Translocation and oligomerization of Bax is regulated independently by activation of p38 MAPK and caspase-2 during MN9D dopaminergic neurodegeneration |
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Authors: | Chang-Ki Oh Baek-Soo Han Won-Seok Choi Moussa B H Youdim Young J Oh |
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Institution: | (1) Department of Biology, Yonsei University College of Life Science and Biotechnology, 134 Shinchon-dong Seodaemoon-gu, Seoul, 120-749, Korea;(2) Brain Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon, 305-806, Korea;(3) Israel Technion Institute of Technology, Haifa, Israel; |
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Abstract: | Bax is translocated into the mitochondrial membrane and oligomerized therein to initiate mitochondrial apoptotic signaling.
Our previous study indicated that reactive oxygen species (ROS)-mediated activation of mitogen-activated protein kinase (MAPK)
and caspase is critically involved in 6-hydroxydopamine (6-OHDA)-mediated neurodegeneration. Here, we specifically attempted
to examine whether and how these death signaling pathways may be linked to Bax translocation and oligomerization. We found
that 6-OHDA treatment triggered translocation and oligomerization of Bax onto the mitochondria in MN9D dopaminergic neuronal
cells. These events preceded cytochrome c release into the cytosol. Cross-linking assay revealed that co-treatment with a ROS scavenger or a pan-caspase inhibitor
inhibited 6-OHDA-induced Bax oligomerization. Among several candidates of ROS-activated MAPKs and caspases, we found that
co-treatment with PD169316 or VDVAD specifically inhibited 6-OHDA-induced Bax oligomerization, suggesting critical involvement
of p38 MAPK and caspase-2. Consequently, overexpression of a dominant negative form of p38 MAPK or a shRNA-mediated knockdown
of caspase-2 indeed inhibited 6-OHDA-induced Bax oligomerization. However, activation of p38 MAPK and caspase-2 was independently
linked to oligomerization of Bax. This specificity was largely confirmed with a Bax 6A7 antibody known to detect activated
forms of Bax on the mitochondria. Taken together, our data suggest that there is an independent amplification loop of Bax
translocation and oligomerization via caspase-2 and p38 MAPK during ROS-mediated dopaminergic neurodegeneration. |
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