| Apoptosis in hematopoietic cells (FL5.12) caused by interleukin-3 withdrawal: relationship to caspase activity and the loss of glutathione. | |
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MedLine Citation:
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PMID: 10200549 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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The mechanism of cell death caused by cytokine deprivation remains largely unknown. FL5.12 cells (a murine prolymphocytic cell line), following interleukin-3 (IL-3) withdrawal, undergo a decrease in intracellular glutathione (GSH) that precedes the onset of apoptosis. In the present study, the induction of apoptosis following IL-3 withdrawal or GSH depletion with DL-buthionine-[S,R,]-sulfoximine (BSO) was examined. Both conditions caused time-dependent increases in phosphatidylserine externalization, acridine orange and ethidium bromide staining, decreases in mitochondrial membrane potential, processing and activation of caspase-3 and proteolysis of the endogenous caspase substrate poly(adenosine diphosphate ribose)polymerase (PARP). Apoptosis induced by IL-3 deprivation but not BSO also caused lamin B1 cleavage, suggesting activation of caspase-6. Despite a more profound depletion of GSH after BSO than withdrawal of IL-3, the extent of apoptosis was somewhat lower. Benzyloxycarbonyl-Val-Ala-Asp(OMe)fluoromethyl ketone (z-VAD.fmk) blocked this caspase activity and prevented cell death after BSO exposure but not after IL-3 deprivation. Following IL-3 withdrawal, the caspase inhibitors z-VAD.fmk and boc-asp(OMe)fluoromethylketone (boc-asp.fmk) prevented the cleavage and activation of caspase-3, the breakdown of lamin B1 and partially mitigated PARP degradation. However, the externalization of phosphatidylserine, the fall in mitochondrial membrane potential and subsequent apoptotic cell death still occurred. These results suggest that IL-3 withdrawal may mediate cell death by a mechanism independent of both caspase activation and the accompanying loss of GSH. |
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Authors:
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H K Bojes; X Feng; J P Kehrer; G M Cohen |
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Publication Detail:
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Type: Journal Article; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, P.H.S. |
Journal Detail:
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Title: Cell death and differentiation Volume: 6 ISSN: 1350-9047 ISO Abbreviation: Cell Death Differ. Publication Date: 1999 Jan |
Date Detail:
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Created Date: 1999-04-29 Completed Date: 1999-04-29 Revised Date: 2007-11-14 |
Medline Journal Info:
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Nlm Unique ID: 9437445 Medline TA: Cell Death Differ Country: ENGLAND |
Other Details:
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Languages: eng Pagination: 61-70 Citation Subset: IM |
Affiliation:
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Division of Pharmacology and Toxicology, College of Pharmacy, The University of Texas at Austin, Texas, USA. |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Amino Acid Chloromethyl Ketones
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pharmacology Animals Apoptosis* Buthionine Sulfoximine / pharmacology Caspase 3 Caspases / metabolism* Cell Line Coumarins / metabolism Glutathione / metabolism* Glutathione Disulfide / metabolism Hematopoietic Stem Cells Interleukin-3 / metabolism* Lamin Type B* Lamins Membrane Potentials / drug effects Mice Mitochondria / drug effects Nuclear Proteins / metabolism Oligopeptides / metabolism Phosphatidylserines / metabolism Poly(ADP-ribose) Polymerases Protease Inhibitors / pharmacology Proteins / metabolism |
| Grant Support | |
ID/Acronym/Agency:
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ES 07247/ES/NIEHS NIH HHS; ES 07784/ES/NIEHS NIH HHS; HL 51005/HL/NHLBI NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/Amino Acid Chloromethyl Ketones; 0/Coumarins; 0/Interleukin-3; 0/Lamin Type B; 0/Lamins; 0/Nuclear Proteins; 0/Oligopeptides; 0/Phosphatidylserines; 0/Protease Inhibitors; 0/Proteins; 0/acetyl-aspartyl-glutamyl-valyl-aspartyl-amino-4-methylcoumarin; 0/benzyloxycarbonylvalyl-alanyl-aspartyl fluoromethyl ketone; 0/butyloxycarbonyl-O-methyl-aspartyl-fluoromethyl ketone; 0/lamin B1; 27025-41-8/Glutathione Disulfide; 5072-26-4/Buthionine Sulfoximine; 70-18-8/Glutathione; EC 2.4.2.30/Parp1 protein, mouse; EC 2.4.2.30/Poly(ADP-ribose) Polymerases; EC 3.4.22.-/Casp3 protein, mouse; EC 3.4.22.-/Caspase 3; EC 3.4.22.-/Caspases |
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