title: NF-κB potentiates caspase independent hydrogen peroxide induced cell death.
abstract: BACKGROUND
  The pro-survival activity of NF-κB in response to a variety of stimuli has been extensively characterized. Although there have been a few reports addressing the pro-cell death role of NF-κB, the precise mechanism of NF-κB's pro-cell death function still remains elusive.
  
  
  RESULTS
  In the present study, we investigated the role of NF-κB in cell death induced by chronic insult with hydrogen peroxide (H(2)O(2)). Here, we show that NF-κB promotes H(2)O(2) induced caspase independent but PARP dependent fibroblast cell death. The pro-death activity of NF-κB is due to the DNA binding activity of RelA, which is induced through IKK- mediated IκBα degradation. NF-κB dependent pro-survival genes, Bcl-2 and XIAP, were significantly repressed, while NF-κB dependent pro-death genes, TNFα and Fas Ligand, were induced in response to H(2)O(2).
  
  
  CONCLUSIONS
  We discovered an unexpected function of NF-κB, in that it potentiates chronic H(2)O(2) exposure induced cell death, and suggest that NF-κB mediates cell death through the repression of pro-survival genes and induction of pro-death genes. Since unremitting exposure of tissues to H(2)O(2) and other reactive oxygen species can lead to several degenerative disorders and diseases, our results have important implications for the use of NF-κB inhibitors in therapeutic drug design.
authors.affiliation: Department of Chemistry and Biochemistry, University of California San Diego, La Jolla, California, United States of America.
authors.forename: Jessica Q
authors.initials: JQ
authors.lastname: Ho
authors.forename: Masataka
authors.initials: M
authors.lastname: Asagiri
authors.forename: Alexander
authors.initials: A
authors.lastname: Hoffmann
authors.forename: Gourisankar
authors.initials: G
authors.lastname: Ghosh
mesh_terms: D000818:Animals; D020169:Caspases / Q000378:metabolism*; D016923:Cell Death / Q000187:drug effects / Q000235:genetics; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics; D004247:DNA / Q000378:metabolism; D015536:Down-Regulation / Q000187:drug effects; D053222:Fas Ligand Protein / Q000235:genetics; D057809:HEK293 Cells; D006801:Humans; D006861:Hydrogen Peroxide / Q000494:pharmacology*; D008025:Ligases / Q000378:metabolism; D051379:Mice; D016328:NF-kappa B / Q000378:metabolism*; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics; D051636:X-Linked Inhibitor of Apoptosis Protein / Q000235:genetics
chemical_list: D053222:Fas Ligand Protein; D016328:NF-kappa B; D019253:Proto-Oncogene Proteins c-bcl-2; D014409:Tumor Necrosis Factor-alpha; D051636:X-Linked Inhibitor of Apoptosis Protein; D004247:DNA; D006861:Hydrogen Peroxide; C499321:Parp1 protein, mouse; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases; D020169:Caspases; D008025:Ligases; C028812:guanosine 3',5'-polyphosphate synthetases