TY - JOUR
T1 - Prostaglandin EP1 receptor down-regulates expression of cyclooxygenase-2 by facilitating its proteasomal degradation
AU - Haddad, Ariz
AU - Flint-Ashtamker, Galit
AU - Minzel, Waleed
AU - Sood, Rapita
AU - Rimon, Gilad
AU - Barki-Harrington, Liza
PY - 2012/5/18
Y1 - 2012/5/18
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=84861220041&partnerID=8YFLogxK
U2 - 10.1074/jbc.M111.304220
DO - 10.1074/jbc.M111.304220
M3 - Article
C2 - 22474323
AN - SCOPUS:84861220041
SN - 0021-9258
VL - 287
SP - 17214
EP - 17223
JO - Journal of Biological Chemistry
JF - Journal of Biological Chemistry
IS - 21
ER -