Molecular Determinants of Kinase Pathway Activation by Apo2 Ligand/Tumor Necrosis Factor-related Apoptosis-inducing Ligand

Varfolomeev, Eugene; Maecker, Heather; Sharp, Darcie; Lawrence, David A.; Renz, Mark; Vucic, Domagoj; Ashkenazi, Avi

doi:10.1074/jbc.m509560200

Cited by 252 publications

(273 citation statements)

References 58 publications

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“…For example, in addition to promoting cell survival through nuclear factor (NF)-kB, under certain circumstances, TNFR1 may also induce cell death through the assembly of two alternative signaling platforms (complex IIa and IIb), both of which recruit FADD and caspase-8 (Wilson et al, 2009). Similarly, under specific conditions, DR4 and/or DR5 may trigger the NF-kB and mitogenactivated protein kinase (MAPK) pathways, by promoting the recruitment of RIP1, TRAF2 and NEMO/ IKK-g into a secondary intracellular complex seeded downstream of the DISC by FADD and caspase-8 (Varfolomeev et al, 2005).…”

Section: Drsmentioning

confidence: 99%

New insights into apoptosis signaling by Apo2L/TRAIL

2010

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Section: Drsmentioning

confidence: 99%

New insights into apoptosis signaling by Apo2L/TRAIL

2010

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“…However, the significance of TRAIL-induced cytokine production is still not fully understood. It is conceivable that these cytokines may elicit both autocrine and paracrine effects on tumor cells and stromal cells [14,18,19]. Several studies indicate that TRAIL-induced cytokine production could counterbalance TRAIL apoptotic effects [16,20,21].…”

Section: Introductionmentioning

confidence: 99%

Multiple effects of TRAIL in human carcinoma cells: Induction of apoptosis, senescence, proliferation, and cytokine production

Levina

Marrangoni

DeMarco

et al. 2008

Experimental Cell Research

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TRAIL is a death ligand that induces apoptosis in malignant but not normal cells. Recently the ability of TRAIL to induce proliferation in apoptosis-resistant normal and malignant cells was reported. In this study, we analyzed TRAIL effects in apoptosis sensitive MCF7, OVCAR3 and H460 human tumor cell lines. TRAIL at low concentrations preferentially induced cell proliferation. At 100 ng/ ml apoptotic death was readily observed, however surviving cells acquired higher proliferative capacity. TRAIL stimulated production of several cytokines, IL-8, RANTES, MCP-1 and bFGF, and activation of caspases 1 and 8 was essential for this effect. Antibodies to IL-8, RANTES, and bFGF blocked TRAIL-induced cell proliferation and further stimulated apoptosis. For the first time, we report that high TRAIL concentrations induced cell senescence as determined by altered morphology and expression of several senescence markers: SA-β-gal, p21 Waf1/Cip1 , p16 INK4a , and HMGA. Caspase 9 inhibition protected TRAIL-treated cells from senescence, whereas inhibition of caspases 1 and 8 increased yield of SLP cells. In conclusion, in cultured human carcinoma cells, TRAIL therapy results in three functional outcomes, apoptosis, proliferation and senescence. TRAIL induced proapoptotic and prosurvival responses correlate with strength of signaling. TRAIL-induced cytokine production is responsible for its proliferative and prosurvival effects.

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“…This secondary complex is hypothesized to activate the IKK, allowing for NF-KB activation and transcription. In fact, besides activating the NF-KB pathway it is also believed to signal through MAPK, JNK and p38 (Varfolomeev et al, 2005). The NF-KB induction has been correlated with TRAIL resistance in multiple cell lines, supporting the proposal of its activity as TRAIL-regulatory (Ravi et al, 2006, Zwacka et al, 2000.…”

Section: Trail: Other Signaling Pathwaysmentioning

confidence: 86%