The DOI matches its Crossref record; 47 of the 47 references it cites were found in a registry or an index.
Proteasome inhibitors disrupt the unfolded protein response in myeloma cells
Open accessAbstract
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, IRE1α, 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 IRE1α/XBP-1 may yield novel therapies for the treatment of multiple myeloma and other malignancies that rely on an intact UPR.
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Cites
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Cited by
Mechanisms, regulation and functions of the unfolded protein response
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Self-citation
Metadata
- Authors
- Lee, A.-H., Iwakoshi, N. N., Anderson, K. C., & Glimcher, L. H.
- Venue
- Proceedings of the National Academy of Sciences
- Published
- 2003-08-05
- Volume
- 100
- Issue
- 17
- Pages
- 9946-9951
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- OpenAlex
- W2072714194
- Cited by
- 601
- References
- 47
- FWCI
- 9.27
- Type
- journal article
- Language
- en
- Open access
- green
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