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

Laiqun Zhang; Martin R Dittmer; Ken Blackwell; Lauren M Workman; Bruce Hostager; Hasem Habelhah

doi:10.1016/j.cellsig.2014.11.014

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

Journal article

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

Laiqun Zhang, Martin R Dittmer, Ken Blackwell, Lauren M Workman, Bruce Hostager and Hasem Habelhah

Cellular signalling, Vol.27(2), pp.306-314

02/2015

DOI: 10.1016/j.cellsig.2014.11.014

PMCID: PMC4276503

PMID: 25446254

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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. •TRAIL induces two phases of JNK and NF-κB activation.•The early phase is activated by TRAF2/cIAP1-mediated ubiquitination of RIP1.•The delayed phase is mediated by caspase-dependent activation of MEKK1.•cFLIP exerts opposite effects on the early and delayed phases of pathway activation.•These findings clarify conflicting reports in the field of TRAIL study.

Caspase-8

NF-κB

TRAIL

cFLIP

RIP1

Apoptosis

Details

Title: Subtitle: TRAIL activates JNK and NF-κB through RIP1-dependent and -independent pathways
Creators: Laiqun Zhang - Department of Pathology, Carver College of Medicine, the University of Iowa, Iowa City, IA 52242, United States
Martin R Dittmer - Iowa Medical Student Research Program, Carver College of Medicine, the University of Iowa, Iowa City, IA 52242, United States
Ken Blackwell - Department of Pathology, Carver College of Medicine, the University of Iowa, Iowa City, IA 52242, United States
Lauren M Workman - Interdisciplinary Graduate Program in Molecular and Cellular Biology, Carver College of Medicine, the University of Iowa, Iowa City, IA 52242, United States
Bruce Hostager - Department of Pediatrics, Carver College of Medicine, the University of Iowa, Iowa City, IA 52242, United States
Hasem Habelhah - Department of Pathology, Carver College of Medicine, the University of Iowa, Iowa City, IA 52242, United States
Resource Type: Journal article
Publication Details: Cellular signalling, Vol.27(2), pp.306-314
DOI: 10.1016/j.cellsig.2014.11.014
PMID: 25446254
PMCID: PMC4276503
NLM abbreviation: Cell Signal
ISSN: 0898-6568
eISSN: 1873-3913
Publisher: Elsevier Inc
Grant note: DOI: 10.13039/501100002387, name: NCI, award: CA138475
Language: English
Date published: 02/2015
Academic Unit: Microbiology and Immunology; Pathology
Record Identifier: 9984046819902771

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