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. 2010 Feb 22;285(17):13079–13091. doi: 10.1074/jbc.M109.044206

FIGURE 9.

FIGURE 9.

A speculative mechanism of α-ESA-mediated cell death. A, staurosporine + Z-VAD-fmk treatment induces Bax/Bak-mediated Cyt-c, AIF, and other apoptotic mitochondrial proteins such Smac/Diablo, although caspase is blocked by Z-VAD-fmk. This type of apoptosis is blocked by pro-survival Bcl-2 protein. B, MNNG, NMDA, or hypoxia ischemia induces the increase in an intracellular Ca2+ concentration ([Ca2+]i), intracellular ROS production, and DNA alkylation followed by PARP-1 activation, which results in PARP-1-mediated AIF release, leading to the caspase-independent cell death. C, α-ESA induces PARP-1-independent AIF-release, resulting in a novel caspase-independent apoptosis. U0126 and MEK1/2 knockdown block the cell death by unknown mechanisms. ERK1/2 is certainly involved in the cell death. α-Toc blocks ROS production in the mitochondria and cell death without the influence on ERK1/2. PARP-1 is not involved in α-ESA-mediated cell death. α-ESA appears to act separately on MEK1/2-ERK1/2 and superoxide production leading to the reduction of the membrane potential.