Two Coordinated Mechanisms Underlie Tumor Necrosis Factor Alpha-Induced Immediate and Delayed IκB Kinase Activation

Blackwell, Ken; Zhang, Laiqun; Workman, Lauren M.; Ting, Adrian T.; Iwaï, Kazuhiro; Habelhah, Hasem

doi:10.1128/mcb.01416-12

Cited by 42 publications

(49 citation statements)

References 46 publications

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“…We found in this study that the immediate, but not the delayed, phase of IKK activation is completely impaired in TRAF2-KO, TRAF2/5-DKO and IAP1-and IAP2-depleted primary cells. These results are identical to those we have reported recently in RIP1-KO MEFs (Blackwell et al, 2013). Collectively, those published findings and our current data suggest that TRAF2, Bone marrow cells that had been isolated from 8-week-old mice were cultured in 15% FBS with DMEM containing 20% L929 conditioned medium for 10 days before TNFα (5 ng/ml) treatment, and then classic IKK activity was determined by using kinase assays.…”

Section: Discussionsupporting

confidence: 81%

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TRAF2 exerts opposing effects on basal and TNFα-induced activation of the classic IKK complex in hematopoietic cells in mice

Zhang

Blackwell

Workman

et al. 2016

Journal of Cell Science

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The role of TRAF2 and TRAF5 in TNFα-induced NF-κB activation has become complicated owing to the accumulation of conflicting data. Here, we report that 7-day-old TRAF2-knockout (KO) and TRAF2 TRAF5 double KO (TRAF2/5-DKO) mice exhibit enhanced canonical IκB kinase (IKK) and caspase-8 activation in spleen and liver, and that subsequent knockout of TNFα suppresses the basal activity of caspase-8, but not of IKK. In primary TRAF2 KO and TRAF2/5-DKO cells, TNFα-induced immediate IKK activation is impaired, whereas delayed IKK activation occurs normally; as such, owing to elevated basal and TNFα-induced delayed IKK activation, TNFα stimulation leads to significantly increased induction of a subset of NF-κB-dependent genes in these cells. In line with this, both TRAF2 KO and TRAF2/5-DKO mice succumb to a sublethal dose of TNFα owing to increased expression of NF-κB target genes, diarrhea and bradypnea. Notably, depletion of IAP1 and IAP2 (also known as BIRC2 and BIRC3, respectively) also results in elevated basal IKK activation that is independent of autocrine TNFα production and that impairs TNFα-induced immediate IKK activation. These data reveal that TRAF2, IAP1 and IAP2, but not TRAF5, cooperatively regulate basal and TNFα-induced immediate IKK activation.

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Section: Discussionsupporting

confidence: 81%

“…Western blot analysis and real-time RT-PCR were performed as described previously (Blackwell et al, 2013).…”

Section: Western Blot Analysis and Real-time Rt-pcrmentioning

confidence: 99%

TRAF2 exerts opposing effects on basal and TNFα-induced activation of the classic IKK complex in hematopoietic cells in mice

Zhang

Blackwell

Workman

et al. 2016

Journal of Cell Science

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“…[5][6][7][8][9] c-IAP1/2 and LUBAC target RIP1 for K11, K63 and linear polyubiquitination priming RIP1 for the recruitment of two kinase-containing complexes, namely, TAK1/TAK1-binding protein 1 (TAB1)/TAB2 and NEMO/ inhibitor of NF-κB kinase α (IKKα)/IKKβ. 5,[10][11][12][13] Ultimately, activation of IKKβ leads to the phosphorylation and proteasomal degradation of IκBα and the nuclear translocation of NF-κB, a pathway defined as the classical, or the canonical, NF-κB pathway. [14][15][16] Besides its role in the activation of NF-κB, the dissociation of complex I from TNFR1 triggers the recruitment of Fas-associated protein with death domain (FADD) and caspase-8 to form a cytosolic death complex, initially defined as complex II.…”

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confidence: 99%

NIK promotes tissue destruction independently of the alternative NF-κB pathway through TNFR1/RIP1-induced apoptosis

et al. 2015

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NF-κB-inducing kinase (NIK) is well-known for its role in promoting p100/NF-κB2 processing into p52, a process defined as the alternative, or non-canonical, NF-κB pathway. Here we reveal an unexpected new role of NIK in TNFR1-mediated RIP1-dependent apoptosis, a consequence of TNFR1 activation observed in c-IAP1/2-depleted conditions. We show that NIK stabilization, obtained by activation of the non-death TNFRs Fn14 or LTβR, is required for TNFα-mediated apoptosis. These apoptotic stimuli trigger the depletion of c-IAP1/2, the phosphorylation of RIP1 and the RIP1 kinase-dependent assembly of the RIP1/FADD/caspase-8 complex.In the absence of NIK, the phosphorylation of RIP1 and the formation of RIP1/FADD/caspase-8 complex are compromised while c-IAP1/2 depletion is unaffected. In vitro kinase assays revealed that recombinant RIP1 is a bona fide substrate of NIK. In vivo, we demonstrated the requirement of NIK pro-death function, but not the processing of its substrate p100 into p52, in a mouse model of TNFR1/LTβR-induced thymus involution. In addition, we also highlight a role for NIK in hepatocyte apoptosis in a mouse model of virus-induced TNFR1/RIP1-dependent liver damage. We conclude that NIK not only contributes to lymphoid organogenesis, inflammation and cell survival but also to TNFR1/RIP1-dependent cell death independently of the alternative NF-κB pathway.

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“…This results in stabilization of RIP1 through K63-linked polyubiquitination and/or linear ubiquitination of the protein carried out by TRAF2/cIAPs and linear ubiquitin chain assembly complex (LUBAC), respectively (8,(11)(12)(13). K63 polyubiquitin and linear ubiquitin chains linked to RIP1 serve as substrates for binding of the TAB2/TAB3/TAK1 complex and NEMO, leading to activation of NF-kB, which plays an important role in regulating many cellular processes (11,12).…”

Section: Introductionmentioning

confidence: 99%

RIP1 Kinase Is an Oncogenic Driver in Melanoma

et al. 2015

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Although many studies have uncovered an important role for the receptor-binding protein kinase RIP1 in controlling cell death signaling, its possible contributions to cancer pathogenesis have been little explored. Here, we report that RIP1 functions as an oncogenic driver in human melanoma. Although RIP1 was commonly upregulated in melanoma, RIP1 silencing inhibited melanoma cell proliferation in vitro and retarded the growth of melanoma xenografts in vivo. Conversely, while inducing apoptosis in a small proportion of melanoma cells, RIP1 overexpression enhanced proliferation in the remaining cells. Mechanistic investigations revealed that the proliferative effects of RIP1 overexpression were mediated by NF-kB activation. Strikingly, ectopic expression of RIP1 enhanced the proliferation of primary melanocytes, triggering their anchorageindependent cell growth in an NF-kB-dependent manner. We identified DNA copy-number gain and constitutive ubiquitination by a TNFa autocrine loop mechanism as two mechanisms of RIP1 upregulation in human melanomas. Collectively, our findings define RIP1 as an oncogenic driver in melanoma, with potential implications for targeting its NF-kB-dependent activation mechanism as a novel approach to treat this disease.

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Two Coordinated Mechanisms Underlie Tumor Necrosis Factor Alpha-Induced Immediate and Delayed IκB Kinase Activation

Cited by 42 publications

References 46 publications

TRAF2 exerts opposing effects on basal and TNFα-induced activation of the classic IKK complex in hematopoietic cells in mice

TRAF2 exerts opposing effects on basal and TNFα-induced activation of the classic IKK complex in hematopoietic cells in mice

NIK promotes tissue destruction independently of the alternative NF-κB pathway through TNFR1/RIP1-induced apoptosis

RIP1 Kinase Is an Oncogenic Driver in Melanoma

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