Functional characterization of a chimeric soluble Fas ligand polymer with in vivo anti-tumor activity.
Binding of ligand FasL to its receptor Fas triggers apoptosis via the caspase cascade. FasL itself is homotrimeric, and a productive apoptotic signal requires that FasL be oligomerized beyond the homotrimeric state. We generated a series of FasL chimeras by fusing FasL to domains of the Leukemia Inh...
Main Authors: | , , , , , , , , , , , , , |
---|---|
Format: | Article |
Language: | English |
Published: |
Public Library of Science (PLoS)
2013-01-01
|
Series: | PLoS ONE |
Online Access: | http://europepmc.org/articles/PMC3541234?pdf=render |
id |
doaj-afb7f3fbf7614d238e2ba382fd4086a6 |
---|---|
record_format |
Article |
spelling |
doaj-afb7f3fbf7614d238e2ba382fd4086a62020-11-25T01:13:35ZengPublic Library of Science (PLoS)PLoS ONE1932-62032013-01-0181e5400010.1371/journal.pone.0054000Functional characterization of a chimeric soluble Fas ligand polymer with in vivo anti-tumor activity.Sophie DaburonChristel DevaudPierre CostetAurore MorelloLaure Garrigue-AntarMike MaillassonNathalie HargousDelphine LapaillerieMarc BonneuJulie Dechanet-MervillePatrick LegembreMyriam CaponeJean-François MoreauJean-Luc TaupinBinding of ligand FasL to its receptor Fas triggers apoptosis via the caspase cascade. FasL itself is homotrimeric, and a productive apoptotic signal requires that FasL be oligomerized beyond the homotrimeric state. We generated a series of FasL chimeras by fusing FasL to domains of the Leukemia Inhibitory Factor receptor gp190 which confer homotypic oligomerization, and analyzed the capacity of these soluble chimeras to trigger cell death. We observed that the most efficient FasL chimera, called pFasL, was also the most polymeric, as it reached the size of a dodecamer. Using a cellular model, we investigated the structure-function relationships of the FasL/Fas interactions for our chimeras, and we demonstrated that the Fas-mediated apoptotic signal did not solely rely on ligand-mediated receptor aggregation, but also required a conformational adaptation of the Fas receptor. When injected into mice, pFasL did not trigger liver injury at a dose which displayed anti-tumor activity in a model of human tumor transplanted to immunodeficient animals, suggesting a potential therapeutic use. Therefore, the optimization of the FasL conformation has to be considered for the development of efficient FasL-derived anti-cancer drugs targeting Fas.http://europepmc.org/articles/PMC3541234?pdf=render |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Sophie Daburon Christel Devaud Pierre Costet Aurore Morello Laure Garrigue-Antar Mike Maillasson Nathalie Hargous Delphine Lapaillerie Marc Bonneu Julie Dechanet-Merville Patrick Legembre Myriam Capone Jean-François Moreau Jean-Luc Taupin |
spellingShingle |
Sophie Daburon Christel Devaud Pierre Costet Aurore Morello Laure Garrigue-Antar Mike Maillasson Nathalie Hargous Delphine Lapaillerie Marc Bonneu Julie Dechanet-Merville Patrick Legembre Myriam Capone Jean-François Moreau Jean-Luc Taupin Functional characterization of a chimeric soluble Fas ligand polymer with in vivo anti-tumor activity. PLoS ONE |
author_facet |
Sophie Daburon Christel Devaud Pierre Costet Aurore Morello Laure Garrigue-Antar Mike Maillasson Nathalie Hargous Delphine Lapaillerie Marc Bonneu Julie Dechanet-Merville Patrick Legembre Myriam Capone Jean-François Moreau Jean-Luc Taupin |
author_sort |
Sophie Daburon |
title |
Functional characterization of a chimeric soluble Fas ligand polymer with in vivo anti-tumor activity. |
title_short |
Functional characterization of a chimeric soluble Fas ligand polymer with in vivo anti-tumor activity. |
title_full |
Functional characterization of a chimeric soluble Fas ligand polymer with in vivo anti-tumor activity. |
title_fullStr |
Functional characterization of a chimeric soluble Fas ligand polymer with in vivo anti-tumor activity. |
title_full_unstemmed |
Functional characterization of a chimeric soluble Fas ligand polymer with in vivo anti-tumor activity. |
title_sort |
functional characterization of a chimeric soluble fas ligand polymer with in vivo anti-tumor activity. |
publisher |
Public Library of Science (PLoS) |
series |
PLoS ONE |
issn |
1932-6203 |
publishDate |
2013-01-01 |
description |
Binding of ligand FasL to its receptor Fas triggers apoptosis via the caspase cascade. FasL itself is homotrimeric, and a productive apoptotic signal requires that FasL be oligomerized beyond the homotrimeric state. We generated a series of FasL chimeras by fusing FasL to domains of the Leukemia Inhibitory Factor receptor gp190 which confer homotypic oligomerization, and analyzed the capacity of these soluble chimeras to trigger cell death. We observed that the most efficient FasL chimera, called pFasL, was also the most polymeric, as it reached the size of a dodecamer. Using a cellular model, we investigated the structure-function relationships of the FasL/Fas interactions for our chimeras, and we demonstrated that the Fas-mediated apoptotic signal did not solely rely on ligand-mediated receptor aggregation, but also required a conformational adaptation of the Fas receptor. When injected into mice, pFasL did not trigger liver injury at a dose which displayed anti-tumor activity in a model of human tumor transplanted to immunodeficient animals, suggesting a potential therapeutic use. Therefore, the optimization of the FasL conformation has to be considered for the development of efficient FasL-derived anti-cancer drugs targeting Fas. |
url |
http://europepmc.org/articles/PMC3541234?pdf=render |
work_keys_str_mv |
AT sophiedaburon functionalcharacterizationofachimericsolublefasligandpolymerwithinvivoantitumoractivity AT christeldevaud functionalcharacterizationofachimericsolublefasligandpolymerwithinvivoantitumoractivity AT pierrecostet functionalcharacterizationofachimericsolublefasligandpolymerwithinvivoantitumoractivity AT auroremorello functionalcharacterizationofachimericsolublefasligandpolymerwithinvivoantitumoractivity AT lauregarrigueantar functionalcharacterizationofachimericsolublefasligandpolymerwithinvivoantitumoractivity AT mikemaillasson functionalcharacterizationofachimericsolublefasligandpolymerwithinvivoantitumoractivity AT nathaliehargous functionalcharacterizationofachimericsolublefasligandpolymerwithinvivoantitumoractivity AT delphinelapaillerie functionalcharacterizationofachimericsolublefasligandpolymerwithinvivoantitumoractivity AT marcbonneu functionalcharacterizationofachimericsolublefasligandpolymerwithinvivoantitumoractivity AT juliedechanetmerville functionalcharacterizationofachimericsolublefasligandpolymerwithinvivoantitumoractivity AT patricklegembre functionalcharacterizationofachimericsolublefasligandpolymerwithinvivoantitumoractivity AT myriamcapone functionalcharacterizationofachimericsolublefasligandpolymerwithinvivoantitumoractivity AT jeanfrancoismoreau functionalcharacterizationofachimericsolublefasligandpolymerwithinvivoantitumoractivity AT jeanluctaupin functionalcharacterizationofachimericsolublefasligandpolymerwithinvivoantitumoractivity |
_version_ |
1725161361816682496 |