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Proteasome inhibition upregulates Bim and induces caspase-3-dependent apoptosis in human mast cells expressing the Kit D816V mutation

The majority of patients with systemic mastocytosis exhibit a D816V mutation in the activating loop of the Kit receptor expressed on mast cells. The Kit ligand regulates mast cell survival by transcriptional repression of the proapoptotic BH3-only protein Bim and by promoting Bim phosphorylation tha...

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Autores principales: Möller Westerberg, C, Hägglund, H, Nilsson, G
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group 2012
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3542593/
https://www.ncbi.nlm.nih.gov/pubmed/23152053
http://dx.doi.org/10.1038/cddis.2012.157
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author Möller Westerberg, C
Hägglund, H
Nilsson, G
author_facet Möller Westerberg, C
Hägglund, H
Nilsson, G
author_sort Möller Westerberg, C
collection PubMed
description The majority of patients with systemic mastocytosis exhibit a D816V mutation in the activating loop of the Kit receptor expressed on mast cells. The Kit ligand regulates mast cell survival by transcriptional repression of the proapoptotic BH3-only protein Bim and by promoting Bim phosphorylation that makes it vulnerable for proteasomal-dependent degradation. We investigated here whether prevention of Bim degradation by a proteasomal inhibitor, MG132, would induce apoptosis in mast cells with the D816V mutation. Human umbilical cord blood-derived mast cells (CBMCs) with wild-type (wt) Kit and two different subclones of the human mast cell line-1 (HMC-1) were used for the study: HMC-1.1 with the V560G mutation in the juxtamembrane domain and HMC-1.2 carrying the V560G mutation together with the D816V mutation. MG132 at 1 μM induced apoptosis in all cell types, an effect accompanied by increased BH3-only proapoptotic protein Bim. The raise of Bim was accompanied by caspase-3 activation, and a caspase-3 inhibitor reduced MG132-induced apoptosis. Further, MG132 caused a reduction of activated Erk, a negative regulator of Bim expression, and thus Bim upregulation. We conclude that decreased phosphorylation and increased levels of Bim overcome the prosurvival effect of the D816V mutation and that the results warrant further investigations of the clinical effects of proteasomal inhibition in systemic mastocytosis.
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spelling pubmed-35425932013-01-11 Proteasome inhibition upregulates Bim and induces caspase-3-dependent apoptosis in human mast cells expressing the Kit D816V mutation Möller Westerberg, C Hägglund, H Nilsson, G Cell Death Dis Original Article The majority of patients with systemic mastocytosis exhibit a D816V mutation in the activating loop of the Kit receptor expressed on mast cells. The Kit ligand regulates mast cell survival by transcriptional repression of the proapoptotic BH3-only protein Bim and by promoting Bim phosphorylation that makes it vulnerable for proteasomal-dependent degradation. We investigated here whether prevention of Bim degradation by a proteasomal inhibitor, MG132, would induce apoptosis in mast cells with the D816V mutation. Human umbilical cord blood-derived mast cells (CBMCs) with wild-type (wt) Kit and two different subclones of the human mast cell line-1 (HMC-1) were used for the study: HMC-1.1 with the V560G mutation in the juxtamembrane domain and HMC-1.2 carrying the V560G mutation together with the D816V mutation. MG132 at 1 μM induced apoptosis in all cell types, an effect accompanied by increased BH3-only proapoptotic protein Bim. The raise of Bim was accompanied by caspase-3 activation, and a caspase-3 inhibitor reduced MG132-induced apoptosis. Further, MG132 caused a reduction of activated Erk, a negative regulator of Bim expression, and thus Bim upregulation. We conclude that decreased phosphorylation and increased levels of Bim overcome the prosurvival effect of the D816V mutation and that the results warrant further investigations of the clinical effects of proteasomal inhibition in systemic mastocytosis. Nature Publishing Group 2012-11 2012-11-15 /pmc/articles/PMC3542593/ /pubmed/23152053 http://dx.doi.org/10.1038/cddis.2012.157 Text en Copyright © 2012 Macmillan Publishers Limited http://creativecommons.org/licenses/by-nc-nd/3.0/ This work is licensed under the Creative Commons Attribution-NonCommercial-No Derivative Works 3.0 Unported License. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-nd/3.0/
spellingShingle Original Article
Möller Westerberg, C
Hägglund, H
Nilsson, G
Proteasome inhibition upregulates Bim and induces caspase-3-dependent apoptosis in human mast cells expressing the Kit D816V mutation
title Proteasome inhibition upregulates Bim and induces caspase-3-dependent apoptosis in human mast cells expressing the Kit D816V mutation
title_full Proteasome inhibition upregulates Bim and induces caspase-3-dependent apoptosis in human mast cells expressing the Kit D816V mutation
title_fullStr Proteasome inhibition upregulates Bim and induces caspase-3-dependent apoptosis in human mast cells expressing the Kit D816V mutation
title_full_unstemmed Proteasome inhibition upregulates Bim and induces caspase-3-dependent apoptosis in human mast cells expressing the Kit D816V mutation
title_short Proteasome inhibition upregulates Bim and induces caspase-3-dependent apoptosis in human mast cells expressing the Kit D816V mutation
title_sort proteasome inhibition upregulates bim and induces caspase-3-dependent apoptosis in human mast cells expressing the kit d816v mutation
topic Original Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3542593/
https://www.ncbi.nlm.nih.gov/pubmed/23152053
http://dx.doi.org/10.1038/cddis.2012.157
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