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      Essential role of the voltage-dependent anion channel (VDAC) in mitochondrial permeability transition pore opening and cytochrome c release induced by arsenic trioxide.

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          Abstract

          The precise molecular mechanism underlying arsenic trioxide (As(2)O(3))-induced apoptosis is a subject of extensive study. Here, we show that clinically relevant doses of As(2)O(3) can induce typical apoptosis in IM-9, a multiple myeloma cell line, in a Bcl-2 inhibitable manner. We confirmed that As(2)O(3) 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 As(2)O(3) responsible for eliciting cyto c release in apoptosis. First, pretreatment of the isolated mitochondria with an anti-VDAC antibody specifically prevented As(2)O(3)-induced cyto c release. Second, in proteoliposome experiments, VDAC by itself was sufficient to mediate As(2)O(3)-induced cyto c release, which could be specifically inhibited by Bcl-X(L). Third, As(2)O(3) induced mitochondria membrane potential (DeltaPsim) reduction and cyto c release only in the VDAC-expressing, but not in the VDAC-deficient yeast strain. Finally, we found that As(2)O(3) 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.

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          Author and article information

          Journal
          Oncogene
          Oncogene
          Springer Science and Business Media LLC
          0950-9232
          0950-9232
          Feb 12 2004
          : 23
          : 6
          Affiliations
          [1 ] The Laboratory of Apoptosis and Cancer Biology, The State Key Laboratory of Biomembrane and Membrane Biotechnology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100080, PR China.
          Article
          1207205 NIHMS223296
          10.1038/sj.onc.1207205
          2913247
          14647451
          d6ce29f3-99cb-422d-9f57-363f30a15b81
          History

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