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.
Article navigation
Related articles
Cited by...
More in this TOC section
Similar articles
Other journals from The Company of Biologists
Editors’ choice – Loss of Cln5 causes altered neurogenesis in a mouse model of a childhood neurodegenerative disorder
In our latest Editors' choice article, Katja M. Kanninen and colleagues examine neurogenesis in the neuronal ceroid lipofuscinoses – neurodegenerative disorders caused by loss of the Cln5 gene – and report a novel function of the CLN5 protein.
Call for papers: Cancer metabolism special collection
DEADLINE EXTENDED TO MONDAY 16TH OCTOBER 2016
DMM invites you to submit original research for a special collection focused on the dysregulation of metabolic pathways in cancer initiation, progression and resistance to treatment. This ongoing collection will be launched with a special issue scheduled for publication in spring 2018, with the special issue guest edited by Almut Schulze (University of Würzberg, Germany) and Mariia Yuneva (Crick Institute, London, UK).
Find out more here.
Review – Human pluripotent stem cell models of cardiac disease: from mechanisms to therapies
Richard P. Davis and colleagues review how human pluripotent stem cells have revolutionised the study of cardiac disease, highlighting their impact in investigating pathogenesis and their use in drug discovery, and look at current challenges facing the field.
First person – Lucía Zacchi
We continue our new series of interviews with the first authors of articles published in DMM, giving authors the opportunity to promote themselves alongside their papers. In this issue we feature Lucía Zacchi, first author on a Resource article describing a novel yeast screen to identify genetic modifiers of protein levels in dystonia.