title: TRAIL activates JNK and NF-κB through RIP1-dependent and -independent pathways.
abstract: The death receptor (DR) ligand TRAIL is being evaluated in clinical trials as an anti-cancer agent; however, many studies have found that TRAIL also enhances tumor progression by activating the NF-κB pathway in apoptosis-resistant cells. Although RIP1, cFLIP and caspase-8 have been implicated in TRAIL-induced JNK and NF-κB activation, underlying mechanisms are unclear. By examining the kinetics of pathway activation in TRAIL-sensitive lymphoma cells wild-type or deficient for RIP1, TRAF2, cIAP1/2 or HOIP, we report here that TRAIL induces two phases of JNK and NF-κB activation. The early phase is activated by TRAF2- and cIAP1-mediated ubiquitination of RIP1, whereas the delayed phase is induced by caspase-dependent activation of MEKK1 independent of RIP1 and TRAF2 expression. cFLIP overexpression promotes the early phase but completely suppresses the delayed phase of pathway activation in lymphoma cells, whereas Bcl-2 overexpression promotes both the early and delayed phases of the pathways. In addition, stable overexpression of cFLIP in RIP1- or TRAF2-deficient cells confers resistance to apoptosis, but fails to mediate NF-κB activation. HOIP is not essential for, but contributes to, TRAIL-induced NF-κB activation in cFLIP-overexpressing cells. These findings not only elucidate details of the mechanisms underlying TRAIL-induced JNK and NF-κB activation, but also clarify conflicting reports in the field.
authors.affiliation: Department of Pathology, Carver College of Medicine, the University of Iowa, Iowa City, IA 52242, United States.
authors.forename: Laiqun
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Iowa Medical Student Research Program, Carver College of Medicine, the University of Iowa, Iowa City, IA 52242, United States.
authors.forename: Martin R
authors.initials: MR
authors.lastname: Dittmer
authors.affiliation: Department of Pathology, Carver College of Medicine, the University of Iowa, Iowa City, IA 52242, United States.
authors.forename: Ken
authors.initials: K
authors.lastname: Blackwell
authors.affiliation: Interdisciplinary Graduate Program in Molecular and Cellular Biology, Carver College of Medicine, the University of Iowa, Iowa City, IA 52242, United States.
authors.forename: Lauren M
authors.initials: LM
authors.lastname: Workman
authors.affiliation: Department of Pediatrics, Carver College of Medicine, the University of Iowa, Iowa City, IA 52242, United States.
authors.forename: Bruce
authors.initials: B
authors.lastname: Hostager
authors.affiliation: Department of Pathology, Carver College of Medicine, the University of Iowa, Iowa City, IA 52242, United States. Electronic address: hasem-habelhah@uiowa.edu.
authors.forename: Hasem
authors.initials: H
authors.lastname: Habelhah
mesh_terms: D000075747:Baculoviral IAP Repeat-Containing 3 Protein; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D057809:HEK293 Cells; D006801:Humans; D051550:I-kappa B Kinase / Q000235:genetics / Q000378:metabolism; D051034:Inhibitor of Apoptosis Proteins / Q000378:metabolism; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism*; D019169:Jurkat Cells; D048728:MAP Kinase Kinase Kinase 1 / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism*; D028861:Nuclear Pore Complex Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D016601:RNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D011994:Recombinant Proteins / Q000096:biosynthesis / Q000235:genetics / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects*; D047992:TNF Receptor-Associated Factor 2 / Q000378:metabolism; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology*; D015533:Transcriptional Activation / Q000187:drug effects; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism; D054875:Ubiquitination / Q000187:drug effects
chemical_list: C119724:AGFG1 protein, human; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein; D051034:Inhibitor of Apoptosis Proteins; D016328:NF-kappa B; D028861:Nuclear Pore Complex Proteins; D016601:RNA-Binding Proteins; D011994:Recombinant Proteins; D047992:TNF Receptor-Associated Factor 2; D053221:TNF-Related Apoptosis-Inducing Ligand; C494832:BIRC3 protein, human; D000075747:Baculoviral IAP Repeat-Containing 3 Protein; D044767:Ubiquitin-Protein Ligases; D051550:I-kappa B Kinase; D048031:JNK Mitogen-Activated Protein Kinases; D048728:MAP Kinase Kinase Kinase 1
keywords: Apoptosis; Caspase-8; NF-κB; RIP1; TRAIL; cFLIP