TAK1 is required for survival of mouse fibroblasts treated with TRAIL, and does so by NF-kappaB dependent induction of cFLIPL.
Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) is known as a "death ligand"-a member of the TNF superfamily that binds to receptors bearing death domains. As well as causing apoptosis of certain types of tumor cells, TRAIL can activate both NF-kappaB and JNK signalling pathways. To determine the role of TGF-beta-Activated Kinase-1 (TAK1) in TRAIL signalling, we analyzed the effects of adding TRAIL to mouse embryonic fibroblasts (MEFs) derived from TAK1 conditional knockout mice. TAK1-/- MEFs were significantly more sensitive to killing by TRAIL than wild-type MEFs, and failed to activate NF-kappaB or JNK. Overexpression of IKK2-EE, a constitutive activator of NF-kappaB, protected TAK1-/- MEFs against TRAIL killing, suggesting that TAK1 activation of NF-kappaB is critical for the viability of cells treated with TRAIL. Consistent with this model, TRAIL failed to induce the survival genes cIAP2 and cFlipL in the absence of TAK1, whereas activation of NF-kappaB by IKK2-EE restored the levels of both proteins. Moreover, ectopic expression of cFlipL, but not cIAP2, in TAK1-/- MEFs strongly inhibited TRAIL-induced cell death. These results indicate that cells that survive TRAIL treatment may do so by activation of a TAK1-NF-kappaB pathway that drives expression of cFlipL, and suggest that TAK1 may be a good target for overcoming TRAIL resistance.
Lluis
Josep Maria
JM
Deparment of Biochemistry, La Trobe University, Bundoora, Australia.
Nachbur
Ulrich
U
Cook
Wendy Diane
WD
Gentle
Ian Edward
IE
Moujalled
Donia
D
Moulin
Maryline
M
Wong
Wendy Wei-Lynn
WW
Khan
Nufail
N
Chau
Diep
D
Callus
Bernard Andrew
BA
Vince
James Edward
JE
Silke
John
J
Vaux
David Lawrence
DL
D000818:Animals; D001483:Base Sequence; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein / Q000096:biosynthesis*; D053181:Caspase 8 / Q000378:metabolism; D002470:Cell Survival / Q000502:physiology*; D002478:Cells, Cultured; D017931:DNA Primers; D005347:Fibroblasts / Q000166:cytology; D020930:MAP Kinase Kinase Kinases / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D016328:NF-kappa B / Q000502:physiology*; D015398:Signal Transduction; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000008:administration & dosage*; D000099151:MAP Kinase Kinase Kinase 7
D053446:CASP8 and FADD-Like Apoptosis Regulating Protein; D053181:Caspase 8; D017931:DNA Primers; D020930:MAP Kinase Kinase Kinases; D016328:NF-kappa B; D053221:TNF-Related Apoptosis-Inducing Ligand; D000099151:MAP Kinase Kinase Kinase 7; C506387:Cflar protein, mouse; C505654:Tnfsf10 protein, mouse