The imbalance between Bim and Mcl-1 expression controls the survival of human myeloma cells.
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.
INSERM, U601, Département de Cancérologie LNC Label, Institut de Biologie, Nantes, France.
Patricia
P
Gomez-Bougie
Régis
R
Bataille
Martine
M
Amiot
D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000502:physiology*; D051017:Apoptosis Regulatory Proteins; D000072224:Bcl-2-Like Protein 11; D002352:Carrier Proteins / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000235:genetics / Q000276:immunology; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000502:physiology; D003513:Cycloheximide / Q000494:pharmacology; D003609:Dactinomycin / Q000494:pharmacology; D006801:Humans; D015850:Interleukin-6 / Q000276:immunology; D053614:Janus Kinase 2; D008565:Membrane Proteins / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000235:genetics / Q000276:immunology; D009101:Multiple Myeloma / Q000276:immunology / Q000378:metabolism / Q000473:pathology*; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000235:genetics / Q000276:immunology; D020033:Protein Isoforms; D011500:Protein Synthesis Inhibitors / Q000494:pharmacology; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000276:immunology; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000235:genetics / Q000276:immunology; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000235:genetics / Q000276:immunology; D014158:Transcription, Genetic / Q000276:immunology; D020032:Tyrphostins / Q000494:pharmacology
D000970:Antineoplastic Agents; D051017:Apoptosis Regulatory Proteins; C000606775:BCL2L11 protein, human; D000072224:Bcl-2-Like Protein 11; D002352:Carrier Proteins; D015850:Interleukin-6; D008565:Membrane Proteins; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D009363:Neoplasm Proteins; D020033:Protein Isoforms; D011500:Protein Synthesis Inhibitors; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D020032:Tyrphostins; C095512:alpha-cyano-(3,4-dihydroxy)-N-benzylcinnamide; D003609:Dactinomycin; D003513:Cycloheximide; D011505:Protein-Tyrosine Kinases; C507924:JAK2 protein, human; D053614:Janus Kinase 2