Gene induction by coagulation factor Xa is mediated by activation of protease-activated receptor 1

Riewald, Matthias; Kravchenko, Vladimir V.; Petrovan, Ramona J.; O’Brien, Peter J.; Brass, Lawrence F.; Ulevitch, Richard J.; Ruf, Wolfram

doi:10.1182/blood.v97.10.3109

Cited by 179 publications

(149 citation statements)

References 62 publications

(56 reference statements)

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“…8B) is capable of pairing with TNF to lead to functional expression of TF. Because fXa activates both PAR2 and -1 (20,21), and thrombin activates PAR1, it would be interesting to speculate on the relative contributions of the two receptors (PAR1 and -2) to the observed synergistic activity of fXa. Based on previous work by Coughlin (18) and Ossovskaya and Bunnett (19), our initial doseresponse studies were carried out in the peptide concentration range of 1-100 M. It is likely that the agonist peptide concentration (100 M) used in the present study (Figs.…”

Section: Discussionmentioning

confidence: 99%

“…Endothelial cells express two of the PAR receptors, PAR1 and -2. Thrombin activates PAR1, whereas fXa has been demonstrated to activate both (20,21). Because TF on activated endothelial cells binds coagulation factor VIIa to initiate the coagulation cascade by converting factor X to fXa, which in turn converts prothrombin to thrombin, it is apparent that the induced expression of TF also provides the opportunity for augmenting the endothelial cell response.…”

mentioning

confidence: 99%

“…fXa has been demonstrated (20,21) to elicit its cellular effects through activation of PAR1 and -2 receptors. Thus, we were interested in determining whether PAR1 and -2 agonists could mimic the inhibitory effects of fXa (Fig.…”

Section: The Expression Of E-selectin Is Also Up-regulated By Fxa Andmentioning

confidence: 99%

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Synergistic induction of tissue factor by coagulation factor Xa and TNF: Evidence for involvement of negative regulatory signaling cascades

Hezi-Yamit

Wong

Bien-Ly

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

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Enzymes of the blood coagulation pathway enhance the inflammatory response leading to endothelial dysfunction, accounting, in part, for the vascular complications occurring in sepsis and cardiovascular disease. The responses of endothelial cell activation include induction of the expression of tissue factor (TF), a membrane glycoprotein that promotes thrombosis, and of E-selectin, a cell adhesion molecule that promotes inflammation. In this report, we demonstrate synergistic interactions between the coagulation factor Xa (fXa) and the proinflammatory cytokines TNF, IL-1␤, and CD40L, leading to enhanced expression of TF and E-selectin in endothelial cells. A detailed analysis of the molecular pathways that could account for this activity of fXa showed that fXa inhibited the cytokine-induced expression of dual specificity phosphatases, MAP kinase phosphatase-L, -4, -5, and -7, blocking a negative regulatory effect on c-Jun N-terminal kinase. The synergistic interaction between fXa and TNF was also involved in the inhibition of A20 and I B␣ expression in the I B kinase-NF-B pathway. The data indicate that inhibition of negative regulatory signaling accounts for the amplification of cytokine-induced endothelial cell activation by fXa.cytokines ͉ endothelial cells ͉ factor Xa ͉ inflammation

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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Synergistic induction of tissue factor by coagulation factor Xa and TNF: Evidence for involvement of negative regulatory signaling cascades

Hezi-Yamit

Wong

Bien-Ly

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

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“…Briefly, HaCaT cells or murine SMCs were switched for 3 h to serum-free DMEM followed by the addition of proteases in the presence of 2 M hirudin to prevent thrombin signaling due to coagulation factor carryover from the culture medium (39). Cells were lysed in sample buffer for SDS-PAGE and Western blotting for phospho-ERK1/2, or mRNA was isolated from cells with TRIzol reagent (Invitrogen) for quantitative mRNA determinations (4).…”

Section: Methodsmentioning

confidence: 99%

The Endothelial Protein C Receptor Supports Tissue Factor Ternary Coagulation Initiation Complex Signaling through Protease-activated Receptors

Disse

Petersen

Larsen

et al. 2011

Journal of Biological Chemistry

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125

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“…PAR1, the prototypic receptor of the family, is activated via a spectrum of serine proteases taking part in the thrombotic/hemostasis cascade, including thrombin (3), plasmin (4), Xa (5), and activated protein C (6). Human Par1 (hPar1) plays a distinct role in the progression of malignant epithelia as well as in the physiologic invasion process of trophoblast implantation in the uterus decidua (7)(8)(9)(10).…”

Section: Introductionmentioning

confidence: 99%

Protease-Activated Receptor-1 (hPar1), A Survival Factor Eliciting Tumor Progression

Salah

Maoz

Pokroy

et al. 2007

Molecular Cancer Research

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Although ample evidence point to the central involvement of protease activated receptor-1 (PAR1) in tumor progression, little is known about the fate of the tumor when hPar1 is being silenced. We observed that hPar1 antisense clones exhibit low PAR1 levels, attenuated cell proliferation and invasion in vitro, and tumor formation in vivo. These clones showed noticeably reduced paxillin phosphorylation compared with the parental A375SM cells, whereas no change in the integrin levels was noticed. Antisense clones injected into the mice resulted in very few and only occasional small tumors, whereas advanced and vascularized tumors were observed in A375SM cells. The antisense-derived tumor sections expressed active caspase-3, increased terminal deoxynucleotidyl transferase -mediated nick-end labeling staining, and a markedly reduced proliferating cell nuclear antigen level compared with A375SM cell -derived tissue sections. Likewise, ablation of the hPar1 gene in a tetracyclineinducible hPar1 system leads to apoptosis in immature blood vessels, whereas mature vessels were unaffected. The activation of PAR1-induced pAkt/protein kinase B abrogated serum-deprived Bim EL induction and also markedly inhibited Bax levels. On the other hand, small interfering RNA silencing of the hPar1 gene induced the expression of Bim EL , a direct substrate of Akt/protein kinase B and also induced expression of active caspase-9 and caspase-3. These results altogether identify PAR1 as a survival factor that protects cells from undergoing apoptosis. We conclude that whereas PAR1 gene expression correlates with tumor progression, its neutralization effectively initiates an apoptotic pathway leading at least in part to significantly reduced tumor formation. (Mol Cancer Res 2007;5(3):229 -40)

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Gene induction by coagulation factor Xa is mediated by activation of protease-activated receptor 1

Cited by 179 publications

References 62 publications

Synergistic induction of tissue factor by coagulation factor Xa and TNF: Evidence for involvement of negative regulatory signaling cascades

Synergistic induction of tissue factor by coagulation factor Xa and TNF: Evidence for involvement of negative regulatory signaling cascades

The Endothelial Protein C Receptor Supports Tissue Factor Ternary Coagulation Initiation Complex Signaling through Protease-activated Receptors

Protease-Activated Receptor-1 (hPar1), A Survival Factor Eliciting Tumor Progression

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