Intravenous somatic gene transfer with antisense tissue factor restores blood flow by reducing tumor necrosis factor-induced tissue factor expression and fibrin deposition in mouse meth-A sarcoma.

Zhang, Y; Deng, Youhua; Wendt, Th.; Liliensiek, Birgit; Bierhaus, Angelika; Greten, J; He, Wen; Chen, B; Hach-Wunderle, V.; Waldherr, Rüdiger; Ziegler, Reinhard; Dn, Männel; Stern, David M.; Nawroth, Peter P.

doi:10.1172/jci118662

Cited by 58 publications

(47 citation statements)

References 35 publications

(36 reference statements)

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“…Administration of the PKC␤ inhibitor suppressed neovascularization, consistent with a contribution of PKC␤ to cellular events underlying angiogenesis. In this context, tissue factor expression (shown to be induced by hypoxia in our studies) (19) has been associated with angiogenesis, especially in tumor neovasculature (53)(54)(55), and it is possible that hypoxia-regulated PKC␤ activation provides a link between these two events. However, most attention with regard to participation of PKC␤II in vascular pathology has focused on cultured endothelial cells exposed to high levels of ambient glucose and implications of the observed PKC␤II activation for vascular complications in diabetes (45).…”

Section: Discussionmentioning

confidence: 72%

Hypoxia-associated Induction of Early Growth Response-1 Gene Expression

Yan¹,

Lu²,

Zou³

et al. 1999

Journal of Biological Chemistry

236

187

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1998) Proc. Natl. Acad. Sci. U. S. A. 95, 8298 -8303). Now, we show that cultured monocytes subjected to hypoxia (pO 2 Ϸ 12 torr) displayed increased Egr-1 expression because of de novo biosynthesis, with a Ϸ10-fold increased rate of transcription. Transfection of monocytes with Egr-1 promoter-luciferase constructs localized elements responsible for hypoxia-enhanced expression to ؊424/؊65, a region including EBS (ets binding site)-SRE (serum response element)-EBS and SRE-EBS-SRE sites. Further studies with each of these regions ligated to the basal thymidine kinase promoter and luciferase demonstrated that EBS sites in the element spanning ؊424/؊375 were critical for hypoxia-enhanceable gene expression. These data suggested that an activated ets factor, such as Elk-1, in complex with serum response factor, was the likely proximal trigger of Egr-1 transcription. Indeed, hypoxia induced activation of Elk-1, and suppression of Elk-1 blocked up-regulation of Egr-1 transcription. The signaling cascade preceding Elk-1 activation in response to oxygen deprivation was traced to activation of protein kinase C-␤II, Raf, mitogen-activated protein kinase/extracellular signal-regulated protein kinase kinase and mitogen-activated protein kinases. Comparable hypoxiamediated Egr-1 induction and activation were observed in cultured hepatoma-derived cells deficient in HIF-1␤ and wild-type hepatoma cells, indicating that the HIF-1 and Egr-1 pathways are initiated independently in response to oxygen deprivation. We propose that activation of Egr-1 in response to hypoxia induces a different facet of the adaptive response than HIF-1, one component of which causes expression of tissue factor, resulting in fibrin deposition.

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Section: Discussionmentioning

confidence: 72%

Hypoxia-associated Induction of Early Growth Response-1 Gene Expression

Yan¹,

Lu²,

Zou³

et al. 1999

Journal of Biological Chemistry

236

187

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“…Accordingly, scTNF showed a significantly lower toxicity in vivo, which was unexpected in light of the enhanced in vivo half-life of scTNF. We next investigated the antitumoral efficacy of scTNF in a Meth-A-induced solid tumor mouse model (26). The hemorrhagic necrotic area of a central tumor section was inspected 6 days after a single i.p.…”

Section: Antitumoral Activity Of Sctnfmentioning

confidence: 99%

Single-Chain TNF, a TNF Derivative with Enhanced Stability and Antitumoral Activity

Krippner‐Heidenreich¹,

Grunwald

Zimmermann

et al. 2008

The Journal of Immunology

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The inflammatory and proapoptotic cytokine TNF possesses a compelling potential as an antitumoral therapeutic agent. Possible target cells include the malignant cells themselves, the tumor vasculature, or the immune system. As the clinical use of TNF is limited by systemic toxicity, targeting strategies using TNF-based fusion proteins are currently used. A major obstacle, however, is that homotrimeric TNF ligands are prone to activity loss due to dissociation into their monomers. In this study, we report the construction of single-chain TNF molecule, a TNF mutant consisting of three TNF monomers fused by short peptide linkers. In comparison to wild-type TNF, single-chain TNF was found to possess increased stability in vitro and in vivo, displayed reduced systemic toxicity yet slightly enhanced antitumoral activity in mouse models. Creation of single-chain variants is a new approach for improvement of functional activity of therapeutics based on TNF family ligands.

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“…Consumptive coagulopathy, resulting from tissue factor-mediated activation of the procoagulant pathway, is a consequence of LPS-cellular interactions and a cause of disseminated intravascular coagulation with resultant thrombotic and hemorrhagic complications (27)(28)(29). In vitro studies have shown the tissue factor gene to be under control of a cis -acting NF B site (12)(13)(14)(15)(30)(31)(32)(33)(34) and TNF ␣ directly contributes to activation of this transcription factor leading to upregulation of tissue factor expression (12)(13)(14)(15)(35)(36)(37)(38)(39)(40)(41)(42)(43)(44).…”

Section: Introductionmentioning

confidence: 99%