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Molecular and Cellular Biology, January 2006, p. 569-579, Vol. 26, No. 2
0270-7306/06/$08.00+0     doi:10.1128/MCB.26.2.569-579.2006
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

Tissue Transglutaminase Serves as an Inhibitor of Apoptosis by Cross-Linking Caspase 3 in Thapsigargin-Treated Cells

Drug Discovery Program, H. Lee Moffitt Cancer Center and Research Institute, Department of Interdisciplinary Oncology, University of South Florida College of Medicine, Tampa, Florida 33612

Received 26 May 2005/ Returned for modification 30 June 2005/ Accepted 18 October 2005

Thapsigargin (THG) is an inhibitor of the endoplasmic reticulum Ca²⁺-ATPase that induces caspase 3 activation and apoptosis in HCT116 cells through a Bax-dependent pathway. In Bax-deficient HCT116 cells, however, THG specifically generates two additional species of caspase 3, termed p40 and p64, with molecular masses of approximately 40 and 64 kDa, respectively, through unknown mechanisms. Here, we report that the Ca²⁺-dependent protein cross-linking enzyme tissue transglutaminase (tTGase) is involved in THG-induced p40 and p64 formation by catalyzing caspase 3 cross-linking reactions, thereby inactivating caspase 3 and apoptosis in Bax-deficient cells. Overexpression of tTGase increases p40 and p64 in THG-treated cells, and purified tTGase catalyzes procaspase 3 cross-linking in vitro. Inhibition of tTGase activity by either the tTGase inhibitor monodansylcadaverine or short-hairpin RNA reduces the cross-linked species p40 and p64 and restores caspase 3 activation in response to THG treatment. Moreover, prolonged exposure to THG results in a decrease in protein levels of XIAP and cIAP-1, which is subsequently followed by an increase in tTGase protein expression and activity. Expression of cytosolic Smac sensitizes Bax-deficient cells to THG-induced apoptosis; however, this effect is diminished by coexpression of tTGase. Taken together, these results suggest a novel role for tTGase as a new type of caspase 3 inhibitor in THG-mediated apoptosis.

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