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Ubiquitin-proteasomal degradation of COX-2 in TGF-β stimulated human endometrial cells is mediated through endoplasmic reticulum mannosidase I.
- Source :
-
Endocrinology [Endocrinology] 2012 Jan; Vol. 153 (1), pp. 426-37. Date of Electronic Publication: 2011 Nov 22. - Publication Year :
- 2012
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Abstract
- Cyclooxygenase (COX)-2 is a key regulatory enzyme in the production of prostaglandins (PG) during various physiological processes. Mechanisms of COX-2 regulation in human endometrial stromal cells (human endometrial stromal cells) are not fully understood. In this study, we investigate the role of TGF-β in the regulation of COX-2 in human uterine stromal cells. Each TGF-β isoform decreases COX-2 protein level in human uterine stromal cells in Smad2/3-dependent manner. The decrease in COX-2 is accompanied by a decrease in PG synthesis. Knockdown of Smad4 using specific small interfering RNA prevents the decrease in COX-2 protein, confirming that Smad pathway is implicated in the regulation of COX-2 expression in human endometrial stromal cells. Pretreatment with 26S proteasome inhibitor, MG132, significantly restores COX-2 protein and PG synthesis, indicating that COX-2 undergoes proteasomal degradation in the presence of TGF-β. In addition, each TGF-β isoform up-regulates endoplasmic reticulum (ER)-mannosidase I (ERManI) implying that COX-2 degradation is mediated through ER-associated degradation pathway in these cells. Furthermore, inhibition of ERManI activity using the mannosidase inhibitor (kifunensine), or small interfering RNA-mediated knockdown of ERManI, prevents TGF-β-induced COX-2 degradation. Taken together, these studies suggest that TGF-β promotes COX-2 degradation in a Smad-dependent manner by up-regulating the expression of ERManI and thereby enhancing ER-associated degradation and proteasomal degradation pathways.
- Subjects :
- Base Sequence
Cyclooxygenase 2 genetics
DNA Primers genetics
Endometrium cytology
Endoplasmic Reticulum metabolism
Endoplasmic Reticulum-Associated Degradation drug effects
Female
Gene Knockdown Techniques
Humans
Leupeptins pharmacology
Mannosidases antagonists & inhibitors
Mannosidases genetics
Models, Biological
Prostaglandins metabolism
Protease Inhibitors pharmacology
Proteasome Endopeptidase Complex metabolism
Proteasome Inhibitors
RNA, Small Interfering genetics
Smad4 Protein antagonists & inhibitors
Smad4 Protein genetics
Smad4 Protein metabolism
Stromal Cells drug effects
Stromal Cells metabolism
Transforming Growth Factor beta metabolism
Ubiquitin metabolism
Cyclooxygenase 2 metabolism
Endometrium drug effects
Endometrium metabolism
Mannosidases metabolism
Transforming Growth Factor beta pharmacology
Subjects
Details
- Language :
- English
- ISSN :
- 1945-7170
- Volume :
- 153
- Issue :
- 1
- Database :
- MEDLINE
- Journal :
- Endocrinology
- Publication Type :
- Academic Journal
- Accession number :
- 22109885
- Full Text :
- https://doi.org/10.1210/en.2011-1438