1. p53 translocation to mitochondria precedes its nuclear translocation and targets mitochondrial oxidative defense protein-manganese superoxide dismutase.
- Author
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Zhao Y, Chaiswing L, Velez JM, Batinic-Haberle I, Colburn NH, Oberley TD, and St Clair DK
- Subjects
- Animals, Apoptosis physiology, Biomimetic Materials pharmacology, Cell Line, DNA metabolism, Immunohistochemistry, Metalloporphyrins pharmacology, Mice, Mitochondria enzymology, Proto-Oncogene Proteins c-bcl-2 biosynthesis, Proto-Oncogene Proteins c-bcl-2 genetics, Skin cytology, Skin drug effects, Skin metabolism, Skin Neoplasms chemically induced, Skin Neoplasms genetics, Skin Neoplasms metabolism, Skin Neoplasms pathology, Superoxide Dismutase antagonists & inhibitors, Tetradecanoylphorbol Acetate pharmacology, Transcriptional Activation physiology, Tumor Suppressor Protein p53 genetics, bcl-2-Associated X Protein, Cell Nucleus metabolism, Mitochondria metabolism, Superoxide Dismutase metabolism, Tumor Suppressor Protein p53 metabolism
- 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.
- Published
- 2005
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