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Activation of Cell Death Mediated by Apoptosis-Inducing Factor Due to the Absence of Poly(ADP-ribose) Glycohydrolase.
MedLine Citation:
PMID:  21366272     Owner:  NLM     Status:  Publisher    
Abstract/OtherAbstract:
We previously demonstrated that the absence of poly(ADP-ribose) glycohydrolase (PARG) led to increased cell death following DNA-damaging treatments. Here, we investigated cell death pathways following UV treatment. Decreased amounts of PARG-null embryonic trophoblast stem (TS) cells were observed following doses of 10-100 J/m2 as compared to wild-type. In wild-type cells, caspase-cleaved poly(ADP-ribose) polymerase-1 (PARP-1) and activated caspase-3 were detected at 12 to 24 h after UV treatment. Surprisingly, both were detected at decreased levels only after 24 h in PARG null-TS cells, indicating a decreased and delayed presence of caspase-mediated events. Further, a time and dose-dependent accumulation of poly(ADP-ribose) (PAR) levels after UV was observed in PARG null-TS cells and not in wild-type cells. Determination of the levels of nicotinamide adenine dinucleotide (NAD+), the substrate for PAR synthesis and a coenzyme in cellular redox reactions, demonstrated a UV dose-dependent decrease of NAD+ in wild-type cells, while NAD+ levels in PARG null-TS cells remained at higher levels. This indicates no depletion of NAD+ in PARG null-TS cells following increased levels of PAR. Lastly, cell death mediated by apoptosis-inducing factor (AIF) was analyzed due to its dependence on increased PAR levels. The results demonstrate nuclear AIF translocation only in PARG null-TS cells, which demonstrates the presence of AIF-mediated cell death. Taken together, we provide compelling evidence that the absence of PARG leads to decreased caspase-3 activity and the specific activation of AIF-mediated cell death. Therefore, the absence of PARG may provide a strategy to specifically induce an alternative apoptotic pathway.
Authors:
Yiran Zhou; Xiaoxing Feng; David W Koh
Publication Detail:
Type:  JOURNAL ARTICLE     Date:  2011-3-2
Journal Detail:
Title:  Biochemistry     Volume:  -     ISSN:  1520-4995     ISO Abbreviation:  -     Publication Date:  2011 Mar 
Date Detail:
Created Date:  2011-3-3     Completed Date:  -     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  0370623     Medline TA:  Biochemistry     Country:  -    
Other Details:
Languages:  ENG     Pagination:  -     Citation Subset:  -    
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