| Anti-apoptotic Bcl-2 fails to form efficient complexes with pro-apoptotic Bak to protect from Celecoxib-induced apoptosis. | |
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MedLine Citation:
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PMID: 20836993 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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The non-steroidal anti-inflammatory drug Celecoxib is a specific inhibitor of cyclooxygenase-2. Apart from its inhibitor function, Celecoxib induces apoptosis through the intrinsic pathway which is controlled by the Bcl-2 family members. In Jurkat T lymphoma cells, treatment with Celecoxib results in a rapid decline of the anti-apoptotic Bcl-2-related protein Mcl-1. The depletion of Mcl-1 is sufficient for apoptosis induction and can be blocked by overexpression of Bcl-xL but not by the close homologue Bcl-2. The present investigation analyzed the mechanism by which Bcl-xL prevents apoptosis induction whereas Bcl-2 failed to. Our data show that the involvement of the orphan nuclear receptor Nur77/TR3 specifically targeting Bcl-2 but not Bcl-xL was not involved in Celecoxib-induced apoptosis. Surprisingly, BH3-only proteins Bid, Bim, and Puma of the Bcl-2 family were not needed either. However, unlike Bcl-2, Mcl-1, and Bcl-xL sequestered Bak preventing it from activation through a direct interaction. Thus, when abundantly expressed, Bcl-xL can substitute for the loss of Mcl-1 whereas Bcl-2, incapable of forming a high affinity complex with Bak, could not. |
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Authors:
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Justine Rudner; Simon J Elsaesser; Verena Jendrossek; Stephan M Huber |
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Publication Detail:
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Type: Journal Article; Research Support, Non-U.S. Gov't Date: 2010-09-15 |
Journal Detail:
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Title: Biochemical pharmacology Volume: 81 ISSN: 1873-2968 ISO Abbreviation: Biochem. Pharmacol. Publication Date: 2011 Jan |
Date Detail:
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Created Date: 2010-11-24 Completed Date: 2010-12-30 Revised Date: - |
Medline Journal Info:
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Nlm Unique ID: 0101032 Medline TA: Biochem Pharmacol Country: England |
Other Details:
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Languages: eng Pagination: 32-42 Citation Subset: IM |
Copyright Information:
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Copyright © 2010 Elsevier Inc. All rights reserved. |
Affiliation:
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Department of Radiation Oncology, University Hospital of Tübingen, Hoppe-Seyler-Str. 3, 72076 Tübingen, Germany. justine.rudner@med.uni-tuebingen.de |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Apoptosis
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drug effects* Cyclooxygenase 2 Inhibitors / pharmacology* Gene Expression Regulation Humans Jurkat Cells Nuclear Receptor Subfamily 4, Group A, Member 1 / genetics, metabolism Proto-Oncogene Proteins c-bcl-2 / genetics, metabolism* Pyrazoles / pharmacology* Sulfonamides / pharmacology* bcl-2 Homologous Antagonist-Killer Protein / genetics, metabolism* bcl-X Protein / genetics, metabolism |
| Chemical | |
Reg. No./Substance:
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0/BCL2L1 protein, human; 0/Cyclooxygenase 2 Inhibitors; 0/NR4A1 protein, human; 0/Nuclear Receptor Subfamily 4, Group A, Member 1; 0/Proto-Oncogene Proteins c-bcl-2; 0/Pyrazoles; 0/Sulfonamides; 0/bcl-2 Homologous Antagonist-Killer Protein; 0/bcl-X Protein; 0/myeloid cell leukemia sequence 1 protein; 169590-42-5/celecoxib |
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