Expression of COX-2 in platelet-monocyte interactions occurs via combinatorial regulation involving adhesion and cytokine signaling

Dixon, Dan A.; Tolley, Neal D.; Bemis–Standoli, Kristi; Martinez, Mark L.; Weyrich, Andrew S.; Morrow, Jason D.; Prescott, Stephen M.; Zimmerman, Guy A.

doi:10.1172/jci27209.

Cited by 121 publications

(15 citation statements)

References 89 publications

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“…The binding of TTP leads to a decrease in the stability of COX-2 mRNA (18), whereas the binding of HuR and, as shown here and by others, CUGBP2 stabilizes COX-2 mRNA (14,17,19,21). There is mounting evidence that these RNA-binding proteins are effectors for discrete signaling pathways.…”

Section: Discussionmentioning

confidence: 66%

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Platelet-derived Growth Factor-induced Stabilization of Cyclooxygenase 2 mRNA in Rat Smooth Muscle Cells Requires the c-Src Family of Protein-tyrosine Kinases

Xu¹,

Kitchen²,

Shu

et al. 2007

Journal of Biological Chemistry

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Cyclooxygenases (COXs) are crucial rate-limiting enzymes required for the biosynthesis of prostaglandins. COX-2 is an inducible isoform of this enzyme, which is believed to play important roles in the development of atherosclerotic vascular disease. We found that COX-2 expression rapidly increases in response to various signaling events, including activation of the platelet-derived growth factor (PDGF) pathway. Activation of PDGF receptor (PDGFR) in rat aortic vascular smooth muscle cells leads to c-Src-dependent stabilization of COX-2 mRNA requiring an AU-rich region within the 3-untranslated region of this transcript. This regulation correlates with tyrosine phosphorylation of the RNA-associated protein, CUG-binding protein 2 (CUGBP2), which appears to enhance its interaction with COX-2 mRNA. Site-directed mutagenesis of putative tyrosine phosphorylation sites in CUGBP2 identified tyrosine 39 as a c-Src target, and a CUGBP2 with a mutated tyrosine 39 displayed an attenuated ability to bind COX-2 mRNA. We further show that silencing of CUGBP2 with specific small interference RNAs significantly reduces PDGF-dependent induction of COX-2 at both mRNA and protein levels. Furthermore, forced expression of CUGBP2 or constitutively active c-Src leads to stabilization of co-expressed COX-2 mRNA. Finally, in vitro RNA decay assay demonstrates that CUGBP2 is functionally required for the stabilization of COX-2 mRNA. Therefore, our data suggest that tyrosine phosphorylation of CUGBP2 is an important underlying mechanism for the ability of PDGFR/c-Src signaling to control the stability of COX-2 mRNA.

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Section: Discussionmentioning

confidence: 66%

“…RNA-binding proteins such as HuR, AUF1, and TTP have been shown to bind to the AREs found in COX-2 mRNA (13,(17)(18)(19)(20). A more recent study demonstrates that CUG-binding protein 2 (CUGBP2) also binds to AREs in the COX-2 3Ј-UTR and protects COX-2 mRNA from degradation (21,22).…”

mentioning

confidence: 99%

Platelet-derived Growth Factor-induced Stabilization of Cyclooxygenase 2 mRNA in Rat Smooth Muscle Cells Requires the c-Src Family of Protein-tyrosine Kinases

Xu¹,

Kitchen²,

Shu

et al. 2007

Journal of Biological Chemistry

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“…To create the mutant Abcg1 3Ј-UTR (LUC⌬3Ј-UTR) that containing no 3Ј-UTR, we cut plasmids with Apa1 to remove the AU-rich element-containing region and religated the remaining vector with the 5Ј proximal region of UTR. All constructs were sequenced, and the correct clones were further propagated to isolate plasmid DNA (25).…”

Section: Methodsmentioning

confidence: 99%

Adenosine Monophosphate-activated Protein Kinase Induces Cholesterol Efflux from Macrophage-derived Foam Cells and Alleviates Atherosclerosis in Apolipoprotein E-deficient Mice*

Wang

et al. 2010

Journal of Biological Chemistry

108

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Increasing evidence suggests that adenosine monophosphate-activated protein kinase (AMPK) exerts protective effects for cardiovascular diseases apart from the regulation of energy homeostasis. However, the role of AMPK and its underlying mechanism on macrophage foam cell formation are poorly understood. In this study, we sought to investigate the potential effects of AMPK in modulating cholesterol deposition by using murine macrophage-derived foam cells. Incubation with 5-aminoimidazole-4-carboxyamide ribonucleoside (AICAR) markedly attenuated the cholesterol ester accumulation in oxidized low density lipoprotein-loaded macrophages. Notably, AICAR treatment significantly increased ATP-binding cassette transporters G1 (Abcg1) mRNA and protein levels without affecting mRNA and protein expression of ABCA1, scavenger receptors, including scavenger receptor-A, CD36, and scavenger receptor-BI (SR-BI), and cholesterol synthesis-related genes. The upregulation of Abcg1 by AICAR was independent of the liver X receptor/retinoid X receptor pathway but dependent on ERK activation. AICAR elevates Abcg1 expression through a posttranscriptional mechanism that stabilizes the mRNA. Using a heterologous system with luciferase as a reporter, we further identify the Abcg1 mRNA 3-UTR responsible for the regulatory effect of AICAR. Prevention of ABCG1 expression by small interfering RNA abolished the AICAR-mediated attenuation on foam cell formation. Furthermore, increased ABCG1 expression and reduced lipid accumulation were demonstrated in AICAR-treated macrophages isolated from apolipoprotein E-deficient mice (apoE ؊/؊ mice). AICAR treatment also inhibited atherosclerotic plaque formation in apoE ؊/؊ mice. Our findings elucidate a precise mechanism involved in the prevention of atherogenesis by AMPK.

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“…72 COX-2 induces the production of prostaglandins and has therefore been implicated in the progression of a number of inflammatory diseases, including atherosclerosis. 73 Initial interactions between PSGL-1 and P-selectin induce stable interactions between monocytes and platelets, which is sufficient for the induction of COX-2 mRNA, following 18 hours of coincubation.…”

Section: Signaling Pathways Downstream Of Psgl-1mentioning

confidence: 99%

The Pathophysiological Relevance of Monocyte-platelet Interactions in Inflammatory Disease

Stephen

Dransfield

2010

Journal of Experimental & Clinical Medicine

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Expression of COX-2 in platelet-monocyte interactions occurs via combinatorial regulation involving adhesion and cytokine signaling

Cited by 121 publications

References 89 publications

Platelet-derived Growth Factor-induced Stabilization of Cyclooxygenase 2 mRNA in Rat Smooth Muscle Cells Requires the c-Src Family of Protein-tyrosine Kinases

Platelet-derived Growth Factor-induced Stabilization of Cyclooxygenase 2 mRNA in Rat Smooth Muscle Cells Requires the c-Src Family of Protein-tyrosine Kinases

Adenosine Monophosphate-activated Protein Kinase Induces Cholesterol Efflux from Macrophage-derived Foam Cells and Alleviates Atherosclerosis in Apolipoprotein E-deficient Mice*

The Pathophysiological Relevance of Monocyte-platelet Interactions in Inflammatory Disease

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