The cell death-inducing activity of the peptide containing Noxa mitochondrial-targeting domain is associated with calcium release.
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.
Seo
Young-Woo
YW
Departments of Biochemistry, Anatomy, and Medical Science and Engineering Research Center for Resistant Cells, Chosun University School of Medicine, Gwang-ju, Korea.
Woo
Ha-Na
HN
Piya
Sujan
S
Moon
Ae Ran
AR
Oh
Jae-Wook
JW
Yun
Cheol-Won
CW
Kim
Kyung-Keun
KK
Min
Ji-Young
JY
Jeong
Seon-Yong
SY
Chung
Seyung
S
Song
Peter I
PI
Jeong
Seong-Yun
SY
Choi
Eun Kyung
EK
Seol
Dai-Wu
DW
Kim
Tae-Hyoung
TH
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
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