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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.
AuthorsYoung-Woo Seo, Ha-Na Woo, Sujan Piya, Ae Ran Moon, Jae-Wook Oh, Cheol-Won Yun, Kyung-Keun Kim, Ji-Young Min, Seon-Yong Jeong, Seyung Chung, Peter I Song, Seong-Yun Jeong, Eun Kyung Choi, Dai-Wu Seol, Tae-Hyoung Kim
JournalCancer research (Cancer Res) Vol. 69 Issue 21 Pg. 8356-65 (Nov 01 2009) ISSN: 1538-7445 [Electronic] United States
PMID19826054 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • Mitochondrial Membrane Transport Proteins
  • Mitochondrial Permeability Transition Pore
  • PMAIP1 protein, human
  • Pmaip1 protein, mouse
  • Proto-Oncogene Proteins c-bcl-2
  • Tumor Suppressor Protein p53
  • Calcium
Topics
  • Animals
  • Apoptosis
  • Calcium (metabolism)
  • HeLa Cells
  • Humans
  • Mice
  • Mice, Inbred BALB C
  • Mitochondria (metabolism)
  • Mitochondrial Membrane Transport Proteins (drug effects)
  • Mitochondrial Permeability Transition Pore
  • Neoplasms, Experimental (genetics, pathology, prevention & control)
  • Protein Structure, Tertiary
  • Proto-Oncogene Proteins c-bcl-2 (genetics, metabolism)
  • Survival Rate
  • Tumor Suppressor Protein p53 (genetics, metabolism)

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