| Evidence for the critical roles of NF-κB p65 and specificity proteins in the apoptosis-inducing activity of proteasome inhibitors in leukemia cells. | |
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MedLine Citation:
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PMID: 22265847 Owner: NLM Status: Publisher |
Abstract/OtherAbstract:
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Although proteasome inhibitors, such as Bortezomib, have been approved for the treatment of multiple myeloma and mantle cell lymphoma, the mechanism by which they induce apoptosis is still incompletely understood. In the present study, we demonstrate that genetic deletion of the NF-κB p65 subunit abolished the ability of Bortezomib to induce apoptosis, indicating that p65 is needed for apoptosis. Although Bortezomib inhibited TNF-induced NF-κB activation through suppression of IκBα degradation, it also induced proteolytic degradation of constitutive NF-κB proteins, including p65, IκBα and p105. These effects were also observed with two other proteasome inhibitors, N-acetyl-leucylleucyl-norleucinal (ALLN) and MG132. The p65 is known to be linked with Specific proteins (Sp), and we found that proteasome inhibition also induced degradation of Sp-1, Sp-3, and Sp-4 proteins. Bortezomib induced apoptosis in cells expressing caspase-3 but not in cells that lack caspase-3, indicating the critical role for this enzyme in the apoptotic action of Bortezomib. Furthermore, inhibition of pan-caspases abolished Bortezomib-induced degradation of p65, p105 and Sp proteins, but not that of IκBα. Overall, our results demonstrate for the first time a critical role for the degradation of NF-κB and Sp proteins by caspases in the apoptosis-inducing activity of proteasome inhibitors, such as Bortezomib. |
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Authors:
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Simone Reuter; Subash C Gupta; Ramaswamy Kannappan; Bharat B Aggarwal |
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Publication Detail:
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Type: JOURNAL ARTICLE Date: 2012-1-10 |
Journal Detail:
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Title: Biochimica et biophysica acta Volume: - ISSN: 0006-3002 ISO Abbreviation: - Publication Date: 2012 Jan |
Date Detail:
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Created Date: 2012-1-23 Completed Date: - Revised Date: - |
Medline Journal Info:
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Nlm Unique ID: 0217513 Medline TA: Biochim Biophys Acta Country: - |
Other Details:
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Languages: ENG Pagination: - Citation Subset: - |
Copyright Information:
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Copyright © 2012. Published by Elsevier B.V. |
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From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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