title: Nuclear interaction between ADR-induced p65 and p53 mediates cardiac injury in iNOS (-/-) mice.
abstract: Adriamycin (ADR) treatment causes an imbalance in the levels of nitric oxide ((•)NO) and superoxide (O2(•-)) production leading to cardiac injury. Previously we demonstrated that mice lacking inducible nitric oxide synthase (iNOS) have increased oxidative stress and mitochondrial injury. The molecular events leading to increased mitochondrial injury in iNOS deficient mice is unknown. ADR in the absence of iNOS preferentially activates a proapoptotic pathway without a concurrent increase in prosurvival pathways. Treatment with ADR leads to an increase in DNA binding activity of nuclear factor kappa B (NFκB) and p53 in wildtype mice. Following ADR treatment, p53, but not NFκB DNA binding activity, as well as the level of Bax, a p53 target gene, was increased in iNOS (-/-) mice. This apoptotic signaling effect in iNOS (-/-) is alleviated by overexpression of manganese superoxide dismutase (MnSOD). Increases in NFκB and p53 in ADR-treated wildtype mice did not lead to increases in target genes such as MnSOD, bcl-xL, or Bax. Moreover, co-immunoprecipitation analysis revealed that p65, a prominent member of the NFκB family, interacts with p53 in the nucleus. These results suggest that NFκB and p53 may counter act one another's actions in ADR-treated wildtype (WT) mice. Further, these results identify a novel mechanism by which oxidative stress may regulate transcription of proapoptotic genes.
authors.affiliation: Biochemistry and Molecular Biology, University of Louisville, Louisville, Kentucky, United States of America.
authors.forename: Marsha P
authors.initials: MP
authors.lastname: Cole
authors.affiliation: School of Allied Health Sciences and Public Health, Walailak University, Nakhon Si Thammarat, Thailand.
authors.forename: Jitbanjong
authors.initials: J
authors.lastname: Tangpong
authors.affiliation: Department of Pathology, VA Hospital, University of Wisconsin, Madison, Wisconsin, United States of America.
authors.forename: Terry D
authors.initials: TD
authors.lastname: Oberley
authors.affiliation: Department of Pathology, VA Hospital, University of Wisconsin, Madison, Wisconsin, United States of America.
authors.forename: Luksana
authors.initials: L
authors.lastname: Chaiswing
authors.affiliation: Pharmaceutical, Social and Administrative Sciences, Belmont College of Pharmacy, Nashville, Tennessee, United States of America.
authors.forename: Kinsley K
authors.initials: KK
authors.lastname: Kiningham
authors.affiliation: Graduate Centers for Toxicology and Nutritional Sciences, University of Kentucky, Lexington, Kentucky, United States of America.
authors.forename: Daret K
authors.initials: DK
authors.lastname: St Clair
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism; D004317:Doxorubicin / Q000494:pharmacology*; D006335:Heart Injuries / Q000139:chemically induced* / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism*; D018384:Oxidative Stress / Q000187:drug effects; D013482:Superoxide Dismutase / Q000378:metabolism; D051996:Transcription Factor RelA / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*; D051028:bcl-2-Associated X Protein / Q000378:metabolism; D051020:bcl-X Protein / Q000378:metabolism
chemical_list: C494812:Bcl2l1 protein, mouse; D051996:Transcription Factor RelA; D016159:Tumor Suppressor Protein p53; D051028:bcl-2-Associated X Protein; D051020:bcl-X Protein; D004317:Doxorubicin; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse; D013482:Superoxide Dismutase