title: TAK1 is required for survival of mouse fibroblasts treated with TRAIL, and does so by NF-kappaB dependent induction of cFLIPL.
abstract: 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.
authors.affiliation: Deparment of Biochemistry, La Trobe University, Bundoora, Australia.
authors.forename: Josep Maria
authors.initials: JM
authors.lastname: Lluis
authors.forename: Ulrich
authors.initials: U
authors.lastname: Nachbur
authors.forename: Wendy Diane
authors.initials: WD
authors.lastname: Cook
authors.forename: Ian Edward
authors.initials: IE
authors.lastname: Gentle
authors.forename: Donia
authors.initials: D
authors.lastname: Moujalled
authors.forename: Maryline
authors.initials: M
authors.lastname: Moulin
authors.forename: Wendy Wei-Lynn
authors.initials: WW
authors.lastname: Wong
authors.forename: Nufail
authors.initials: N
authors.lastname: Khan
authors.forename: Diep
authors.initials: D
authors.lastname: Chau
authors.forename: Bernard Andrew
authors.initials: BA
authors.lastname: Callus
authors.forename: James Edward
authors.initials: JE
authors.lastname: Vince
authors.forename: John
authors.initials: J
authors.lastname: Silke
authors.forename: David Lawrence
authors.initials: DL
authors.lastname: Vaux
mesh_terms: 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
chemical_list: 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