title: Prostaglandin EP1 receptor down-regulates expression of cyclooxygenase-2 by facilitating its proteasomal degradation.
abstract: The enzyme cyclooxygenase-2 (COX-2) is rapidly and transiently up-regulated by a large variety of signals and implicated in pathologies such as inflammation and tumorigenesis. Although many signals cause COX-2 up-regulation, much less is known about mechanisms that actively down-regulate its expression. Here we show that the G protein-coupled receptor prostaglandin E(1) (EP(1)) reduces the expression of COX-2 in a concentration-dependent manner through a mechanism that does not require receptor activation. The reduction in COX-2 protein is not due to decreased protein synthesis and occurs because of enhancement of substrate-independent COX-2 proteolysis. Although EP(1) does not interfere with the entry of COX-2 into the endoplasmic reticulum-associated degradation cascade, it facilitates COX-2 ubiquitination through complex formation. Blockade of proteasomal activity results in degradation of the receptor and concomitant recovery in the expression of COX-2, suggesting that EP(1) may scaffold an unknown E3 ligase that ubiquitinates COX-2. These findings propose a new role for the EP(1) receptor in resolving inflammation through down-regulation of COX-2.
authors.affiliation: Department of Human Biology, Faculty of Natural Sciences, University of Haifa, Mt. Carmel, Haifa 31905, Israel.
authors.forename: Ariz
authors.initials: A
authors.lastname: Haddad
authors.affiliation: Department of Human Biology, Faculty of Natural Sciences, University of Haifa, Mt. Carmel, Haifa 31905, Israel.
authors.forename: Galit
authors.initials: G
authors.lastname: Flint-Ashtamker
authors.affiliation: Department of Human Biology, Faculty of Natural Sciences, University of Haifa, Mt. Carmel, Haifa 31905, Israel.
authors.forename: Waleed
authors.initials: W
authors.lastname: Minzel
authors.affiliation: Department of Human Biology, Faculty of Natural Sciences, University of Haifa, Mt. Carmel, Haifa 31905, Israel.
authors.forename: Rapita
authors.initials: R
authors.lastname: Sood
authors.affiliation: Department of Clinical Pharmacology, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva 84105, Israel.
authors.forename: Gilad
authors.initials: G
authors.lastname: Rimon
authors.affiliation: Department of Human Biology, Faculty of Natural Sciences, University of Haifa, Mt. Carmel, Haifa 31905, Israel. Electronic address: lbarki@psy.haifa.ac.il.
authors.forename: Liza
authors.initials: L
authors.lastname: Barki-Harrington
mesh_terms: D045744:Cell Line, Tumor; D051546:Cyclooxygenase 2 / Q000096:biosynthesis* / Q000235:genetics; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation; D004721:Endoplasmic Reticulum / Q000235:genetics / Q000378:metabolism; D015971:Gene Expression Regulation, Enzymologic; D057809:HEK293 Cells; D006801:Humans; D007249:Inflammation / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D011458:Prostaglandins E / Q000378:metabolism / Q000494:pharmacology; D046988:Proteasome Endopeptidase Complex / Q000235:genetics / Q000378:metabolism*; D059748:Proteolysis; D058306:Receptors, Prostaglandin E, EP1 Subtype / Q000235:genetics / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism; D054875:Ubiquitination / Q000235:genetics
chemical_list: C545635:PTGER1 protein, human; D011458:Prostaglandins E; D058306:Receptors, Prostaglandin E, EP1 Subtype; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D044767:Ubiquitin-Protein Ligases; D046988:Proteasome Endopeptidase Complex