ZFIN ID: ZDB-PUB-120909-5
TNF receptors regulate vascular homeostasis through a caspase-8, caspase-2 and P53 apoptotic program that bypasses caspase-3
Espín, R., Roca, F.J., Candel, S., Sepulcre, M.P., González-Rosa, J.M., Alcaraz-Pérez, F., Meseguer, J., Cayuela, M.L., Mercader, N., and Mulero, V.
Date: 2013
Source: Disease models & mechanisms   6(2): 383-396 (Journal)
Registered Authors: Mulero, Victor, Roca, Francisco Jose
Keywords: none
MeSH Terms:
  • Animals
  • Apoptosis*
  • Blood Circulation
  • Blood Vessels/metabolism*
  • Caspase 2/metabolism
  • Caspase 3/metabolism
  • Caspase 8/metabolism
  • Caspases/metabolism*
  • Conserved Sequence
  • DNA Fragmentation
  • Embryo, Nonmammalian/metabolism
  • Endothelial Cells/cytology
  • Endothelial Cells/enzymology
  • Evolution, Molecular
  • Gene Deletion
  • Homeostasis*
  • Humans
  • Models, Biological
  • Receptors, Tumor Necrosis Factor, Type I/deficiency
  • Receptors, Tumor Necrosis Factor, Type I/metabolism*
  • Signal Transduction
  • Tumor Suppressor Protein p53/metabolism*
  • Zebrafish/embryology
  • Zebrafish/metabolism*
PubMed: 22956347 Full text @ Dis. Model. Mech.

Although it is known that TNF receptor signaling plays a critical 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 and that, in endothelial cells, TNFRSF1A signals apoptosis through caspase-8, while 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 evolutionary conserved apoptotic pathway involved in vascular homeostasis that provides new therapeutic targets for the control of inflammation and tumor driven angiogenesis.