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EMAP-II facilitates TNF-R1 apoptotic signalling in endothelial cells and induces TRADD mobilization

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Abstract

Endothelial monocyte-activating polypeptide-II (EMAP-II), a proinflammatory cytokine with antiangiogenic properties, renders tumours sensitive to tumour necrosis factor-alpha (TNF) treatment. The exact mechanisms for this effect remain unclear. Here we show that human endothelial cells (EC) are insensitive to TNF-induced apoptosis but after a short pre-treatment with EMAP-II, EC quickly undergo TNF-induced apoptosis. We further analysed this EMAP-II pre-treatment effect and found no increase of TNF-R1 protein expression but rather an induction of TNF-R1 redistribution from Golgi storage pools to cell membranes. In addition, we observed EMAP-II induced mobilization and membrane expression of the TNF-R1-Associated Death Domain (TRADD) protein. Immunofluorescence co-staining experiments revealed that these two effects occurred at the same time in the same cell but TNF-R1 and TRADD were localized in different vesicles. These findings suggest that EMAP-II sensitises EC to apoptosis by facilitating TNF-R1 apoptotic signalling via TRADD mobilization and introduce a molecular and antiangiogenic explanation for the TNF sensitising properties of EMAP-II in tumours.

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Author notes

  1. Remco van Horssen

    Present address: Department of Cell Biology, NCMLS, Radboud University Medical Centre, Nijmegen, The Netherlands

Authors and Affiliations

  1. Laboratory of Experimental Surgical Oncology, Department of Surgical Oncology, 3000 Daniel den Hoed Cancer Centre, Erasmus MC-Room Ee 0104, PO Box 1738, Rotterdam, The Netherlands

    Remco van Horssen, Joost A. P. Rens, Debby Schipper, Alexander M. M. Eggermont & Timo L. M. ten Hagen

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  1. Remco van Horssen
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  2. Joost A. P. Rens
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  3. Debby Schipper
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  4. Alexander M. M. Eggermont
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  5. Timo L. M. ten Hagen
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Corresponding author

Correspondence to Timo L. M. ten Hagen.

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Horssen, R.v., Rens, J.A.P., Schipper, D. et al. EMAP-II facilitates TNF-R1 apoptotic signalling in endothelial cells and induces TRADD mobilization. Apoptosis 11, 2137–2145 (2006). https://doi.org/10.1007/s10495-006-0284-5

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  • DOI: https://doi.org/10.1007/s10495-006-0284-5

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