PUBLICATION

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

Authors
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.
ID
ZDB-PUB-120909-5
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.
Abstract

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.

Genes / Markers
Figures
Show all Figures
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Antibodies
Orthology
Engineered Foreign Genes
Mapping