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

Exp Mol Med. 2010 Sep 30;42(9):639-50. doi: 10.3858/emm.2010.42.9.063.


An abrupt increase of intracellular Ca(2+) is observed in cells under hypoxic or oxidatively stressed conditions. The dysregulated increase of cytosolic Ca(2+) triggers apoptotic cell death through mitochondrial swelling and activation of Ca(2+)-dependent enzymes. Transglutaminase 2 (TG2) is a Ca(2+)-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 Ca(2+)-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 Ca(2+)-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 Ca(2+)-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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Apoptosis Regulatory Proteins / metabolism
  • Apoptosis*
  • 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
  • Protein Glutamine gamma Glutamyltransferase 2
  • Transglutaminases / metabolism*
  • bcl-2-Associated X Protein / genetics
  • bcl-2-Associated X Protein / metabolism*


  • Apoptosis Regulatory Proteins
  • BAX protein, human
  • Ionophores
  • bcl-2-Associated X Protein
  • Calcimycin
  • Cytochromes c
  • Protein Glutamine gamma Glutamyltransferase 2
  • Transglutaminases
  • Caspases
  • GTP-Binding Proteins
  • Calcium