Abstract
Multiple myeloma is a fatal B cell malignancy characterized by the accumulation of plasma cells within the bone marrow. IL-6 is a major survival factor for myeloma cells. Bcl-2 protein family regulates pathways to apoptosis that are activated upon growth factor deprivation. Pro-apoptotic proteins that have only a single Bcl-2 homology domain, BH3-only, are potent inducers of apoptosis. In myeloma cells, Mcl-1 has been shown to be a major anti-apoptotic protein that appears to regulate cell survival through the JAK/STAT pathway. In this study, we examined the regulation of the BH3-only protein Bim and its interaction with Mcl-1. The three major Bim isoforms are expressed in myeloma cells and are negatively regulated by IL-6. Blockade of IL-6 signaling induces an up-regulation of Bim concomitant to Mcl-1 down-regulation. Of major interest, Bim is found strongly associated with Mcl-1 in viable myeloma cells while this interaction is disrupted under apoptosis induction. Of note, while Bim is also found strongly associated to Bcl-2, this interaction is not changed under apoptosis induction. Thus, in myeloma cells, Mcl-1 neutralizes Bim through complex formation and therefore prevents apoptosis. Under apoptosis induction, the disappearance of Mcl-1 allows Bim to exercise its pro-apoptotic function and to activate Bax.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Antineoplastic Agents / pharmacology
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Apoptosis / physiology*
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Apoptosis Regulatory Proteins
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Bcl-2-Like Protein 11
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Carrier Proteins / antagonists & inhibitors
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Carrier Proteins / biosynthesis*
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Carrier Proteins / genetics
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Carrier Proteins / immunology
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Cell Line, Tumor
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Cell Survival / physiology
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Cycloheximide / pharmacology
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Dactinomycin / pharmacology
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Humans
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Interleukin-6 / immunology
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Janus Kinase 2
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Membrane Proteins / antagonists & inhibitors
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Membrane Proteins / biosynthesis*
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Membrane Proteins / genetics
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Membrane Proteins / immunology
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Multiple Myeloma / immunology
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Multiple Myeloma / metabolism
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Multiple Myeloma / pathology*
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Myeloid Cell Leukemia Sequence 1 Protein
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Neoplasm Proteins / antagonists & inhibitors
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Neoplasm Proteins / biosynthesis*
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Neoplasm Proteins / genetics
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Neoplasm Proteins / immunology
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Protein Isoforms
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Protein Synthesis Inhibitors / pharmacology
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Protein-Tyrosine Kinases / antagonists & inhibitors
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Protein-Tyrosine Kinases / immunology
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Proto-Oncogene Proteins / antagonists & inhibitors
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Proto-Oncogene Proteins / biosynthesis*
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Proto-Oncogene Proteins / genetics
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Proto-Oncogene Proteins / immunology
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Proto-Oncogene Proteins c-bcl-2 / antagonists & inhibitors
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Proto-Oncogene Proteins c-bcl-2 / biosynthesis*
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Proto-Oncogene Proteins c-bcl-2 / genetics
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Proto-Oncogene Proteins c-bcl-2 / immunology
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Transcription, Genetic / immunology
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Tyrphostins / pharmacology
Substances
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Antineoplastic Agents
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Apoptosis Regulatory Proteins
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BCL2L11 protein, human
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Bcl-2-Like Protein 11
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Carrier Proteins
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Interleukin-6
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Membrane Proteins
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Myeloid Cell Leukemia Sequence 1 Protein
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Neoplasm Proteins
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Protein Isoforms
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Protein Synthesis Inhibitors
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Proto-Oncogene Proteins
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Proto-Oncogene Proteins c-bcl-2
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Tyrphostins
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alpha-cyano-(3,4-dihydroxy)-N-benzylcinnamide
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Dactinomycin
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Cycloheximide
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Protein-Tyrosine Kinases
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JAK2 protein, human
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Janus Kinase 2