title: Down-regulation of cyclooxygenase-2 by the carboxyl tail of the angiotensin II type 1 receptor.
abstract: The enzyme cyclooxygenase-2 (COX-2) plays an important role in the kidney by up-regulating the production of the vasoconstrictor hormone angiotensin II (AngII), which in turn down-regulates COX-2 expression via activation of the angiotensin II type 1 receptor (AT1) receptor. Chemical inhibition of the catalytic activity of COX-2 is a well-established strategy for treating inflammation but little is known of cellular mechanisms that dispose of the protein itself. Here we show that in addition to its indirect negative feedback on COX-2, AT1 also down-regulates the expression of the COX-2 protein via a pathway that does not involve G-protein or β-arrestin-dependent signaling. Instead, AT1 enhances the ubiquitination and subsequent degradation of the enzyme in the proteasome through elements in its cytosolic carboxyl tail (CT). We find that a mutant receptor that lacks the last 35 amino acids of its CT (Δ324) is devoid of its ability to reduce COX-2, and that expression of the CT sequence alone is sufficient to down-regulate COX-2. Collectively these results propose a new role for AT1 in regulating COX-2 expression in a mechanism that deviates from its canonical signaling pathways. Down-regulation of COX-2 by a short peptide that originates from AT1 may present as a basis for novel therapeutic means of eliminating excess COX-2 protein.
authors.affiliation: From the Department of Human Biology, Faculty of Natural Sciences, University of Haifa, Haifa, Israel 3498838 and.
authors.forename: Rapita
authors.initials: R
authors.lastname: Sood
authors.affiliation: From the Department of Human Biology, Faculty of Natural Sciences, University of Haifa, Haifa, Israel 3498838 and.
authors.forename: Waleed
authors.initials: W
authors.lastname: Minzel
authors.affiliation: Department of Clinical Biochemistry and Pharmacology, Faculty of Health Sciences, Ben-Gurion University of the Negev, Be'er-Sheva 84105, Israel.
authors.forename: Gilad
authors.initials: G
authors.lastname: Rimon
authors.affiliation: From the Department of Human Biology, Faculty of Natural Sciences, University of Haifa, Haifa, Israel 3498838 and.
authors.forename: Sharon
authors.initials: S
authors.lastname: Tal
authors.affiliation: From the Department of Human Biology, Faculty of Natural Sciences, University of Haifa, Haifa, Israel 3498838 and lbarki@psy.haifa.ac.il.
authors.forename: Liza
authors.initials: L
authors.lastname: Barki-Harrington
mesh_terms: D020816:Amino Acid Motifs; D001426:Bacterial Proteins / Q000378:metabolism; D020134:Catalytic Domain; D003001:Cloning, Molecular; D051546:Cyclooxygenase 2 / Q000378:metabolism*; D015536:Down-Regulation; D015971:Gene Expression Regulation, Enzymologic; D057809:HEK293 Cells; D006801:Humans; D007249:Inflammation; D008164:Luminescent Proteins / Q000378:metabolism; D009154:Mutation; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D011863:Radioimmunoassay; D044140:Receptor, Angiotensin, Type 1 / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: D001426:Bacterial Proteins; D008164:Luminescent Proteins; D044140:Receptor, Angiotensin, Type 1; C054562:yellow fluorescent protein, Bacteria; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D046988:Proteasome Endopeptidase Complex
keywords: Angiotensin II; G Protein-coupled Receptor (GPCR); Proteasome; Protein Degradation; Protein Motif