title: The cell death-inducing activity of the peptide containing Noxa mitochondrial-targeting domain is associated with calcium release.
abstract: DNA damage stabilizes the p53 tumor suppressor protein that determines the cell fate by either cell cycle arrest or cell death induction. Noxa, the BH3-only Bcl-2 family protein, was shown to be a key player in p53-induced cell death through the mitochondrial dysfunction; however, the molecular mechanism by which Noxa induces the mitochondrial dysfunction to cause cell death in response to genotoxic agents is largely unknown. Here, we show that the mitochondrial-targeting domain (MTD) of Noxa is a prodeath domain. Peptide containing MTD causes massive necrosis in vitro through cytosolic calcium increase; it is released from the mitochondria by opening the mitochondrial permeability transition pore. MTD peptide-induced cell death can be inhibited by calcium chelator BAPTA-AM. Moreover, MTD peptide shows the potent tumor-killing activities in mice by joining with tumor-homing motifs.
authors.affiliation: Departments of Biochemistry, Anatomy, and Medical Science and Engineering Research Center for Resistant Cells, Chosun University School of Medicine, Gwang-ju, Korea.
authors.forename: Young-Woo
authors.initials: YW
authors.lastname: Seo
authors.forename: Ha-Na
authors.initials: HN
authors.lastname: Woo
authors.forename: Sujan
authors.initials: S
authors.lastname: Piya
authors.forename: Ae Ran
authors.initials: AR
authors.lastname: Moon
authors.forename: Jae-Wook
authors.initials: JW
authors.lastname: Oh
authors.forename: Cheol-Won
authors.initials: CW
authors.lastname: Yun
authors.forename: Kyung-Keun
authors.initials: KK
authors.lastname: Kim
authors.forename: Ji-Young
authors.initials: JY
authors.lastname: Min
authors.forename: Seon-Yong
authors.initials: SY
authors.lastname: Jeong
authors.forename: Seyung
authors.initials: S
authors.lastname: Chung
authors.forename: Peter I
authors.initials: PI
authors.lastname: Song
authors.forename: Seong-Yun
authors.initials: SY
authors.lastname: Jeong
authors.forename: Eun Kyung
authors.initials: EK
authors.lastname: Choi
authors.forename: Dai-Wu
authors.initials: DW
authors.lastname: Seol
authors.forename: Tae-Hyoung
authors.initials: TH
authors.lastname: Kim
mesh_terms: D000818:Animals; D017209:Apoptosis; D002118:Calcium / Q000378:metabolism*; D006367:HeLa Cells; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D008928:Mitochondria / Q000378:metabolism*; D033681:Mitochondrial Membrane Transport Proteins / Q000187:drug effects; D000083162:Mitochondrial Permeability Transition Pore; D009374:Neoplasms, Experimental / Q000235:genetics / Q000473:pathology / Q000517:prevention & control*; D017434:Protein Structure, Tertiary; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000378:metabolism*; D015996:Survival Rate; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism
chemical_list: D033681:Mitochondrial Membrane Transport Proteins; D000083162:Mitochondrial Permeability Transition Pore; C498702:PMAIP1 protein, human; C408009:Pmaip1 protein, mouse; D019253:Proto-Oncogene Proteins c-bcl-2; D016159:Tumor Suppressor Protein p53; D002118:Calcium