Abstract
| Original language | English |
|---|---|
| Pages (from-to) | 808 - 815 |
| Number of pages | 8 |
| Journal | Cell Death and Differentiation |
| Volume | 19 |
| Issue number | 5 |
| DOIs | |
| Publication status | Published - 2012 |
Cite this
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In mouse embryonic fibroblasts, neither caspase-8 nor cellular FLICE-inhibitory protein (FLIP) is necessary for TNF to activate NF-kappaB, but caspase-8 is required for TNF to cause cell death, and induction of FLIP by NF-kappaB is required to preven. / Moujalled, Donia; Cook, Wendy; Lluis, Josep; Khan, Nufail; Ahmed, Afsar; Callus, Bernard; Vaux, David.
In: Cell Death and Differentiation, Vol. 19, No. 5, 2012, p. 808 - 815.Research output: Contribution to journal › Article › Research › peer-review
TY - JOUR
T1 - In mouse embryonic fibroblasts, neither caspase-8 nor cellular FLICE-inhibitory protein (FLIP) is necessary for TNF to activate NF-kappaB, but caspase-8 is required for TNF to cause cell death, and induction of FLIP by NF-kappaB is required to preven
AU - Moujalled, Donia
AU - Cook, Wendy
AU - Lluis, Josep
AU - Khan, Nufail
AU - Ahmed, Afsar
AU - Callus, Bernard
AU - Vaux, David
PY - 2012
Y1 - 2012
N2 - Binding of TNF to TNF receptor-1 can give a pro-survival signal through activation of p65/RelA NF-kappaB, but also signals cell death. To determine the roles of FLICE-inhibitory protein (FLIP) and caspase-8 in TNF-induced activation of NF-kappaB and apoptosis, we used mouse embryonic fibroblasts derived from FLIP and caspase-8 gene-deleted mice, and treated them with TNF and a smac-mimetic compound that causes degradation of cellular inhibitor of apoptosis proteins (cIAPs). In cells treated with smac mimetic, TNF and Fas Ligand caused wild-type and FLIP(-/-) MEFs to die, whereas caspase-8(-/-) MEFs survived, indicating that caspase-8 is necessary for death of MEFs triggered by these ligands when IAPs are degraded. By contrast, neither caspase-8 nor FLIP was required for TNF to activate p65/RelA NF-kappaB, because IkappaB was degraded, p65 translocated to the nucleus, and an NF-kappaB reporter gene activated normally in caspase-8(-/-) or FLIP(-/-) MEFs. Reconstitution of FLIP(-/-) MEFs with the FLIP isoforms FLIP-L, FLIP-R, or FLIP-p43 protected these cells from dying when treated with TNF or FasL, whether or not cIAPs were depleted. These results show that in MEFs, caspase-8 is necessary for TNF- and FasL-induced death, and FLIP is needed to prevent it, but neither caspase-8 nor FLIP is required for TNF to activate NF-kappaB.
AB - Binding of TNF to TNF receptor-1 can give a pro-survival signal through activation of p65/RelA NF-kappaB, but also signals cell death. To determine the roles of FLICE-inhibitory protein (FLIP) and caspase-8 in TNF-induced activation of NF-kappaB and apoptosis, we used mouse embryonic fibroblasts derived from FLIP and caspase-8 gene-deleted mice, and treated them with TNF and a smac-mimetic compound that causes degradation of cellular inhibitor of apoptosis proteins (cIAPs). In cells treated with smac mimetic, TNF and Fas Ligand caused wild-type and FLIP(-/-) MEFs to die, whereas caspase-8(-/-) MEFs survived, indicating that caspase-8 is necessary for death of MEFs triggered by these ligands when IAPs are degraded. By contrast, neither caspase-8 nor FLIP was required for TNF to activate p65/RelA NF-kappaB, because IkappaB was degraded, p65 translocated to the nucleus, and an NF-kappaB reporter gene activated normally in caspase-8(-/-) or FLIP(-/-) MEFs. Reconstitution of FLIP(-/-) MEFs with the FLIP isoforms FLIP-L, FLIP-R, or FLIP-p43 protected these cells from dying when treated with TNF or FasL, whether or not cIAPs were depleted. These results show that in MEFs, caspase-8 is necessary for TNF- and FasL-induced death, and FLIP is needed to prevent it, but neither caspase-8 nor FLIP is required for TNF to activate NF-kappaB.
UR - http://www.nature.com/cdd/journal/v19/n5/pdf/cdd2011151a.pdf
U2 - 10.1038/cdd.2011.151
DO - 10.1038/cdd.2011.151
M3 - Article
VL - 19
SP - 808
EP - 815
JO - Cell Death and Differentiation
JF - Cell Death and Differentiation
SN - 1350-9047
IS - 5
ER -