Gas1 is induced by VE-cadherin and vascular endothelial growth factor and inhibits endothelial cell apoptosis

Spagnuolo, Raffaella; Corada, Monica; Orsenigo, Fabrizio; Zanetta, Lucia; Deuschle, Ulrich; Sandy, Péter; Schneider, Claudio; Drake, Christopher J.; Breviario, Ferruccio; Dejana, Elisabetta

doi:10.1182/blood-2003-07-2459

Cited by 65 publications

(54 citation statements)

References 49 publications

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“…A low basal level of PKB/Akt phosphorylation was observed in both adherent and spheroid HUVEC (Figure 3d), the latter consistent with VE-cadherin-dependent cell-cell adhesion (Spagnuolo et al, 2004). TNF7IFNg treatment induced a strong transient PKB/Akt phosphorylation in adherent HUVEC, but not in spheroids (Figure 3d).…”

Section: Resultssupporting

confidence: 67%

“…As a main model, we used the endothelial cell spheroid model reported by Korff and Augustin (1998). It allows bypassing anoikis that rapidly occurs in single-cell suspensions (Meredith et al, 1993), thereby allowing to keep HUVEC viable for the duration of the experiment under conditions of integrin-independent but VE-cadherin-dependent adhesion (Spagnuolo et al, 2004). The main conclusions of this work are as follows: (i) Concomitant PKB/Akt and NF-kB activation is essential for the survival of endothelial cells exposed to TNF, and integrin ligation acts permissive for TNFmediated PKB/Akt, but not NF-kB activation.…”

Section: Discussionmentioning

confidence: 99%

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Distinctive role of integrin-mediated adhesion in TNF-induced PKB/Akt and NF-κB activation and endothelial cell survival

Bieler¹,

Hasmim²,

Monnier³

et al. 2007

Oncogene

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Section: Resultssupporting

confidence: 67%

Section: Discussionmentioning

confidence: 99%

Distinctive role of integrin-mediated adhesion in TNF-induced PKB/Akt and NF-κB activation and endothelial cell survival

Bieler¹,

Hasmim²,

Monnier³

et al. 2007

Oncogene

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“…By contrast, one gene, Gas1, was markedly down-regulated (∼11-fold) in B16-F10 cells. Gas1 encodes a pleiotropic 45-kDa glycosylphosphatidylinositol-anchored membrane protein (Stebel et al 2000) that has been shown to play a role in both negative (Del Sal et al 1992;Lee et al 2001;Mellstrom et al 2002;Zamorano et al 2003Zamorano et al , 2004 and positive regulation of cell growth (Liu et al 2001;Spagnuolo et al 2004), as well as in embryonic development through regulation of Sonic Hedgehog signaling (for review, see Martinelli and Fan 2007b).…”

Section: Down-regulation Of Gas1 In B16-f10 Cells Contributes To Theimentioning

confidence: 99%

A genome-wide shRNA screen identifies GAS1 as a novel melanoma metastasis suppressor gene

Gobeil¹,

Zhu²,

Doillon³

et al. 2008

Genes Dev.

110

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Metastasis suppressor genes inhibit one or more steps required for metastasis without affecting primary tumor formation. Due to the complexity of the metastatic process, the development of experimental approaches for identifying genes involved in metastasis prevention has been challenging. Here we describe a genome-wide RNAi screening strategy to identify candidate metastasis suppressor genes. Following expression in weakly metastatic B16-F0 mouse melanoma cells, shRNAs were selected based upon enhanced satellite colony formation in a three-dimensional cell culture system and confirmed in a mouse experimental metastasis assay. Using this approach we discovered 22 genes whose knockdown increased metastasis without affecting primary tumor growth. We focused on one of these genes, Gas1 (Growth arrest-specific 1), because we found that it was substantially down-regulated in highly metastatic B16-F10 melanoma cells, which contributed to the high metastatic potential of this mouse cell line. We further demonstrated that Gas1 has all the expected properties of a melanoma tumor suppressor including: suppression of metastasis in a spontaneous metastasis assay, promotion of apoptosis following dissemination of cells to secondary sites, and frequent down-regulation in human melanoma metastasis-derived cell lines and metastatic tumor samples. Thus, we developed a genome-wide shRNA screening strategy that enables the discovery of new metastasis suppressor genes.[Keywords: Metastasis suppressor gene; melanoma; GAS1; RNAi screen; three-dimensional cell culture system] Supplemental material is available at http://www.genesdev.org. Received July 10, 2008; revised version accepted September 8, 2008. Metastatic dissemination of a primary tumor to a secondary site is the major cause of deaths from solid tumors (for review, see Gupta and Massague 2006;Nguyen and Massague 2007). The progression to metastasis involves a series of discrete steps, commonly known as the metastatic cascade, which minimally includes: invasion of the tumor border, intravasation into vascular structures, survival during transport to the secondary site, extravasation, and colonization of the secondary site (for review, see Gupta and Massague 2006;Steeg 2006). The complex process of metastasis is controlled by multiple genes that either increase or decrease metastatic potential (Berger et al. 2005;Nguyen and Massague 2007). Although many genes have been identified that promote metastasis, a relatively small number of metastasis suppressor genes have been documented (Rinker-Schaeffer et al. 2006). This is due, at least in part, to a lack of experimental approaches for the systematic identification of genes that specifically inhibit metastasis.Three-dimensional (3D) cell culture systems comprising cancer cell lines grown in matrices of collagen and fibrin provide an ex vivo model system for studying tumor cell invasion and expansion into the extracellular matrix (Doillon et al. 2004). Using this bicomposite gel technology system, it has been shown that a vari...

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“…Transfection medium was maintained on cells for 3 hours and was then removed and substituted with complete medium. The reduction in GRP78 protein, 48 hours after transfection, was estimated by Western blot analysis (31).…”

Section: Methodsmentioning

confidence: 99%

Kringle 5 of Human Plasminogen Induces Apoptosis of Endothelial and Tumor Cells through Surface-Expressed Glucose-Regulated Protein 78

Davidson¹,

Haskell²,

Majest³

et al. 2005

Cancer Research

228

216

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Kringle 5 (K5) of human plasminogen has been shown to inhibit angiogenesis by inducing the apoptosis of proliferating endothelial cells. Peptide regions around the lysine-binding pocket of K5 largely mediate these effects, particularly the peptide PRKLYDY, which we show to compete with K5 for the binding to endothelial cells. The cell surface binding site for K5 that mediates these effects has not been defined previously. Here, we report that glucose-regulated protein 78, exposed on cell surfaces of proliferating endothelial cells as well as on stressed tumor cells, plays a key role in the antiangiogenic and antitumor activity of K5. We also report that recombinant K5-induced apoptosis of stressed HT1080 fibrosarcoma cells involves enhanced activity of caspase-7, consistent with the disruption of glucose-regulated protein 78-procaspase-7 complexes. These results establish recombinant K5 as an inhibitor of a stress response pathway, which leads to both endothelial and tumor cell apoptosis. (Cancer Res 2005; 65(11): 4663-72)

show abstract

Gas1 is induced by VE-cadherin and vascular endothelial growth factor and inhibits endothelial cell apoptosis

Cited by 65 publications

References 49 publications

Distinctive role of integrin-mediated adhesion in TNF-induced PKB/Akt and NF-κB activation and endothelial cell survival

Distinctive role of integrin-mediated adhesion in TNF-induced PKB/Akt and NF-κB activation and endothelial cell survival

A genome-wide shRNA screen identifies GAS1 as a novel melanoma metastasis suppressor gene

Kringle 5 of Human Plasminogen Induces Apoptosis of Endothelial and Tumor Cells through Surface-Expressed Glucose-Regulated Protein 78

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