期刊
JOURNAL OF BIOLOGICAL CHEMISTRY
卷 285, 期 15, 页码 11584-11595出版社
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.M109.087809
关键词
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资金
- National R & D Program for Cancer Control, Ministry of Health Welfare
- Translational Research Center for Protein Function Control, KRF [2009-0083522]
- Korean Government [2009-0092964]
- Brain Korea 21 project of the Republic of Korea
- National Institutes of Health [HL35440, HL079650]
Cellular oxygen sensing is required for hypoxia-inducible factor-1 alpha stabilization, which is important for tumor cell survival, proliferation, and angiogenesis. Here we find that terpestacin, a small molecule previously identified in a screen of microbial extracts, binds to the 13.4-kDa subunit (UQCRB) of mitochondrial Complex III, resulting in inhibition of hypoxia-induced reactive oxygen species generation. Consequently, such inhibition blocks hypoxia-inducible factor activation and tumor angiogenesis in vivo, without inhibiting mitochondrial respiration. Overexpression of UQCRB or its suppression using RNA interference demonstrates that it plays a crucial role in the oxygen sensing mechanism that regulates responses to hypoxia. These findings provide a novel molecular basis of terpestacin targeting UQCRB of Complex III in selective suppression of tumor progression.
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