Document Detail


Role of poly(ADP-ribose) polymerase (PARP) cleavage in apoptosis. Caspase 3-resistant PARP mutant increases rates of apoptosis in transfected cells.
MedLine Citation:
PMID:  10438458     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
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.
Authors:
A H Boulares; A G Yakovlev; V Ivanova; B A Stoica; G Wang; S Iyer; M Smulson
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Publication Detail:
Type:  Journal Article; Research Support, U.S. Gov't, Non-P.H.S.; Research Support, U.S. Gov't, P.H.S.    
Journal Detail:
Title:  The Journal of biological chemistry     Volume:  274     ISSN:  0021-9258     ISO Abbreviation:  J. Biol. Chem.     Publication Date:  1999 Aug 
Date Detail:
Created Date:  1999-09-01     Completed Date:  1999-09-01     Revised Date:  2007-11-14    
Medline Journal Info:
Nlm Unique ID:  2985121R     Medline TA:  J Biol Chem     Country:  UNITED STATES    
Other Details:
Languages:  eng     Pagination:  22932-40     Citation Subset:  IM    
Affiliation:
Department of Biochemistry and Molecular Biology, Georgetown University School of Medicine, Washington, D.C. 20007, USA.
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MeSH Terms
Descriptor/Qualifier:
Apoptosis* / 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:
1P01CA74175/CA/NCI NIH HHS; CA25344/CA/NCI NIH HHS
Chemical
Reg. No./Substance:
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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