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The cell death-inducing activity of the peptide containing Noxa mitochondrial-targeting domain is associated with calcium release.

Authors
Seo, YW; Woo, HN; Piya, S; Moon, AR; Oh, JW; Yun, CW; Kim, KK; Min, JY; Jeong, SY; Chung, S; Song, PI; Choi, EK; Seol, DW; Kim, TH
Citation
Cancer research, 69(21):8356-8365, 2009
Journal Title
Cancer research
ISSN
0008-54721538-7445
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.
MeSH terms
AnimalsApoptosis*Calcium/metabolism*Hela CellsHumansMiceMice, Inbred BALB CMitochondria/metabolism*Mitochondrial Membrane Transport Proteins/drug effectsNeoplasms, Experimental/geneticsNeoplasms, Experimental/pathologyNeoplasms, Experimental/prevention & control*Protein Structure, TertiaryProto-Oncogene Proteins c-bcl-2/geneticsProto-Oncogene Proteins c-bcl-2/metabolism*Survival RateTumor Suppressor Protein p53/geneticsTumor Suppressor Protein p53/metabolism
DOI
10.1158/0008-5472.CAN-09-0349
PMID
19826054
Appears in Collections:
Journal Papers > School of Medicine / Graduate School of Medicine > Medical Genetics
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