TNF receptors regulate vascular homeostasis in zebrafish through a caspase-8, caspase-2 and P53 apoptotic program that bypasses caspase-3

Espín, Raquel; Roca, Francisco J; Candel, Sergio; Sepulcre, María P; González-Rosa, Juan M; Alcaraz-Pérez, Francisca; Meseguer, José; Cayuela, María L; Mercader Huber, Nadia; Mulero, Victoriano (2013). TNF receptors regulate vascular homeostasis in zebrafish through a caspase-8, caspase-2 and P53 apoptotic program that bypasses caspase-3. Disease models & mechanisms, 6(2), pp. 383-396. Company of Biologists Ltd. 10.1242/dmm.010249

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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.

Item Type:

Journal Article (Original Article)

Division/Institute:

04 Faculty of Medicine > Pre-clinic Human Medicine > Institute of Anatomy

UniBE Contributor:

Mercader Huber, Nadia

Subjects:

600 Technology > 610 Medicine & health

ISSN:

1754-8403

Publisher:

Company of Biologists Ltd.

Language:

English

Submitter:

Nadia Isabel Mercader Huber

Date Deposited:

09 Jun 2016 15:54

Last Modified:

19 Jun 2016 01:21

Publisher DOI:

10.1242/dmm.010249

PubMed ID:

22956347

BORIS DOI:

10.7892/boris.79618

URI:

https://boris.unibe.ch/id/eprint/79618

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