Specificity, diversity, and convergence in VEGF and TNF‐α signaling events leading to tissue factor up regulation via EGR‐1 in endothelial cells

Mechtcheriakova, Diana; Schabbauer, Gernot; Lucerna, Markus; Clauss, Matthias; R, De Martin; Binder, Bernd R.; Hofer, Erhard

doi:10.1096/fj.00-0247com

Cited by 176 publications

(193 citation statements)

References 73 publications

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“…and NFAT) [27][28][29][30]. In cancer cells, the effects of oncogenic EGFR on TF are mediated through an NFκB dependent mechanism [10], as well as by processes involving AP-1 and c-Jun Nterminal kinase (JNK) activation [12].…”

Section: Discussionmentioning

confidence: 99%

Modulation of the oncogene-dependent tissue factor expression by kinase suppressor of ras 1

Xing

Milsom

et al. 2010

Thrombosis Research

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Introduction: Tissue factor (TF) is the key trigger of the coagulation cascade and the membrane signalling receptor for coagulation protease, factor VIIa. In cancer, TF has been implicated in cancer cell survival, growth, and angiogenesis, and is upregulated as a result of oncogenic transformation. Materials and Methods:We assayed TF expression and tumourigenicity in mice of human cancer cell lines expressing oncogenic receptor tyrosine kinases. These cells were subjected to modulation of the kinase suppressor of ras 1 (KSR1) levels and treated with oncoprotein inhibitors in vitro and in vivo.Results: Here we show that herceptin, AG1478 and CI-1033 inhibitors of two different members of the ErbB family of oncogenes (HER-2 and EGFR) reduce TF levels in epithelial cancer cells. In EGFR-driven A431 cells, TF upregulation is diminished upon genetic targeting of KSR1, the scaffolding protein involved in EGFR signalling. Conversely, upregulation of KSR1 in A431 cells increases their TF expression and tumourigenicity in mice. The latter property remains dependent on EGFR, as pan-Erb (EGFR) inhibitor, CI-1033 blocks TF promoter activity and tumour formation by parental and KSR1 overexpressing A431 cells.

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Section: Discussionmentioning

confidence: 99%

Modulation of the oncogene-dependent tissue factor expression by kinase suppressor of ras 1

Xing

Milsom

et al. 2010

Thrombosis Research

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“…Previous studies have established an important role for MEK/MAP kinase in mediating Egr-1 expression in response to other growth factors and hormones (Hodge et al, 1998;Tsai et al, 2000;Mechtcheriakova et al, 2001;Wu et al, 2002). This signaling pathway regulates Egr-1 gene expression mainly through activation of the SREs in the human Egr-1 promoter.…”

Section: Hgf Stimulates Fibronectin Expression In Melanomas C Gaggiolmentioning

confidence: 99%

HGF induces fibronectin matrix synthesis in melanoma cells through MAP kinase-dependent signaling pathway and induction of Egr-1

et al. 2004

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The matrix fibronectin protein is a multifunctional adhesive molecule that promotes migration and invasiveness of many tumors including melanomas. Increased fibronectin synthesis has been associated with the metastatic potential of melanoma cells; however, the molecular mechanisms underlying fibronectin overexpression during melanoma development are poorly understood. We report that hepatocyte growth factor/scatter factor (HGF) induces fibronectin expression and its extracellular assembly on the surface of melanoma cells through activation of mitogen-activated protein (MAP) kinase pathway, and induction and transcriptional activation of Early growth response-1 (Egr-1). Inhibition of B-RAF/ MAP kinase pathway by dominant-negative mutants and by U0126-abrogated HGF-induced Egr-1, and chromatin immunoprecipitation showed that Egr-1 is bound to the fibronectin promoter in response to HGF. Exogenously expressed Egr-1 increased fibronectin levels, while blockage of Egr-1 activation by expression of the Egr-1 corepressor NAB2 interfered with the upregulation of fibronectin synthesis induced by HGF, indicating that Egr-1 exerts a significant role in fibronectin expression in response to HGF. Finally, analysis of the expression pattern of fibronectin in melanoma cells demonstrated that fibronectin levels are correlated with constitutive MAP kinase signaling. Our data define a novel mechanism that might have important implications in regulation of melanoma progression by autocrine HGF signaling or by constitutive activation of MAP kinase pathway.

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“…Major signals induced by VEGF via VEGFR-2 in endothelial cells include activation of the phosphoinositol 3-kinase/PKB and phospholipase C-␥/PKC pathways (4,5). Whereas activation of PKB has been primarily implicated in cell survival (6), recent in vitro studies have shown that VEGF treatment of endothelial cells leads to a PKC-dependent activation of the MEK/ERK module of MAP kinases resulting in a rapid up-regulation of the transcription factor EGR-1 (7,8), which has been associated with growth and differentiation of various cell types (9,10). Furthermore, EGR-1 is critically involved in the up-regulation of genes such as tissue factor (TF) (7,8), VEGF receptor-1 (VEGFR-1) (11,12), and urokinase-type plasminogen activator (uPA) (13).…”

mentioning

confidence: 99%

“…Whereas activation of PKB has been primarily implicated in cell survival (6), recent in vitro studies have shown that VEGF treatment of endothelial cells leads to a PKC-dependent activation of the MEK/ERK module of MAP kinases resulting in a rapid up-regulation of the transcription factor EGR-1 (7,8), which has been associated with growth and differentiation of various cell types (9,10). Furthermore, EGR-1 is critically involved in the up-regulation of genes such as tissue factor (TF) (7,8), VEGF receptor-1 (VEGFR-1) (11,12), and urokinase-type plasminogen activator (uPA) (13). These genes have been proposed to fulfill important functions for different aspects of vasculogenesis and angiogenesis (1,2,14).…”

mentioning

confidence: 99%

NAB2, a Corepressor of EGR-1, Inhibits Vascular Endothelial Growth Factor-mediated Gene Induction and Angiogenic Responses of Endothelial Cells

Lucerna¹,

Mechtcheriakova²,

Kadl³

et al. 2003

Journal of Biological Chemistry

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In this study we have investigated the role of a specific corepressor of EGR-1, NAB2, to down-regulate vascular endothelial growth factor (VEGF)-induced gene expression in endothelial cells and to inhibit angiogenesis. Firstly, we show a reciprocal regulation of EGR-1 and NAB2 following VEGF treatment. During the initial phase EGR-1 is rapidly induced and NAB2 levels are down-regulated. This is followed by a reduction of EGR-1 and a concomitant increase of NAB2. Secondly, using the tissue factor gene as a readout for VEGFinduced and EGR-1-regulated gene expression we demonstrate that NAB2 can completely block VEGF-induced tissue factor reporter gene activity. Thirdly, by adenovirus-mediated expression we show that NAB2 inhibits up-regulation of tissue factor, VEGF receptor-1, and urokinase plasminogen activator mRNAs even when a combination of VEGF and bFGF is used for induction. In addition, NAB2 overexpression significantly reduced tubule and sprout formation in two different in vitro angiogenesis assays and largely prevented the invasion of cells and formation of vessel-like structures in the murine Matrigel model. These data suggest that NAB2 regulation represents a mechanism to guarantee transient EGR-1 activity following exposure of endothelial cells to VEGF and that NAB2 overexpression could be used to inhibit signals involved in the early phase of angiogenesis.

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Specificity, diversity, and convergence in VEGF and TNF‐α signaling events leading to tissue factor up regulation via EGR‐1 in endothelial cells

Cited by 176 publications

References 73 publications

Modulation of the oncogene-dependent tissue factor expression by kinase suppressor of ras 1

Modulation of the oncogene-dependent tissue factor expression by kinase suppressor of ras 1

HGF induces fibronectin matrix synthesis in melanoma cells through MAP kinase-dependent signaling pathway and induction of Egr-1

NAB2, a Corepressor of EGR-1, Inhibits Vascular Endothelial Growth Factor-mediated Gene Induction and Angiogenic Responses of Endothelial Cells

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