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KMID : 0578320120330030235
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Molecules and Cells
2012 Volume.33 No. 3 p.235 ~ p.241
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Doxorubicin Induces the Persistent Activation of Intracellular Transglutaminase 2 That Protects from Cell Death
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Cho Sung-Yup
Jeong Eui-Man
Lee Jin-Haeng
Kim Hyo-Jun
Lim Ji-Sun
Kim Chai-Wan
Shin Dong-Myung
Jeon Ju-Hong
Choi Kyung-Ho
Kim In-Gyu
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Abstract
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The activation of transglutaminase 2 (TG2), an enzyme that catalyzes post-translational modifications of proteins, has been implicated in apoptosis, cell adhesion and inflammatory responses. We previously reported that intracellular TG2 is activated under oxidative stress conditions, such as ultraviolet irradiation, ischemia-reperfusion, and hypo-xia. In this study, we examined the effect of genotoxic stress on the intracellular activity of TG2 using doxorubicin which generates reactive oxygen species that lead to double-strand breakage of DNA. We demonstrated that doxorubicin elicits the persistent activation of TG2. Doxo-rubicin-induced TG2 activity was suppressed by treatment with caffeine at the early phase, N-acetylcysteine at the mid-phase, and EGTA at the late phase. However, treatment with a blocking antibody against TGF? or toll-like receptor 2 showed no effect on TG2 activity, indicating that at least three different signaling pathways may be involved in the process of TG2 activation. In addition, using MEF cells defective for TG2 and cells overexpressing an active-site mutant of TG2, we revealed that doxorubicin-induced cell death is inversely correlated with TG2 activity. Our findings indicate that the persistent activation of TG2 by doxorubicin contributes to cell survival, suggesting that the mechanism-based inhibition of TG2 may be a novel strategy to prevent drug-resistance in doxorubicin treat-ment.
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KEYWORD
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activation, doxorubicin, intracellular activity, transglutaminase 2
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