Integrin-mediated adhesion and soluble ligand binding stabilize COX-2 protein levels in endothelial cells by inducing expression and preventing degradation.

Details

Serval ID
serval:BIB_8AA9F0D60C8E
Type
Article: article from journal or magazin.
Collection
Publications
Institution
Title
Integrin-mediated adhesion and soluble ligand binding stabilize COX-2 protein levels in endothelial cells by inducing expression and preventing degradation.
Journal
Journal of Biological Chemistry
Author(s)
Zaric J., Rüegg C.
ISSN
0021-9258
Publication state
Published
Issued date
2005
Peer-reviewed
Oui
Volume
280
Number
2
Pages
1077-1085
Language
english
Notes
Publication types: Journal Article
Abstract
Cyclooxygenase-2 (COX-2), a key enzyme in prostaglandin synthesis, is highly expressed during inflammation and cellular transformation and promotes tumor progression and angiogenesis. We have previously demonstrated that endothelial cell COX-2 is required for integrin alphaVbeta3-dependent activation of Rac-1 and Cdc-42 and for endothelial cell spreading, migration, and angiogenesis (Dormond, O., Foletti, A., Paroz, C., and Ruegg, C. (2001) Nat. Med. 7, 1041-1047; Dormond, O., Bezzi, M., Mariotti, A., and Ruegg, C. (2002) J. Biol. Chem. 277, 45838-45846). In this study, we addressed the question of whether integrin-mediated cell adhesion may regulate COX-2 expression in endothelial cells. We report that cell detachment from the substrate caused rapid degradation of COX-2 protein in human umbilical vein endothelial cells (HUVEC) independent of serum stimulation. This effect was prevented by broad inhibition of cellular proteinases and by neutralizing lysosomal activity but not by inhibiting the proteasome. HUVEC adhesion to laminin, collagen I, fibronectin, or vitronectin induced rapid COX-2 protein expression with peak levels reached within 2 h and increased COX-2-dependent prostaglandin E2 production. In contrast, nonspecific adhesion to poly-L-lysine was ineffective in inducing COX-2 expression. Furthermore, the addition of matrix proteins in solution promoted COX-2 protein expression in suspended or poly-L-lysine-attached HUVEC. Adhesion-induced COX-2 expression was strongly suppressed by pharmacological inhibition of c-Src, phosphatidylinositol 3-kinase, p38, extracellular-regulated kinase 1/2, and, to a lesser extent, protein kinase C and by the inhibition of mRNA or protein synthesis. In conclusion, this work demonstrates that integrin-mediated cell adhesion and soluble integrin ligands contribute to maintaining COX-2 steady-state levels in endothelial cells by the combined prevention of lysosomal-dependent degradation and the stimulation of mRNA synthesis involving multiple signaling pathways.
Keywords
Animals, Cattle, Cell Adhesion, Cells, Cultured, Cyclooxygenase 2, Endothelial Cells/cytology, Endothelial Cells/enzymology, Extracellular Matrix Proteins/metabolism, Gene Expression Regulation, Enzymologic, Humans, Integrins/metabolism, Ligands, Lysosomes/metabolism, Membrane Proteins, Mice, Prostaglandin-Endoperoxide Synthases/biosynthesis, Prostaglandin-Endoperoxide Synthases/genetics, Protein Biosynthesis, Protein Processing, Post-Translational, RNA, Messenger/biosynthesis, RNA, Messenger/genetics, Rats, Solubility, Substrate Specificity
Pubmed
Web of science
Open Access
Yes
Create date
28/01/2008 9:36
Last modification date
20/08/2019 15:49
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