1. Essential role of the voltage-dependent anion channel (VDAC) in mitochondrial permeability transition pore opening and cytochrome c release induced by arsenic trioxide.
- Author
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Yanhua Zheng, George Q., Yong Shi, Changhai Tian, George Q., Chunsun Jiang, George Q., Haijing Jin, George Q., Jianjun Chen, Hong Tang, Quan Chen, and Alex Almasan, George Q.
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ION channels , *ARSENIC , *APOPTOSIS , *CYTOCHROME c , *MITOCHONDRIA , *YEAST - Abstract
The precise molecular mechanism underlying arsenic trioxide (As2O3)-induced apoptosis is a subject of extensive study. Here, we show that clinically relevant doses of As2O3 can induce typical apoptosis in IM-9, a multiple myeloma cell line, in a Bcl-2 inhibitable manner. We confirmed that As2O3 directly induced cytochrome c (cyto c) release from isolated mouse liver mitochondria via the mitochondrial permeability transition pore, and we further identified the voltage-dependent anion channel (VDAC) as a biological target of As2O3 responsible for eliciting cyto c release in apoptosis. First, pretreatment of the isolated mitochondria with an anti-VDAC antibody specifically prevented As2O3-induced cyto c release. Second, in proteoliposome experiments, VDAC by itself was sufficient to mediate As2O3-induced cyto c release, which could be specifically inhibited by Bcl-XL. Third, As2O3 induced mitochondria membrane potential (??m) reduction and cyto c release only in the VDAC-expressing, but not in the VDAC-deficient yeast strain. Finally, we found that As2O3 induced the increased expression and homodimerization of VDAC in IM-9 cells, but not in Bcl-2 overexpressing cells, suggesting that VDAC homodimerization could potentially determine its gating capacity to cyto c, and Bcl-2 blockage of VDAC homodimerization represents a novel mechanism for its inhibition of apoptosis.Oncogene (2004) 23, 1239-1247. doi:10.1038/sj.onc.1207205 Published online 1 December 2003 [ABSTRACT FROM AUTHOR]
- Published
- 2004
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