| Noxa/Bcl-2 protein interactions contribute to bortezomib resistance in human lymphoid cells. | |
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MedLine Citation:
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PMID: 21454712 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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Previous studies have suggested that the BH3 domain of the proapoptotic Bcl-2 family member Noxa only interacts with the anti-apoptotic proteins Mcl-1 and A1 but not Bcl-2. In view of the similarity of the BH3 binding domains of these anti-apoptotic proteins as well as recent evidence that studies of isolated BH3 domains can potentially underestimate the binding between full-length Bcl-2 family members, we examined the interaction of full-length human Noxa with anti-apoptotic human Bcl-2 family members. Surface plasmon resonance using bacterially expressed proteins demonstrated that Noxa binds with mean dissociation constants (K(D)) of 3.4 nm for Mcl-1, 70 nm for Bcl-x(L), and 250 nm for wild type human Bcl-2, demonstrating selectivity but not absolute specificity of Noxa for Mcl-1. Further analysis showed that the Noxa/Bcl-2 interaction reflected binding between the Noxa BH3 domain and the Bcl-2 BH3 binding groove. Analysis of proteins expressed in vivo demonstrated that Noxa and Bcl-2 can be pulled down together from a variety of cells. Moreover, when compared with wild type Bcl-2, certain lymphoma-derived Bcl-2 mutants bound Noxa up to 20-fold more tightly in vitro, pulled down more Noxa from cells, and protected cells against killing by transfected Noxa to a greater extent. When killing by bortezomib (an agent whose cytotoxicity in Jurkat T-cell leukemia cells is dependent on Noxa) was examined, apoptosis was enhanced by the Bcl-2/Bcl-x(L) antagonist ABT-737 or by Bcl-2 down-regulation and diminished by Bcl-2 overexpression. Collectively, these observations not only establish the ability of Noxa and Bcl-2 to interact but also identify Bcl-2 overexpression as a potential mechanism of bortezomib resistance. |
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Authors:
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Alyson J Smith; Haiming Dai; Cristina Correia; Rie Takahashi; Sun-Hee Lee; Ingo Schmitz; Scott H Kaufmann |
Publication Detail:
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Type: Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't Date: 2011-03-22 |
Journal Detail:
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Title: The Journal of biological chemistry Volume: 286 ISSN: 1083-351X ISO Abbreviation: J. Biol. Chem. Publication Date: 2011 May |
Date Detail:
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Created Date: 2011-05-16 Completed Date: 2011-07-26 Revised Date: 2012-09-18 |
Medline Journal Info:
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Nlm Unique ID: 2985121R Medline TA: J Biol Chem Country: United States |
Other Details:
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Languages: eng Pagination: 17682-92 Citation Subset: IM |
Copyright Information:
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© 2011 by The American Society for Biochemistry and Molecular Biology, Inc. |
Affiliation:
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Department of Molecular Pharmacology, Mayo Clinic, Rochester, Minnesota 55905, USA. |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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Antineoplastic Agents
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pharmacology* Apoptosis / drug effects Boronic Acids / pharmacology* Drug Resistance, Neoplasm / drug effects* Hematologic Neoplasms / genetics, metabolism Humans Jurkat Cells Lymphocytes / metabolism* Protein Binding Protein Structure, Tertiary Proto-Oncogene Proteins c-bcl-2 / genetics, metabolism* Pyrazines / pharmacology* |
| Grant Support | |
ID/Acronym/Agency:
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R01 CA69008/CA/NCI NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/Antineoplastic Agents; 0/Boronic Acids; 0/PMAIP1 protein, human; 0/Proto-Oncogene Proteins c-bcl-2; 0/Pyrazines; 0/bortezomib; 0/myeloid cell leukemia sequence 1 protein |
| Comments/Corrections | |
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