Abstract
Novel agents that target the proteasome, a proteolytic complex responsible for the degradation of ubiquitinated proteins, have demonstrated remarkable therapeutic efficacy in multiple myeloma, a plasma cell malignancy. However, the mechanism by which these compounds act remains unknown. A signaling pathway called the unfolded protein response (UPR) allows cells to handle the proper folding of proteins. The transcription factor XBP-1, a regulator of the UPR, is also required for plasma cell differentiation, suggesting a link between the UPR and plasma cell differentiation. Here we show that proteasome inhibitors target XBP-1 and the UPR in myeloma cells. Proteasome inhibitors suppress the activity of the translumenal endoplasmic reticulum endoribonuclease/kinase, IRE1 alpha, to impair the generation of the active, spliced XBP-1 species and simultaneously stabilize the unspliced species that acts as a dominant negative. Myeloma cells rendered functionally deficient in XBP-1 undergo increased apoptosis in response to endoplasmic reticulum stress. Identification of compounds that target the activity of IRE1 alpha/XBP-1 may yield novel therapies for the treatment of multiple myeloma and other malignancies that rely on an intact UPR.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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3T3 Cells
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Animals
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Apoptosis / drug effects
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Cysteine Endopeptidases
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Cysteine Proteinase Inhibitors / pharmacology*
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DNA-Binding Proteins / genetics
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DNA-Binding Proteins / metabolism
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Endoplasmic Reticulum / drug effects
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Endoribonucleases
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Humans
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Leupeptins / pharmacology
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Membrane Proteins*
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Mice
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Multienzyme Complexes / antagonists & inhibitors*
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Multiple Myeloma / drug therapy*
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Multiple Myeloma / genetics
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Multiple Myeloma / metabolism*
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Neoplasm Proteins / genetics
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Neoplasm Proteins / metabolism
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Proteasome Endopeptidase Complex
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Protein Folding*
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Protein Serine-Threonine Kinases / metabolism
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RNA Splicing / drug effects
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Regulatory Factor X Transcription Factors
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Transcription Factors / genetics
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Transcription Factors / metabolism
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Tumor Cells, Cultured
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Tunicamycin / pharmacology
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X-Box Binding Protein 1
Substances
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Cysteine Proteinase Inhibitors
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DNA-Binding Proteins
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Leupeptins
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Membrane Proteins
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Multienzyme Complexes
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Neoplasm Proteins
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Regulatory Factor X Transcription Factors
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Transcription Factors
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X-Box Binding Protein 1
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XBP1 protein, human
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Xbp1 protein, mouse
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Tunicamycin
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ERN2 protein, human
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Ern2 protein, mouse
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Protein Serine-Threonine Kinases
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Endoribonucleases
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Cysteine Endopeptidases
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Proteasome Endopeptidase Complex
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benzyloxycarbonylleucyl-leucyl-leucine aldehyde