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

Content Provider	World Health Organization (WHO)-Global Index Medicus
Author	Westerberg, C. Möller Hägglund, H. Nilsson, G.
Description	Country affiliation: Sweden Author Affiliation: Westerberg CM ( Department of Medicine, Karolinska Institutet, Stockholm, Sweden. Christine.Moller@ki.se)
Abstract	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.
File Format	HTM / HTML
e-ISSN	20414889
DOI	10.1038/cddis.2012.157
Journal	Cell Death and Disease
Volume Number	3
Language	English
Publisher	Nature Publishing Group
Publisher Date	2012-11-15
Publisher Place	Great Britain (UK)
Access Restriction	Open
Subject Keyword	Cell Line Research Support, Non-u.s. Gov't Phosphorylation Proto-oncogene Proteins Cytology Mutation, Missense Metabolism Proteasome Endopeptidase Complex Physiopathology Membrane Proteins Discipline Cell Biology Apoptosis Regulatory Proteins Proteolysis Down-regulation Up-regulation Caspase 3 Genetics Mastocytosis, Systemic Proto-oncogene Proteins C-kit Enzymology Apoptosis Mast Cells
Content Type	Text
Resource Type	Article

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