title: p53 translocation to mitochondria precedes its nuclear translocation and targets mitochondrial oxidative defense protein-manganese superoxide dismutase.
abstract: The tumor suppressor gene p53 is activated by reactive oxygen species-generating agents. After activation, p53 migrates to mitochondria and nucleus, a response that eventually leads to apoptosis, but how the two events are related is unknown. Herein, we show that p53 translocation to mitochondria precedes its translocation to nucleus in JB6 skin epidermal cells treated with the tumor promoter 12-O-tetradecanoylphorbol-13-acetate (TPA). Translocation of p53 to mitochondria occurs within 10 minutes after TPA application. In the mitochondria, p53 interacts with the primary antioxidant enzyme, manganese superoxide dismutase (MnSOD), consistent with the reduction of its superoxide scavenging activity, and a subsequent decrease of mitochondrial membrane potential. In contrast to the immediate action on mitochondria, p53 transcriptional activity in the nucleus increases at 1 hour following TPA application, accompanied by an increase in the levels of its target gene bax at 15 hours following TPA treatment. Activation of p53 transcriptional activity is preventable by application of a SOD mimetic (MnTE-2-PyP5+). Thus, p53 translocation to mitochondria and subsequent inactivation of MnSOD explains the observed mitochondrial dysfunction, which leads to transcription-dependent mechanisms of p53-induced apoptosis.
authors.affiliation: Graduate Center for Toxicology, University of Kentucky, Lexington, Kentucky 40536, USA.
authors.forename: Yunfeng
authors.initials: Y
authors.lastname: Zhao
authors.forename: Luksana
authors.initials: L
authors.lastname: Chaiswing
authors.forename: Joyce M
authors.initials: JM
authors.lastname: Velez
authors.forename: Ines
authors.initials: I
authors.lastname: Batinic-Haberle
authors.forename: Nancy H
authors.initials: NH
authors.lastname: Colburn
authors.forename: Terry D
authors.initials: TD
authors.lastname: Oberley
authors.forename: Daret K
authors.initials: DK
authors.lastname: St Clair
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000502:physiology; D040761:Biomimetic Materials / Q000494:pharmacology; D002460:Cell Line; D002467:Cell Nucleus / Q000378:metabolism*; D004247:DNA / Q000378:metabolism; D007150:Immunohistochemistry; D008665:Metalloporphyrins / Q000494:pharmacology; D051379:Mice; D008928:Mitochondria / Q000201:enzymology / Q000378:metabolism*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000096:biosynthesis / Q000235:genetics; D012867:Skin / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D012878:Skin Neoplasms / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D013482:Superoxide Dismutase / Q000037:antagonists & inhibitors / Q000378:metabolism*; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D015533:Transcriptional Activation / Q000502:physiology; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*; D051028:bcl-2-Associated X Protein
chemical_list: C494827:Bax protein, mouse; D008665:Metalloporphyrins; D019253:Proto-Oncogene Proteins c-bcl-2; D016159:Tumor Suppressor Protein p53; D051028:bcl-2-Associated X Protein; C431023:manganese (III) meso-tetrakis(N-ethylpyridinium-2-yl)porphyrin; D004247:DNA; D013482:Superoxide Dismutase; D013755:Tetradecanoylphorbol Acetate