The NEDD8-activating enzyme inhibitor MLN4924 sensitizes a TNFR1 subgroup of multiple myeloma cells for TNF-induced cell death.

The NEDD8-activating enzyme (NAE) inhibitor MLN4924 inhibits cullin-RING ubiquitin ligase complexes including the SKP1-cullin-F-box E3 ligase βTrCP. MLN4924 therefore inhibits also the βTrCP-dependent activation of the classical and the alternative NFĸB pathway. In this work, we found that a subgroup of multiple myeloma cell lines (e.

Soluble and transmembrane TNF-like weak inducer of apoptosis differentially activate the classical and noncanonical NF-kappa B pathway.

TNF-like weak inducer of apoptosis, TWEAK, is a typical member of the TNF ligand family. Thus, it is initially expressed as a type II transmembrane protein from which a soluble variant can be released by proteolytic processing. In this study, we show that membrane TWEAK is superior to soluble variant of TWEAK (sTWEAK) with respect to the activation of the classical NF-kappaB pathway, whereas both TWEAK variants are potent inducers of TNFR-associated factor-2 depletion, NF-kappaB-inducing kinase accumulation and p100 processing, hallmarks of activation of the noncanonical NF-kappaB pathway.