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Research Article
TNF receptors regulate vascular homeostasis in zebrafish through a caspase-8, caspase-2 and P53 apoptotic program that bypasses caspase-3
Raquel Espín, Francisco J. Roca, Sergio Candel, María P. Sepulcre, Juan M. González-Rosa, Francisca Alcaraz-Pérez, José Meseguer, María L. Cayuela, Nadia Mercader, Victoriano Mulero
Disease Models & Mechanisms 2012 : dmm.010249 doi: 10.1242/dmm.010249 Published 16 November 2012
Raquel Espín
Universidad de Murcia, Murcia, Spain;
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Francisco J. Roca
Universidad de Murcia, Murcia, Spain;
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Sergio Candel
Universidad de Murcia, Murcia, Spain;
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María P. Sepulcre
Universidad de Murcia, Murcia, Spain;
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Juan M. González-Rosa
Centro Nacional de Investigaciones Cardiovasculares, Madrid, Spain;
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Francisca Alcaraz-Pérez
University Hospital 'Virgen de la Arrixaca', Murcia, Spain
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José Meseguer
Universidad de Murcia, Murcia, Spain;
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María L. Cayuela
University Hospital 'Virgen de la Arrixaca', Murcia, Spain
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Nadia Mercader
Centro Nacional de Investigaciones Cardiovasculares, Madrid, Spain;
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Victoriano Mulero
Universidad de Murcia, Murcia, Spain;
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Summary

Although it is known that tumor necrosis factor receptor (TNFR) signaling plays a crucial role in vascular integrity and homeostasis, the contribution of each receptor to these processes and the signaling pathway involved are still largely unknown. Here, we show that targeted gene knockdown of TNFRSF1B in zebrafish embryos results in the induction of a caspase-8, caspase-2 and P53-dependent apoptotic program in endothelial cells that bypasses caspase-3. Furthermore, the simultaneous depletion of TNFRSF1A or the activation of NF-κB rescue endothelial cell apoptosis, indicating that a signaling balance between both TNFRs is required for endothelial cell integrity. In endothelial cells, TNFRSF1A signals apoptosis through caspase-8, whereas TNFRSF1B signals survival via NF-κB. Similarly, TNFα promotes the apoptosis of human endothelial cells through TNFRSF1A and triggers caspase-2 and P53 activation. We have identified an evolutionarily conserved apoptotic pathway involved in vascular homeostasis that provides new therapeutic targets for the control of inflammation- and tumor-driven angiogenesis.

  • Received May 25, 2012.
  • Accepted August 18, 2012.

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial Share Alike License (http://creativecommons.org/licenses/by-nc-sa/3.0), which permits unrestricted non-commercial use, distribution and reproduction in any medium provided that the original work is properly cited and all further distributions of the work or adaptation are subject to the same Creative Commons License terms.

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TNF receptors regulate vascular homeostasis in zebrafish through a caspase-8, caspase-2 and P53 apoptotic program that bypasses caspase-3
Raquel Espín, Francisco J. Roca, Sergio Candel, María P. Sepulcre, Juan M. González-Rosa, Francisca Alcaraz-Pérez, José Meseguer, María L. Cayuela, Nadia Mercader, Victoriano Mulero
Disease Models & Mechanisms 2012 : dmm.010249 doi: 10.1242/dmm.010249 Published 16 November 2012
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TNF receptors regulate vascular homeostasis in zebrafish through a caspase-8, caspase-2 and P53 apoptotic program that bypasses caspase-3
Raquel Espín, Francisco J. Roca, Sergio Candel, María P. Sepulcre, Juan M. González-Rosa, Francisca Alcaraz-Pérez, José Meseguer, María L. Cayuela, Nadia Mercader, Victoriano Mulero
Disease Models & Mechanisms 2012 : dmm.010249 doi: 10.1242/dmm.010249 Published 16 November 2012

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