitkova, Ivana; Regel, Ivonne; Einwächter, Henrik; Zimmermann, Wolfgang; Röcken, Christoph; Perren, Aurel; Wright, Matthew B; Schmid, Roland M; Seger, Rony; Ebert, Matthias P A (2011). The Ras inhibitors caveolin-1 and docking protein 1 activate peroxisome proliferator-activated receptor ? through spatial relocalization at helix 7 of its ligand-binding domain. Molecular and cellular biology, 31(16), pp. 3497-510. Washington, D.C.: American Society for Microbiology 10.1128/MCB.01421-10

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Peroxisome proliferator-activated receptor ? (PPAR?) is a transcription factor that promotes differentiation and cell survival in the stomach. PPAR? upregulates and interacts with caveolin-1 (Cav1), a scaffold protein of Ras/mitogen-activated protein kinases (MAPKs). The cytoplasmic-to-nuclear localization of PPAR? is altered in gastric cancer (GC) patients, suggesting a so-far-unknown role for Cav1 in spatial regulation of PPAR? 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 PPAR? and enhanced nuclear translocation and ligand-independent transcription of PPAR? target genes. In contrast, Cav1 overexpression sequestered PPAR? in the cytosol through interaction of the Cav1 scaffolding domain (CSD) with a conserved hydrophobic motif in helix 7 of PPAR?'s ligand-binding domain. Cav1 cooperated with the endogenous Ras/MAPK inhibitor docking protein 1 (Dok1) to promote the ligand-dependent transcriptional activity of PPAR? and to inhibit cell proliferation. Ligand-activated PPAR? 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 PPAR? regulation by which Ras/MAPK inhibitors act as scaffold proteins that sequester and sensitize PPAR? to ligands, limiting proliferation of gastric epithelial cells.

Item Type:	Journal Article (Original Article)
Division/Institute:	04 Faculty of Medicine > Service Sector > Institute of Pathology
UniBE Contributor:	Perren, Aurel
ISSN:	0270-7306
Publisher:	American Society for Microbiology
Language:	English
Submitter:	Factscience Import
Date Deposited:	04 Oct 2013 14:18
Last Modified:	05 Dec 2022 14:04
Publisher DOI:	10.1128/MCB.01421-10
PubMed ID:	21690289
Web of Science ID:	000293170200024
URI:	https://boris.unibe.ch/id/eprint/5543 (FactScience: 210296)