Exp Mol Med.  2010 Sep;42(9):639-650. 10.3858/emm.2010.42.9.063.

Transglutaminase 2 inhibits apoptosis induced by calciumoverload through down-regulation of Bax

• Cho SY
• Lee JH
• Bae HD
• Jeong EM
• Jang GY
• Kim CW
• Shin DM
• Jeon JH
• Kim IG

• KMID: 983956
• DOI: http://doi.org/10.3858/emm.2010.42.9.063

Abstract

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.

Keyword

apoptosis; Bax; calcium; mitochondria; transglutaminase 2

MeSH Terms

*Apoptosis
Apoptosis Regulatory Proteins/metabolism
Calcimycin/pharmacology
Calcium/*metabolism
Caspases/metabolism
Cell Death
Cell Survival
Cytochromes c/metabolism
Down-Regulation
GTP-Binding Proteins/*metabolism
HEK293 Cells
Hela Cells
Humans
Ionophores/pharmacology
Mitochondria/metabolism
Transglutaminases/*metabolism
bcl-2-Associated X Protein/genetics/*metabolism