Prostaglandin receptor EP1-mediated differential degradation of cyclooxygenases involves a specific lysine residue |
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Authors: | Almog Spector-Chotiner Niva Shraga-Heled Rapita Sood Gilad Rimon Liza Barki-Harrington |
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Affiliation: | 1. Department of Human Biology, Faculty of Natural Sciences, University of Haifa, Mt. Carmel, Haifa 31905, Israel;2. Department of Clinical Biochemistry and Pharmacology, Faculty of Health Sciences, Ben-Gurion University of the Negev, Be’er-Sheva 84105, Israel |
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Abstract: | The cyclooxygenase (COX) enzyme isoforms COX-1 and COX-2 catalyze the main step in the generation of prostanoids that mediate major physiological functions. Whereas COX-1 is a ubiquitously expressed stable protein, COX-2 is transiently upregulated in many pathologies and is often associated with a poor prognostic outcome. We have recently shown that an interaction of COX-2 with the prostaglandin EP1 receptor accelerates its degradation via a mechanism that augments its level of ubiquitination. Here we show that the sensitivity of both COX-1 and COX-2 to EP1 is altered upon modification of one lysine residue. A point mutation of lysine to-arginine in position 432 of COX-2 (K432R) yields an enzyme with decreased sensitivity to EP1-mediated degradation. In contrast, insertion of a putative ubiquitination site into the corresponding position of COX-1 (H446K′) yields an enzyme with higher levels of ubiquitination and reduced expression. Furthermore, compared to wild type COX-1, H446K′ is significantly more sensitive to downregulation by EP1. Together these data suggest that distinctive ubiquitination of COX-1 and COX-2 may be responsible for their different sensitivity to EP1-mediated degradation. |
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Keywords: | Cyclooxygenase COX-2 COX-1 EP1 Ubiquitination Degradation |
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