Prostaglandin EP1 receptor down-regulates expression of cyclooxygenase-2 by facilitating its proteasomal degradation

Ariz Haddad, Galit Flint-Ashtamker, Waleed Minzel, Rapita Sood, Gilad Rimon, Liza Barki-Harrington

    Research output: Contribution to journalArticlepeer-review

    16 Scopus citations

    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 E1 (EP1) 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 EP1 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 EP1 may scaffold an unknown E3 ligase that ubiquitinates COX-2. These findings propose a new role for the EP1 receptor in resolving inflammation through down-regulation of COX-2.

    Original languageEnglish
    Pages (from-to)17214-17223
    Number of pages10
    JournalJournal of Biological Chemistry
    Volume287
    Issue number21
    DOIs
    StatePublished - 18 May 2012

    ASJC Scopus subject areas

    • Biochemistry
    • Molecular Biology
    • Cell Biology

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