TRAIL activates JNK and NF-κB through RIP1-dependent and -independent pathways

Cell Signal. 2015 Feb;27(2):306-14. doi: 10.1016/j.cellsig.2014.11.014. Epub 2014 Nov 18.


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.

Keywords: Apoptosis; Caspase-8; NF-κB; RIP1; TRAIL; cFLIP.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Baculoviral IAP Repeat-Containing 3 Protein
  • CASP8 and FADD-Like Apoptosis Regulating Protein / genetics
  • CASP8 and FADD-Like Apoptosis Regulating Protein / metabolism
  • Cell Line, Tumor
  • HEK293 Cells
  • Humans
  • I-kappa B Kinase / genetics
  • I-kappa B Kinase / metabolism
  • Inhibitor of Apoptosis Proteins / metabolism
  • JNK Mitogen-Activated Protein Kinases / metabolism*
  • Jurkat Cells
  • MAP Kinase Kinase Kinase 1 / metabolism
  • NF-kappa B / metabolism*
  • Nuclear Pore Complex Proteins / deficiency
  • Nuclear Pore Complex Proteins / genetics
  • Nuclear Pore Complex Proteins / metabolism*
  • RNA-Binding Proteins / genetics
  • RNA-Binding Proteins / metabolism*
  • Recombinant Proteins / biosynthesis
  • Recombinant Proteins / genetics
  • Recombinant Proteins / pharmacology
  • Signal Transduction / drug effects*
  • TNF Receptor-Associated Factor 2 / metabolism
  • TNF-Related Apoptosis-Inducing Ligand / genetics
  • TNF-Related Apoptosis-Inducing Ligand / metabolism
  • TNF-Related Apoptosis-Inducing Ligand / pharmacology*
  • Transcriptional Activation / drug effects
  • Ubiquitin-Protein Ligases / metabolism
  • Ubiquitination / drug effects


  • AGFG1 protein, human
  • CASP8 and FADD-Like Apoptosis Regulating Protein
  • Inhibitor of Apoptosis Proteins
  • NF-kappa B
  • Nuclear Pore Complex Proteins
  • RNA-Binding Proteins
  • Recombinant Proteins
  • TNF Receptor-Associated Factor 2
  • TNF-Related Apoptosis-Inducing Ligand
  • BIRC3 protein, human
  • Baculoviral IAP Repeat-Containing 3 Protein
  • Ubiquitin-Protein Ligases
  • I-kappa B Kinase
  • JNK Mitogen-Activated Protein Kinases
  • MAP Kinase Kinase Kinase 1