Document Detail


Cycling B-CLL cells are highly susceptible to inhibition of the proteasome: involvement of p27, early D-type cyclins, Bax, and caspase-dependent and -independent pathways.
MedLine Citation:
PMID:  12644019     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
OBJECTIVE: Although peripheral blood B-CLL cells are arrested in G0 phase of the cell cycle, a proliferating pool of cells in proliferation centers might be involved in disease progression. We have previously described an in vitro model of this proliferating pool of cells using B-CLL cells stimulated with immunostimulatory oligonucleotides (CpG-ODN) and interleukin-2. Lactacystin is a specific inhibitor of the proteasome and is a potent apoptosis inductor in resting peripheral B-CLL cells. In the present study, we investigated the effect of proteasome inhibition in proliferating B-CLL cells. METHODS: The effect of proteasome inhibition was analyzed using thymidine incorporation, annexin V assays, and TUNEL staining. Immunoblots were performed to evaluate expression of proteins involved in cell cycle and apoptosis regulation. RESULTS: Lactacystin blocked cell cycle progression in activated B-CLL cells and inhibited degradation of p27. Upregulation of cyclin D2 and D3 in activated B-CLL cells was inhibited while the expression of cdk2, cdk4, and cyclin E remained unchanged. Activated B-CLL cells were more susceptible to apoptosis induction as compared to resting B-CLL cells. Apoptosis induction was accompanied by cleavage of Bax, procaspase 8, procaspase 9, and procaspase 3. However, a broad-spectrum caspase inhibitor (z-VAD.fmk) only partially inhibited cell death although DNA degradation was completely inhibited. CONCLUSION: Proteasome inhibition is highly effective in proliferating B-CLL cells and induces apoptosis using a caspase-dependent and -independent pathway.
Authors:
Christian Bogner; Folker Schneller; Susanne Hipp; Ingo Ringshausen; Christian Peschel; Thomas Decker
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  Experimental hematology     Volume:  31     ISSN:  0301-472X     ISO Abbreviation:  Exp. Hematol.     Publication Date:  2003 Mar 
Date Detail:
Created Date:  2003-03-19     Completed Date:  2003-05-09     Revised Date:  2007-11-15    
Medline Journal Info:
Nlm Unique ID:  0402313     Medline TA:  Exp Hematol     Country:  Netherlands    
Other Details:
Languages:  eng     Pagination:  218-25     Citation Subset:  IM    
Copyright Information:
Copyright 2003 International Society for Experimental Hematology
Affiliation:
IIIrd Department of Medicine, Technical University of Munich, Munich, Germany.
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MeSH Terms
Descriptor/Qualifier:
Acetylcysteine / analogs & derivatives*,  pharmacology
Apoptosis / drug effects
Caspases / drug effects,  metabolism
Cell Cycle*
Cell Cycle Proteins / drug effects*
Cell Division / drug effects
Cyclin-Dependent Kinase Inhibitor p27
Cyclins / drug effects
Cysteine Endopeptidases
Cysteine Proteinase Inhibitors / pharmacology*
Dose-Response Relationship, Drug
Humans
Leukemia, Lymphocytic, Chronic, B-Cell / pathology*
Multienzyme Complexes / antagonists & inhibitors*
Proteasome Endopeptidase Complex
Proto-Oncogene Proteins / drug effects,  metabolism
Proto-Oncogene Proteins c-bcl-2*
Tumor Suppressor Proteins / drug effects
bcl-2-Associated X Protein
Chemical
Reg. No./Substance:
0/BAX protein, human; 0/Cell Cycle Proteins; 0/Cyclins; 0/Cysteine Proteinase Inhibitors; 0/Multienzyme Complexes; 0/Proto-Oncogene Proteins; 0/Proto-Oncogene Proteins c-bcl-2; 0/Tumor Suppressor Proteins; 0/bcl-2-Associated X Protein; 133343-34-7/lactacystin; 147604-94-2/Cyclin-Dependent Kinase Inhibitor p27; 616-91-1/Acetylcysteine; EC 3.4.22.-/Caspases; EC 3.4.22.-/Cysteine Endopeptidases; EC 3.4.25.1/Proteasome Endopeptidase Complex

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