| Role of poly(ADP-ribose) polymerase (PARP) cleavage in apoptosis. Caspase 3-resistant PARP mutant increases rates of apoptosis in transfected cells. | |
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MedLine Citation:
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PMID: 10438458 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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An early transient burst of poly(ADP-ribosyl)ation of nuclear proteins was recently shown to be required for apoptosis to proceed in various cell lines (Simbulan-Rosenthal, C., Rosenthal, D., Iyer, S., Boulares, H., and Smulson, M. (1998) J. Biol. Chem. 273, 13703-13712) followed by cleavage of poly(ADP-ribose) polymerase (PARP), catalyzed by caspase-3. This inactivation of PARP has been proposed to prevent depletion of NAD (a PARP substrate) and ATP, which are thought to be required for later events in apoptosis. The role of PARP cleavage in apoptosis has now been investigated in human osteosarcoma cells and PARP -/- fibroblasts stably transfected with a vector encoding a caspase-3-resistant PARP mutant. Expression of this mutant PARP increased the rate of staurosporine and tumor necrosis factor-alpha-induced apoptosis, at least in part by reducing the time interval required for the onset of caspase-3 activation and internucleosomal DNA fragmentation, as well as the generation of 50-kilobase pair DNA breaks, thought to be associated with early chromatin unfolding. Overexpression of wild-type PARP in osteosarcoma cells also accelerated the apoptotic process, although not to the same extent as that apparent in cells expressing the mutant PARP. These effects of the mutant and wild-type enzymes might be due to the early and transient poly(ADP-ribose) synthesis in response to DNA breaks, and the accompanying depletion of NAD apparent in the transfected cells. The accelerated NAD depletion did not seem to interfere with the later stages of apoptosis. These results indicate that PARP activation and subsequent cleavage have active and complex roles in apoptosis. |
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Authors:
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A H Boulares; A G Yakovlev; V Ivanova; B A Stoica; G Wang; S Iyer; M Smulson |
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Publication Detail:
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Type: Journal Article; Research Support, U.S. Gov't, Non-P.H.S.; Research Support, U.S. Gov't, P.H.S. |
Journal Detail:
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Title: The Journal of biological chemistry Volume: 274 ISSN: 0021-9258 ISO Abbreviation: J. Biol. Chem. Publication Date: 1999 Aug |
Date Detail:
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Created Date: 1999-09-01 Completed Date: 1999-09-01 Revised Date: 2007-11-14 |
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: 22932-40 Citation Subset: IM |
Affiliation:
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Department of Biochemistry and Molecular Biology, Georgetown University School of Medicine, Washington, D.C. 20007, USA. |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Apoptosis*
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drug effects Base Sequence Caspase 3 Caspases / metabolism* Cell Survival / drug effects DNA Primers Humans Hydrolysis Mutagenesis, Site-Directed NAD / metabolism Osteosarcoma / enzymology, pathology Poly Adenosine Diphosphate Ribose / metabolism Poly(ADP-ribose) Polymerases / genetics, metabolism* Staurosporine / pharmacology Transfection Tumor Cells, Cultured Tumor Necrosis Factor-alpha / pharmacology |
| Grant Support | |
ID/Acronym/Agency:
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1P01CA74175/CA/NCI NIH HHS; CA25344/CA/NCI NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/DNA Primers; 0/Tumor Necrosis Factor-alpha; 26656-46-2/Poly Adenosine Diphosphate Ribose; 53-84-9/NAD; 62996-74-1/Staurosporine; EC 2.4.2.30/Poly(ADP-ribose) Polymerases; EC 3.4.22.-/CASP3 protein, human; EC 3.4.22.-/Caspase 3; EC 3.4.22.-/Caspases |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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