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1.
Cell Death Dis ; 10(8): 611, 2019 08 13.
Artigo em Inglês | MEDLINE | ID: mdl-31406107

RESUMO

The NEDD8-activating enzyme (NAE) inhibitor MLN4924 inhibits cullin-RING ubiquitin ligase complexes including the SKP1-cullin-F-box E3 ligase ßTrCP. MLN4924 therefore inhibits also the ßTrCP-dependent activation of the classical and the alternative NFĸB pathway. In this work, we found that a subgroup of multiple myeloma cell lines (e.g., RPMI-8226, MM.1S, KMS-12BM) and about half of the primary myeloma samples tested are sensitized to TNF-induced cell death by MLN4924. This correlated with MLN4924-mediated inhibition of TNF-induced activation of the classical NFκB pathway and reduced the efficacy of TNF-induced TNFR1 signaling complex formation. Interestingly, binding studies revealed a straightforward correlation between cell surface TNFR1 expression in multiple myeloma cell lines and their sensitivity for MLN4924/TNF-induced cell death. The cell surface expression levels of TNFR1 in the investigated MM cell lines largely correlated with TNFR1 mRNA expression. This suggests that the variable levels of cell surface expression of TNFR1 in myeloma cell lines are decisive for TNF/MLN4924 sensitivity. Indeed, introduction of TNFR1 into TNFR1-negative TNF/MLN4924-resistant KMS-11BM cells, was sufficient to sensitize this cell line for TNF/MLN4924-induced cell death. Thus, MLN4924 might be especially effective in myeloma patients with TNFR1+ myeloma cells and a TNFhigh tumor microenvironment.


Assuntos
Apoptose/efeitos dos fármacos , Ciclopentanos/farmacologia , Mieloma Múltiplo/patologia , Pirimidinas/farmacologia , Receptores Tipo I de Fatores de Necrose Tumoral/metabolismo , Fator de Necrose Tumoral alfa/farmacologia , Enzimas Ativadoras de Ubiquitina/antagonistas & inibidores , Adulto , Idoso , Bortezomib/farmacologia , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , NF-kappa B/metabolismo , Necrose , Oligopeptídeos/farmacologia , Transdução de Sinais/efeitos dos fármacos , Enzimas Ativadoras de Ubiquitina/metabolismo
2.
J Immunol ; 185(3): 1593-605, 2010 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-20610643

RESUMO

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. Like other soluble TNF ligands with a poor capability to activate their corresponding receptor, sTWEAK acquires an activity resembling those of the transmembrane ligand by oligomerization or cell surface-immobilization. Blockade of the Fn14 receptor inhibited NF-kappaB signaling irrespective of the TWEAK form used for stimulation, indicating that the differential activities of the two TWEAK variants on classical and noncanonical NF-kappaB signaling is not related to the use of different receptors.


Assuntos
Proteínas de Membrana/fisiologia , NF-kappa B/metabolismo , Receptores do Fator de Necrose Tumoral/fisiologia , Transdução de Sinais/imunologia , Animais , Apoptose/imunologia , Linhagem Celular Tumoral , Células Cultivadas , Técnicas de Cocultura , Células HT29 , Células HeLa , Humanos , Ligantes , Proteínas de Membrana/genética , Camundongos , NF-kappa B/fisiologia , Subunidade p52 de NF-kappa B/metabolismo , Processamento de Proteína Pós-Traducional/imunologia , Proteínas Serina-Treonina Quinases/metabolismo , Receptores do Fator de Necrose Tumoral/genética , Proteínas Recombinantes/metabolismo , Solubilidade , Fator 2 Associado a Receptor de TNF/antagonistas & inibidores , Fator 2 Associado a Receptor de TNF/metabolismo , Receptor de TWEAK , Quinase Induzida por NF-kappaB
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