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J Biol Chem, Vol. 274, Issue 48, 34123-34128, November 26, 1999

Inhibition of "Tissue" Transglutaminase Increases Cell Survival by Preventing Apoptosis

Serafina OliverioDagger , Alessandra AmendolaDagger §, Carlo RodolfoDagger , Angelo SpinediDagger , and Mauro Piacentini§parallel

From the Dagger  Department of Biology, University of Rome "Tor Vergata," 00133 Rome, Italy, the § Laboratory of Electron Microscopy and Cell Biology, Istituto di Ricovero e Cura a Carattere Scientifico "L. Spallanzani," 00149 Rome, Italy, and the parallel  Department of Environmental Sciences, "La Tuscia" University, 01100 Viterbo, Italy

Treatment of the human promonocytic cell line U937 with all-trans-retinoic acid (RA) commits these cells to apoptosis, which can be triggered by simply increasing intracellular calcium levels by the ionophore A23187. RA treatment of U937 cells is characterized by a decrease in Bcl-2 and marked induction of "tissue" transglutaminase (tTG) gene expression. In this study, we show that the inhibition of tTG expression in U937 cells undergoing apoptosis prevents their death. In fact, U937 cell-derived clones transfected with the human tTG gene in the antisense orientation showed a pronounced decrease in apoptosis induced by several stimuli. These findings demonstrate that the Ca2+-dependent irreversible cross-linking of intracellular proteins catalyzed by tTG represents an important biochemical event in the gene-regulated cell death in monoblasts. In addition, our data indicate that the apoptotic program in promonocytic cells is strictly regulated by RA and that a key role is played by the free intracellular calcium concentration.

Copyright © 1999 by The American Society for Biochemistry and Molecular Biology, Inc.
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