Document Detail


Anti-apoptotic Bcl-2 fails to form efficient complexes with pro-apoptotic Bak to protect from Celecoxib-induced apoptosis.
MedLine Citation:
PMID:  20836993     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
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.
Authors:
Justine Rudner; Simon J Elsaesser; Verena Jendrossek; Stephan M Huber
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2010-09-15
Journal Detail:
Title:  Biochemical pharmacology     Volume:  81     ISSN:  1873-2968     ISO Abbreviation:  Biochem. Pharmacol.     Publication Date:  2011 Jan 
Date Detail:
Created Date:  2010-11-24     Completed Date:  2010-12-30     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  0101032     Medline TA:  Biochem Pharmacol     Country:  England    
Other Details:
Languages:  eng     Pagination:  32-42     Citation Subset:  IM    
Copyright Information:
Copyright © 2010 Elsevier Inc. All rights reserved.
Affiliation:
Department of Radiation Oncology, University Hospital of Tübingen, Hoppe-Seyler-Str. 3, 72076 Tübingen, Germany. justine.rudner@med.uni-tuebingen.de
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MeSH Terms
Descriptor/Qualifier:
Apoptosis / 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:
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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