Translocation and oligomerization of Bax is regulated independently by activation of p38 MAPK and caspase-2 during MN9D dopaminergic neurodegeneration

Chang Ki Oh, Baek Soo Han, Won Seok Choi, Moussa B.H. Youdim, Young Jun Oh

Research output: Contribution to journalArticle

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Abstract

Bax is translocated into the mitochondrial membrane and oligomerized therein to initiate mitochon-drial 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 cyto-chrome 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 oligo-merization. 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.

Original languageEnglish
Pages (from-to)1087-1100
Number of pages14
JournalApoptosis
Volume16
Issue number11
DOIs
Publication statusPublished - 2011 Nov 1

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Caspase 2
Oligomerization
Oxidopamine
Mitogen-Activated Protein Kinase 1
p38 Mitogen-Activated Protein Kinases
Chemical activation
Reactive Oxygen Species
Mitochondria
Caspases
Caspase Inhibitors
Mitochondrial Membranes
Mitogen-Activated Protein Kinases
Cytosol
Small Interfering RNA
Amplification
Assays
Membranes
Antibodies

All Science Journal Classification (ASJC) codes

  • Pharmacology
  • Pharmaceutical Science
  • Clinical Biochemistry
  • Cell Biology
  • Biochemistry, medical
  • Cancer Research

Cite this

Oh, Chang Ki ; Han, Baek Soo ; Choi, Won Seok ; Youdim, Moussa B.H. ; Oh, Young Jun. / Translocation and oligomerization of Bax is regulated independently by activation of p38 MAPK and caspase-2 during MN9D dopaminergic neurodegeneration. In: Apoptosis. 2011 ; Vol. 16, No. 11. pp. 1087-1100.
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abstract = "Bax is translocated into the mitochondrial membrane and oligomerized therein to initiate mitochon-drial 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 cyto-chrome 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 oligo-merization. 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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Translocation and oligomerization of Bax is regulated independently by activation of p38 MAPK and caspase-2 during MN9D dopaminergic neurodegeneration. / Oh, Chang Ki; Han, Baek Soo; Choi, Won Seok; Youdim, Moussa B.H.; Oh, Young Jun.

In: Apoptosis, Vol. 16, No. 11, 01.11.2011, p. 1087-1100.

Research output: Contribution to journalArticle

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T1 - Translocation and oligomerization of Bax is regulated independently by activation of p38 MAPK and caspase-2 during MN9D dopaminergic neurodegeneration

AU - Oh, Chang Ki

AU - Han, Baek Soo

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AU - Youdim, Moussa B.H.

AU - Oh, Young Jun

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