Document Detail


Alkylating DNA damage stimulates a regulated form of necrotic cell death.
MedLine Citation:
PMID:  15145826     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Necrosis has been considered a passive form of cell death in which the cell dies as a result of a bioenergetic catastrophe imposed by external conditions. However, in response to alkylating DNA damage, cells undergo necrosis as a self-determined cell fate. This form of death does not require the central apoptotic mediators p53, Bax/Bak, or caspases and actively induces an inflammatory response. Necrosis in response to DNA damage requires activation of the DNA repair protein poly(ADP-ribose) polymerase (PARP), but PARP activation is not sufficient to determine cell fate. Cell death is determined by the effect of PARP-mediated beta-nicotinamide adenine dinucleotide (NAD) consumption on cellular metabolism. Cells using aerobic glycolysis to support their bioenergetics undergo rapid ATP depletion and death in response to PARP activation. In contrast, cells catabolizing nonglucose substrates to maintain oxidative phosphorylation are resistant to ATP depletion and death in response to PARP activation. Because most cancer cells maintain their ATP production through aerobic glycolysis, these data may explain the molecular basis by which DNA-damaging agents can selectively induce tumor cell death independent of p53 or Bcl-2 family proteins.
Authors:
Wei-Xing Zong; Dara Ditsworth; Daniel E Bauer; Zhao-Qi Wang; Craig B Thompson
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2004-05-14
Journal Detail:
Title:  Genes & development     Volume:  18     ISSN:  0890-9369     ISO Abbreviation:  Genes Dev.     Publication Date:  2004 Jun 
Date Detail:
Created Date:  2004-06-03     Completed Date:  2004-07-09     Revised Date:  2013-04-18    
Medline Journal Info:
Nlm Unique ID:  8711660     Medline TA:  Genes Dev     Country:  United States    
Other Details:
Languages:  eng     Pagination:  1272-82     Citation Subset:  IM    
Affiliation:
Abramson Family Cancer Research Institute, Department of Cancer Biology, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
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MeSH Terms
Descriptor/Qualifier:
Adenosine Triphosphate / metabolism
Alkylating Agents / pharmacology*
Animals
Base Sequence
Cells, Cultured
DNA Damage / physiology*
Enzyme Activation / drug effects
Fibroblasts / pathology
HMGB1 Protein / metabolism
Inflammation / metabolism,  pathology
Macrophages / drug effects,  metabolism,  pathology
Membrane Proteins / drug effects,  genetics,  metabolism
Mice
Mice, Mutant Strains
Molecular Sequence Data
NAD / metabolism
Necrosis*
Poly(ADP-ribose) Polymerases / drug effects,  metabolism*
Proto-Oncogene Proteins / drug effects,  genetics,  metabolism
Proto-Oncogene Proteins c-bcl-2*
Tumor Necrosis Factor-alpha / metabolism
Tumor Suppressor Protein p53 / drug effects,  genetics,  metabolism
bcl-2 Homologous Antagonist-Killer Protein
bcl-2-Associated X Protein
Chemical
Reg. No./Substance:
0/Alkylating Agents; 0/Bak1 protein, mouse; 0/Bax protein, mouse; 0/HMGB1 Protein; 0/Membrane Proteins; 0/Proto-Oncogene Proteins; 0/Proto-Oncogene Proteins c-bcl-2; 0/Tumor Necrosis Factor-alpha; 0/Tumor Suppressor Protein p53; 0/bcl-2 Homologous Antagonist-Killer Protein; 0/bcl-2-Associated X Protein; 53-84-9/NAD; 56-65-5/Adenosine Triphosphate; EC 2.4.2.30/Poly(ADP-ribose) Polymerases
Comments/Corrections
Comment In:
Genes Dev. 2004 Jun 1;18(11):1223-6   [PMID:  15175258 ]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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