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KMID : 0620920100420090639
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Experimental & Molecular Medicine
2010 Volume.42 No. 9 p.639 ~ p.650
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Transglutaminase 2 inhibits apoptosis induced by calcium- overload through down-regulation of Bax
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Cho Sung-Yup
Lee Jin-Haeng
Bae Han-Dong
Jeong Eui-Man
Jang Gi-Yong
Kim Chai-Wan
Shin Dong-Myung
Jeon Ju-Hong
Kim In-Gyu
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Abstract
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An abrupt increase of intracellular Ca2+ is observed in cells under hypoxic or oxidatively stressed conditions. The dysregulated increase of cytosolic Ca2+ triggers apoptotic cell death through mitochondrial swelling and activation of Ca2+-dependent enzymes. Transglutaminase 2 (TG2) is a Ca2+-dependent enzyme that catalyzes transamidation reaction producing cross-linked and polyaminated proteins. TG2 activity is known to be involved in the apoptotic process. However, the pro-apoptotic role of TG2 is still controversial. In this study, we investigate the role of TG2 in apoptosis induced by Ca2+-overload. Overexpression of TG2 inhibited the A23187-induced apoptosis through suppression of caspase-3 and -9 activities, cytochrome c release into cytosol, and mitochondria membrane depolarization. Conversely, down-regulation of TG2 caused the increases of cell death, caspase-3 activity and cytochrome c in cytosol in response to Ca2+-overload. Western blot analysis of Bcl-2 family proteins showed that TG2 reduced the expression level of Bax protein. Moreover, overexpression of Bax abrogated the anti-apoptotic effect of TG2, indicating that TG2-mediated suppression of Bax is responsible for inhibiting cell death under Ca2+-overloaded conditions. Our findings revealed a novel anti-apoptotic pathway involving TG2, and suggested the induction of TG2 as a novel strategy for promoting cell survival in diseases such as ischemia and neurodegeneration.
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KEYWORD
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apoptosis, Bax, calcium, mitochondria, transglutaminase 2
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